Taysha Gene Therapies, Inc.

Greetings and welcome to the TASER Gene Therapy's third quarter 2024 earnings call. At this time, all participants are in listen-only mode. A question and answer session will follow the formal presentation. As a reminder, this conference is being recorded. If anyone should require operator assistance during the call, please signal for an operator by pressing star and then zero. It is now my pleasure to introduce Haley Collins, the Director and Head of Investor Relations. Thank you, and you may proceed, Haley.

Thank you. Good afternoon, and welcome to Tayshia's third quarter 2024 financial results and corporate update conference call. Earlier today, Tayshia issued a press release announcing financial results for the third quarter ended September 30th, 2024. A copy of this press release is available on the company's website and through our SEC filings. Joining me on today's call are Sean Nolan, FACIA's CEO, Zubimar Negandrin, President and Head of R&D, and Cameron Alam, Chief Financial Officer. We will hold a question and answer session following our prepared remarks. Please note that on today's call, we will be making forward-looking statements, including statements concerning the potential of FACIA 102, including the reproducibility and durability of any favorable results initially seen in patients' dose-to-date and clinical trials to positively impact quality of life and alter the course of disease in the patients we seek to treat, our research, development, and regulatory plans for our product candidates, including the timing of initiating additional trials and reporting data from our clinical trials, the potential for these product candidates to receive regulatory approval from the FDA or equivalent foreign regulatory agencies, The clinical potential of interest-equal administration and our current cash resources supporting our plant operating expenses and capital requirements into the fourth quarter of 2026. These statements may include the expected timing and results of clinical trials for our product candidates and other clinical regulatory plans and the market opportunity for those programs. This call may also contain forward-looking statements relating to CACIA's growth, forecasted cash runway, and future operating results, discovery and development of product candidates, strategic alliances, and intellectual property, as well as matters that are not historical facts or information. Various risks may cause CACIA'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 regulatory interactions for our product candidates our dependence upon strategic alliances and other third-party relationships, our ability to obtain patent protection for 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 we have filed with the Securities and Exchange Commission, including in our annual report on Form 10-K for the full year ended December 31st, 2023, and our quarterly report on Form 10-Q, the quarter ended September 30th, 2024, that we filed today. This conference call contains sensitive information that is accurate only as of the date of this live broadcast, November 13th, 2024. Patient 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 security laws. With that, I would now like to turn the call over to our CEO, John Nolan.

Thank you, Hailey, and welcome, everyone, to our third quarter 2024 financial results and corporate update conference call. I will begin with a brief update on our recent activities. And then Sugandh Gendron, president and head of R&D of Tayshia, will provide an update on our lead Tayshia 102 program and clinical evaluation for Rett syndrome. Cameron Alam, our chief financial officer, will follow up with a financial update. I will then provide closing remarks and open up the call for questions. In the third quarter, we continued to drive progress across our TASHA 102 program and clinical evaluation for pediatric, adolescent, and adult patients with Rett syndrome. Our accomplishments included achieving important clinical and CMC regulatory progress, collecting additional clinical data, further supporting the safety profile of TASHA 102 across different ages and stages of disease, and enrolling additional patients in the high-dose cohort across both our adolescent adult and our pediatric reveal phase 1-2 trials, which support our expeditious development of TASHA 102 for patients and families suffering from RAD syndrome. We recently completed our initial Type B multidisciplinary meeting with the FDA that was granted as a benefit of receiving Regenerative Medicine Advanced Therapy, or RMAT, designation for TASHA-102. We are pleased with the progress made with the FDA on further elucidating the potential regulatory pathway for TASHA-102 as we advance discussions on trial design, endpoints, and the potential use of an established natural history data set for Part B of our revealed trials. Additionally, we aligned on a meeting cadence with the FDA to expedite the development plan for TASHA-102. We recently completed a Type D CMC meeting, which was well attended by the FDA, including senior officials. We obtained FDA approval to use the pivotal TASHA-102 product in our revealed trials based on a successful demonstration of analytical comparability between the clinical product and the product derived from the final commercial manufacturing process. Subsequently, we released the pivotal product, which we intend to use in Part B of our trials. With this progress, we believe we are in a strong position with our CMC activities for Tayshia-102. Sukhu will discuss this in more detail. We also received approval from the Independent Data Monitoring Committee, or IDMC, to proceed with continued enrollment in cohort 2, evaluating the high dose of TASHA-102 of 1 into the 15 total vector genomes for both review phase 1-2 trials, following the IDMC's review of available clinical data from the three patients treated with the high dose. I am pleased to share that the I am pleased to share the high dose of TASHA-102 continues to demonstrate an encouraging safety profile. TASHA-102 was generally well tolerated with no serious adverse events or dose-limiting toxicities in the first two adolescent adult patients as of 20 weeks and nine weeks post-treatment, respectively, and in the first pediatric patient at six weeks post-treatment. Subsequently, we dosed the third patient in the high-dose cohort of the adolescent adult trial and enrolled the second patient in the high-dose cohort of the pediatric trial, with dosing scheduled for the current quarter. As a reminder, Rett syndrome is a rare neurodevelopmental disorder that afflicts an estimated 15,000 to 20,000 patients in the United States, Europe, and the United Kingdom. Currently, there are no approved disease-modifying therapies to treat the genetic root cause of the disease, and there is significant unmet need. Rett syndrome is caused by mutations in the X-linked ME-CP2 gene, which inhibits neuronal development and leads to multi-system complications. It's characterized by loss of communication and hand function, slowing or regression of development, motor and respiratory impairment, and autonomic dysfunction, seizures, intellectual disabilities, and shortened life expectancy. Individuals with Rett syndrome typically require 24-7 care and lifelong assistance with daily activities, resulting in high caregiver burden and significant impact on quality of life. We remain confident in our differentiated gene therapy candidate which we believe has potential to provide meaningful therapeutic benefit to a broad population of patients with Rett syndrome using a minimally invasive delivery approach that has the potential to be administered in the outpatient setting for both children and adults. Patient 102 is a one-time intrinsically delivered gene therapy that was strategically designed to enable optimal and controlled transgene expression across the central nervous system. Threat syndrome is challenging to treat with traditional small molecules and gene therapy approaches due to the random inactivation and subsequent mosaic expression pattern of MECP2 that results in a mixture of cells that are either deficient in MECP2 or express it normally. We believe patient 102 equipped with the novel MiRAIR technology has the potential to appropriately address this challenge by mediating MeCP2 expression in the central nervous system on a cell-by-cell basis. By silencing the transgene in healthy cells expressing MeCP2 and enabling protein production in deficient cells, MiRAIR is designed to overcome the risks associated with both under and over expression of MeCP2. Importantly, our capsid is paired with a self-complementary viral genome to enhance the effectiveness of gene transduction. We made the decision to utilize the mini-MeCP2 gene, which is a smaller version of the MeCP2 gene that contains the essential functional domains necessary for therapeutic benefit, so that we were able to package our construct with a self-complementary vector. Self-complementary vectors have a smaller packaging capacity than the traditional single-stranded vectors, but they offer the important advantage of faster, more efficient transduction because they're able to entirely bypass the step of converting the vector genome into a double-stranded DNA prior to gene expression. As a result, a self-complementary vector can speed up the onset of transgene expression and potentially improve the efficacy of the gene therapy. We believe these strategic attributes of our construct enable the early and consistent clinical improvements that persisted and strengthened over time, as we've seen in the adult and pediatric patients treated with the low dose of TASHA-102. Since Rett syndrome is a progressive disease, we believe early clinical response increases the likelihood of reversing the disease trajectory and may be predictive of long-term clinical outcomes. Rett syndrome requires an increased MeCP2 protein to activate the neural circuits necessary for regaining function. And it also requires time for patients to strengthen these reactivated circuits to enable deeper learning of the skills affected by the disease. We believe the sooner positive clinical impact is observed following treatment, the greater the trajectory of potential improvement and longer-term outcomes. Therefore, early clinical benefit is a strong indicator that ME-CP2 protein has reached therapeutic levels that, in turn, create the opportunity for patients to further strengthen and gain new skills that can positively impact their activities of daily living. Importantly, The clinical data presented from the adult patients with the most advanced stage of the disease treated with the low dose of TASHA-102 indicate a pattern of early clinical improvements and functional gains across multiple domains within four weeks post-treatment that persisted and strengthened over time. Specifically, improvements in autonomic function, including breathing and sleep, were demonstrated as early as two weeks post-treatment. At four weeks, clinical improvements and functional gains were reported across multiple domains impacting daily activities, including time and gross motor skills, socialization and communication, and seizure events. This includes beginning to use eating utensils, sitting without support, saying mama or daddy, petting a dog, improved attentiveness and social interactions with family members, and improved use of IVs through the communication device as documented by video evidence, efficacy measures, and or clinical observations reported by the principal investigator. As the pediatric data mature, We anticipate that the early clinical improvements and functional gains observed should also persist and strengthen over time in the pediatric patients treated with TASHA-102 as the neural network matures and patients develop the strength to gain more complex skills. We look forward to further evaluating the pediatric patients over time. As clinical evaluation of TASHA-102 further progresses, It is important to note that our program leverages a routine, minimally invasive delivery approach that has the potential to be administered in the outpatient setting. Preclinical findings support the clinical potential of intrathecal administration as an effective delivery method for AAV-based gene therapies that are designed to treat the genetic root cause of CNS diseases as it enables widespread and consistent biodistribution across the brain and spinal cord. We believe this widespread distribution has been demonstrated throughout the clinical data. Through the clinical data, we reported that showed broad improvements across key clinical domains important in disease pathology, including fine and gross motor skills, communication and socialization, autonomic and seizure events. Importantly, we saw this consistently in the two adult and two pediatric patients treated with the low dose of TASHA-102. despite differences in baseline disease severity. This was translationally reinforced with data from the analysis of five non-human primate studies that we recently presented at the ESGTC Annual Congress, which demonstrated that intrathecal delivery of gene therapies reaches key areas of the brain and spinal cord. Sukha will discuss this in more depth. Collectively, we believe the strategic design of our constructs has contributed to the encouraging safety and efficacy data we have reported today in both reveal trials, demonstrating early, sustained, and new clinical improvements and functional gains that strengthen over time and across multiple domains. We believe there is potential to see continued improvements as the data mature, and we look forward to reporting longer-term data from the low-dose cohort and data from the high-dose cohort in both reveal trials in the first half of 2025. We plan to continue working closely with the FDA through the RMAT mechanism to solidify the regulatory pathway for Tayshia-102 based on the totality of data, and we remain focused on the execution as we prepare for what we expect to be an impactful year ahead. I will now turn the call over to Sukhu to provide a more in-depth discussion of TASHA 102. Sukhu?

Thank you, Sean, and good afternoon, everyone. I'm pleased to provide an update on our TASHA 102 gene therapy program in clinical evaluation for Rett syndrome. As Sean mentioned, we believe we have achieved important regulatory progress for TASHA 102 over the last quarter. As a reminder, Our approach is to use Part A of the trials to generate data that will inform our development plan for Part B of the trials. Therefore, Part A is hypothesis generating, not hypothesis testing, and was intentionally designed to collect data across a multitude of endpoints to help inform the final key elements for the next phase of our studies. We recently completed an RMAC Type B multidisciplinary meeting with the FDA regarding our ongoing TASHA 102 development plan. I'm pleased to share the meeting was very productive, and we continue to find alignment in the potential regulatory pathway forward for TASHA 102. We advanced discussions with the agency on the trial design, endpoints, and potential use of an established natural history data set for Part B of our revealed trials. Based on FDA feedback from our ongoing discussions, we intend to focus on objective measures that clinically capture functional gains. In line with this focus, the caregiver reported Rett Syndrome Behavior Questionnaire, or RSVQ, will not be included as a primary or secondary endpoint in Part B of our review trials as discussed with the FDA. We will no longer be reporting RSVQ scores as part of future data readouts in our ongoing review of Phase I trials. The FDA confirmed our existing non-clinical data package is adequate to support BLS submission, and we aligned on a meeting cadence with the FDA to expedite the development plans for TASHA 102. We recently completed a Type D CMC meeting with the FDA, and I'm pleased to share the FDA approved the use of pivotal TASHA 1 or 2 product in our review trials based on the successful demonstration of analytical comparability between the clinical product and the product derived from the final commercial manufacturing process. Subsequently, we released the pivotal product, which we intend to use in Part B. The FDA also endorsed the proposed analytical methods and corresponding qualification and validation plans, including mechanism of action potency release assays. We believe this feedback provides further evidence of our meaningful progress towards Part B of the review trials. It also demonstrates our CMC readiness for BLA submission in the completed development of our final commercial scale process and pivotal product release for use in Part B. Importantly, this progress provides a path forward to potentially utilize the clinical data from Part A of our trials in our future BLA submission. Collectively, we believe our discussions with the FDA have been encouraging. We plan to continue working closely with the FDA through the ARGMAT mechanism to solidify the regulatory pathway for TASHA-102 based on the totality of data. Now let's turn to our clinical progress. As a reminder, we have two ongoing Phase II review trials evaluating TASHA-102. an adolescent and adult trial taking place in Canada and the U.S. for patients 12 and older with stage four Rett syndrome, and a pediatric trial taking place in the U.S., the U.K., and Canada for patients five to eight years of age with stage three Rett syndrome. We are currently enrolling patients in Part A, the dose escalation portion of both trials, which is evaluating two dose levels of patient 102. With cohort 1 complete across both revealed trials, which is evaluating the low dose of 5.7E14 total vector genomes, we've made substantial progress in the enrollment of cohort 2, evaluating the high dose of TASHA-102 at 1E15 total vector genomes. The high dose of TASHA-102 continues to be generally well-tolerated with no serious adverse events or dose-limiting toxicities as of 20 and 9 weeks for the first two adolescent adult patients, and as of six weeks for the first pediatric patient treated. Following the IDMC review of this data, we received approval to continue with enrollment in the high-dose cohort. Subsequently, we dosed the third patient in the high-dose cohort of the adolescent adult trial, and we enrolled the second patient in the high-dose cohort of the pediatric trial with dosing scheduled for the current quarter. We also activated additional clinical trial sites across both reveal trials to further support Part B readiness. In collaboration of our intrathecal delivery approach for TASIA-102, we recently presented preclinical biodistribution data that further supports the clinical potential for intrathecal delivery as an effective, safe, and minimally invasive delivery approach for broad targeting of the central nervous system at the annual ESG-CT Congress. Data from the analysis of 28 human primates across five studies evaluating AAV9 gene therapy delivery showed that both lumbar, intrathecal, and intrasystem of MAGNA administration were comparable, consistent, and widespread by distribution of AAV9 vector throughout the brain and spinal cord regions. Importantly, these findings provide translational support for the clinical data we reported across both review trials that demonstrated broad clinical improvements seen across key areas of disease pathology that are known to impact different regions of the brain. We believe our continued clinical trial execution and data collection, supporting a continued, well-tolerated safety profile of TASHA-102 at the low and the high dose, combined with the encouraging regulatory discussions that have further shaped our developmental plan, strongly position us as a success as you work to solidify our developmental plan for Part B of our studies. I will now turn the call over to Cameron to discuss our financial results. Cameron? Thank you, Sukhu.

Research and development expenses were $14.9 million for the three-month-ended September 30, 2024, compared to $11.8 million for the three months ending September 30th, 2023. The $3.1 million increase was driven by a $0.8 million increase in GMP batch activities during the three months ended September 30th, 2024, which is representative of the intended commercial manufacturing process for TASHA-102 and Rett syndrome. Compensation for R&D employees increased as a result of higher headcount, and this is partially offset by lower consultant and contractor expenses. General and administrative expenses were $7.9 million for the three months ended September 30th, 2024, compared to $8.6 million for the three months ended September 30th, 2023. The reduction of $0.7 million was primarily due to the decrease in issuance costs allocated to liability classified 2023 pre-funded warrants associated with the August 2023 financing. Net loss for the three months ended September 30th, 2024 was $25.5 million or 10 cents per share compared to a net loss of $117.1 million or 93 cents per share for the three months ended September 30th, 2023. The reduction in net loss in 2024 was primarily due to a non-cash loss of $100.5 million reported in 2023 from a change in fair value of warrant liability from the 2023 pre-funded warrants associated with the August 2023 financing. As of September 30, 2024, Tayshia had $157.7 million in cash and cash equivalents. Tayshia expects that its current cash resources will support planned operating expenses and capital requirements into the fourth quarter of 2026. I will now turn the call back over to Shawn for his closing remarks. Shawn?

Thank you, Cameron. We are pleased with the continued progress made across our CASIA 102 clinical development program. and we remain confident in the potential of TASHA 102 to provide therapeutic benefit to adult, adolescent, and pediatric patients with Rett syndrome across different genetic mutation severity. We remain steadfast and focused on execution as we prepare for what we expect to be an impactful year ahead, which is planned to include reporting longer-term data from the low-dose cohort, and data from the high-dose cohort in both revealed trials, and solidifying the development plan for Part B of our trials. We look forward to continued discussions with regulatory authorities as we work to bring a new treatment option to patients with Rett syndrome as expeditiously and safely as possible. With that, I will now ask the operator to begin our Q&A session. Operator?

Thank you very much. At this time, we will be conducting a question and answer session. If you would like to ask a question, please press star and then one on your telephone keypad. You may press star and then two if you would like to remove your question from the queue. Please may I ask that you limit your questions to one question and one follow-up question. For participants using speaker equipment, it may be necessary for you to pick up your handset before pressing the star keys. One moment, please, while we poll for questions. The first question comes from Kristin Kluska from Cancer Fitzgerald. Please proceed with your questions, Kristin.

Hi, everyone. Thanks for taking the questions. It sounds like it was a very productive quarter for you. I wanted to ask one on the regulatory side. Considering that the endpoint could focus on objective measures, How are you broadly thinking about this in the context that this is a largely heterogeneous disorder? Will it be more personalized or could it focus on something perhaps that's broad that covers a few areas and specific measures?

Thanks for the question, Kristen. You know, I would say you definitely have to take the heterogeneity into consideration as you're thinking through this. And so as an example of that, we're looking at different types of potential trial and trial designs. You know, possibly thinking about the patient as their own control could be a consideration. And I think from the, you know, to do that, you need to have good natural history. And we've completed our analysis of natural history and look forward to our next discussion with the FDA about how that can be taken into consideration as we think about trial design and potential endpoints. And specific to endpoints, I think at this point, you know, I'd put it into a couple buckets. One would be, you know, looking at milestones and functional gains, right? I mean, to your point, every patient is going to have loss or never having gained certain functions or milestones And if you can potentially restore those, you can have different milestones for different patients, but yet it may be something that's very consistent across all patients is that you would never expect them to have these types of gains. And I think we've seen some preliminary evidence of supporting this kind of thinking actually communicated to the market earlier this week. I also think if you think broadly about the disease, hand function, gross motor function are also aspects that are very consistent across patients that you could consider and you can measure each of these things very specifically, very objectively, and in a standardized approach that would lead to high data integrity and demonstration potentially of a very exciting clinically meaningful effect for patients. Hopefully that gives you a little bit of color.

Yes, it does. Thanks. And then just for the follow-up on that, was hoping to get a little bit more context around the natural history completed analysis and then thinking about using it as a potential comparator here. Are there any stratifications to expect to compare this or will it kind of just be broadly based on many of these patients couldn't achieve milestone X and we're seeing Y in our trial?

Yeah, again, I just want to keep it at a high level. You know, I think there is a distinction between, you know, using it as a comparator to the extent like in SMA, you could say type 1 patients all followed a similar progression. So that's not what the natural history would indicate here. However, you know, there are aspects of the disease, including, you know, when people lose or never gain certain functions seems to be very consistent as well. So, you know, again, we have to think about this, you know, carefully. But when you think there's a path forward here, we've had preliminary discussions with the FDA and look forward to next steps in that discussion, hopefully later on here in the quarter.

And, Kristen, one thing I would add is also the totality of clinical evidence will also play an important role in this disease. As you pointed out, it's heterogeneous, and these patients have many clinical features.

Thank you very much.

The next question comes from Chris Raymond from Piper Sandler. Please proceed with your questions, Chris.

Yeah, thanks. A couple of questions. Maybe just on the safety update you guys had today from the two adults and pediatric patients. It seems at least from NeuroGene's language and the way they were talking with that SAE they saw that showed up, was in a patient that just had been very recently been dosed. I'm just looking, it looks like you guys are 29 and six weeks out with your high dose. Just thinking about maybe the window for an AED-related SAE. Is there a range when you think a patient might be in the clear? And I have a follow-up.

Yeah, and Chris, just to be clear, and I'll turn it over to Sukhu, we've now dosed four high-dose patients.

We reported safety in three because the fourth patient was very recently dosed, so they didn't get that cutoff yet. But to answer your question specifically, I'll turn it over to Sukhu.

Yeah, Chris, I mean, what I'm going to kind of walk you through is based on my experience with both systemic gene therapies as well as other alternative routes, which include intrathecal. So keeping, you know, in mind that with intrathecal ICV, the dosage given could become eventually an important factor in some of these treatments. clinical reactions that you might see in this patient population. So, again, I have no idea what exactly happened with the NeuroGene program, but what I can tell you is the following, right? With intrathecal, about 15 to 20% on ICV, 15 to 20% of that product can get into the systemic circulation, and you can sometimes get an immune response in the liver because AAB9 has significant tropism to the liver, and for whatever reason, Is there an immune response? T cell are sometimes a mixed antibody and T cell response that can result in elevated liver enzymes and so forth. And sometimes the product itself, I guess the purity of the product can also play a role in the immune response. So that's something else to keep in mind. The second is that when you do an ICV procedure, and I'm sure NeuroGene knows this better than we do, when you do an ICV procedure from a surgical standpoint, the needle itself, if it impacts the brain and causes some damage or there's spillage of the product, That can also sometimes cause an immune response, even though the patient may be on triple immunomodulation, and that can cause inflammation in that part of the brain, and that could obviously cause a symptomatic concern within that trial. The other component to keep in mind is as product gets into the systemic circulation, you can get something called TMA, thrombotic microangiopathy, which I've seen many times in the past with DMV. But I think it's pretty unusual when you do an intrathecal ICV approach. So if that is something that's going on, here, obviously, we're ready to see what they share with us. But it also tends to be an immune response. There's complement activation, and then there's the entire cascade of the immune system can get activated, which results in TMA that can then result in a systemic inflammatory response that affects the liver, the kidney, etc., etc. And there might be something else that you're not aware of, and this all circles back to the purity of the product. So that's about all I can tell you based on my past experience, but again, the NeuroGene program, I cannot speculate at all.

Okay, cool. Thanks. And then just on... I know you gave a lot of detail on... RSVQ and not using that in FDA, your discussion with FDA. But it was a co-primary endpoint for trofinetide, but it is also highly variable, as you guys have been pointing out. Just any sort of reaction from KOLs in terms of their reliance on that? Do docs use that? Any sort of reaction to actually paying attention to RSVQ as an endpoint?

I would say in our discussions with KOLs, they are very, I would say, universal in their view that RSVQ is a tool to measure clinical intervention with a therapeutic. It is not a good idea at all. And the first thing they go to is the fact that it was never designed for that purpose. It's highly variable. It's given by caregivers. And if you're going to use it, you're going to have to use a placebo to try to control for it, which is what Trefenetide did. So in our discussions with KOLs, they're supportive and they're actually pleased, you know, with the discussions we've had with the FDA. And instead of looking at that, focusing more on some of these, you know, very clinically meaningful objective type endpoints.

Yeah, and Sean, what I would add to that is that RSVQ, as you said, is very subjective. It's given by a caregiver-based measurement that can vary on a day-to-day basis. And also, from what I'm aware, with profanity, if I remember the original driving force as an endpoint for their phase three trial was RSVQ. And I think CEDA reviewed it and felt there was too much variability. And that's why they had CGII added to make a composite, which then gave you a P-value of significance that allowed, I think, the product to be reviewed and appropriately approved at that point in time. But I guess my point again is that Sean pointed out there's too much variability. And frankly, many of us both who designed clinical trials, and I think some of the KOs already know the scores, RSPQL are relieved that they're not using it.

Yeah, and I guess the last point, Chris, is just keep in mind that the RSPQ measures behavior rather than function. And I think we've given multiple examples where function has improved and the RSPQ gets worse because the behaviors that, like, certain aspects of behavior that people couldn't have done in the past because they didn't have the functions looks to be a negative when the function itself is a positive. So, just another reason to not use that scale in this type of a setting.

Very helpful. Thank you. Sure.

Thank you. The next question comes from Whitney Ijem from Kennecord Community. Please proceed with your questions, Whitney.

Hey, you guys. Congrats on all the progress for me as well. So just curious, enrollment in the high-dose cohort is obviously going really well, but wondering if you can characterize the level of demand or interest in the study, I guess, in the adults in particular, with an eye towards thinking through kind of the ultimate market opportunity and kind of demand from older patients that you might be hearing or seeing.

Yeah, I mean, we've had significant demand. I mean, we've had – you know, there's multiple – patients wanting to get into the slots in both protocols. And I think that we've gotten feedback from the community that they're very pleased that we've cast such a wide net. I mean, oftentimes you start with a younger population and then expand over time possibly. I think they've appreciated the approach and the consideration of the fact that we're trying to take care and offer a potential treatment for all patients suffering from RAD.

Got it. That's helpful. And then just lastly, on the point of the RAD of administration, which is a clear point of differentiation between you guys and NeuroGene, can you walk us through what happens from a patient perspective as it relates to treatment. Like, remind us, what's the immunomodulatory regimen? When does that start? And, like, what does the day look like from a patient's perspective, logistically and timeline-wise, around treatment?

You're talking about the immunotherapy that we're immunosuppression regimen that we're using in our protocol?

Yeah, that and then just kind of, like, what does treatment day look like for these patients?

Oh, treatment day, okay. Oh, okay, okay, I get it.

Yeah, so right now, Whitney, our protocol is such that, if you recall, when we originally started our studies, we were using prednisolone and serolimus, but they were for a much longer duration. And that was done for many different reasons, but as you got more experience with the gene therapy, the procedure and how patients are responding, we've been shortening the immunomodulatory duration because we feel like the patients don't really need it. So right now, prednisolone is started on day minus seven, so roughly one week before the day of administration at one milligram per kilogram. per body weight, and then it's given for six weeks, and then it's tapered off over six weeks. So it's a total of 12 weeks. And then Sirolimus, which was at one point running for almost 37, 40 weeks, is now being reduced to 24 weeks, or 25 weeks, and it's 0.8 milligrams per kilogram. And obviously, Ideally, I would like to see that duration shortened further and keep it as simple as possible for this patient population. So obviously, before a patient is brought in for actual treatment and engagement within the study, they have to go through multiple screening procedures to make sure they actually qualify for the trial. And there's a time range that can run somewhere from, say, 20 days to 50 days. I mean, there's a duration. So I'm not being exact here, but I'm just kind of giving you a feel. So once they qualify through screening, then they're given immunosuppressant modulatory agents at day minus seven, and then they come in on that day, and they have to be prepped for the procedure. Now, the caveat here is, remember, R is a simple number puncture, which can be done inpatient or outpatient, and this has significant impact on... who is actually doing the lumbar puncture, because eventually a lumbar puncture that can be done in an outpatient setting by not necessarily a neurologist, but can be done by an internist or a physician who can administer the procedure and the drug in a very simple manner, and then the patient, I guess, eventually could be discharged. But at the present time for protocol, given it's a first in human study, we have to observe the patient over a certain period of time for the protocol before we can discharge the patient. And then the patient is followed, you know, week one, week two, week three and week four for the first four weeks from a safety standpoint. And then you start doing efficacy assessments as well. As you know, Sean and I pointed out earlier during the call as a hypothesis generating, efficacy measures. Now, the caveat is when you do other procedures like ICV, it's a surgical procedure, very invasive, and then these patients have to be observed sometimes in a surgical unit almost up to a week. So that's kind of the big picture at the present time. So the ease of use, the lot of administration, and obviously the immunosuppressive regimen, keeping it simple and not being too aggressive with it, all of those could make it much easier.

more palatable gene therapy for this disease state with a broad range in application so yeah and the only thing i would add to that just from uh just so you have a sense of time um you know once once the you know the patient is is brought in for the procedure the administration itself you know we're talking 10 to 10 to 20 minutes so it's it's very very short and uh um you know we like to make it as easy as we can on the patients and their families

Very helpful. Thank you.

Sure.

Thank you. The next question comes from Salveen Richter from Goldman Sachs. Please proceed with your question, Salveen.

Good afternoon. Thanks for taking my question. Can you elaborate on the exact objective measures you're looking at in Part B of the REVEAL study based on the FDA feedback and the specific milestones and or functional gains you'll be monitoring? Thank you.

Salveen, I really don't want to get into the details of that at this point in time. I think it's better to keep it high level in terms of the areas that we're looking at, which would be milestones, hand function, gross motor function, and the actual, you know, means that we're going to do that and what we're going to follow. I can tell you we've got a very specific set. It's all been identified and validated with the, you know, coexisting metrics. So there's nothing new that we're introducing here. And I'd prefer to wait until, you know, we have everything, you know, fully and finally fleshed out with the FDA. We've got another meeting with them coming up here, hopefully before the end of the year is the next step. You know, we've talked about locking it all in. in a meeting likely in the first half of next year. We're continuing to make good progress, but I'd hesitate from getting into the details until we're fully aligned.

Selvin, may I just check if you have any further questions?

Thank you so much.

Thank you. The next question comes from Gil Blum from Needham & Co. Please proceed with your questions.

Hi, everyone, and thanks for taking our questions. Maybe a more general question as it relates to your Type D meeting. So were there some garnered synergies from prior experience with Zolgensma that kind of helped you, you know, get the equivalence through here, or is this just, you know, the new product, checking all the boxes, and I have a follow-up?

You're talking about the comparability between the clinical lot and then the product made from the final commercial process?

Yep.

Yeah. Well, I would just keep it at a high level, Gil, and say, you know, we really didn't do much to the upstream. They're very, very similar, you know, between the two processes. What we wanted to do was just to continue, like, one of the things that we brought over from the Suljansma experience is that, you know, we always want to make the most pure product that we can. I mean, then you're minimizing the dose exposure that you're giving the patient. So, you know, while we never had any direction from the FDA or anything like that, I mean, the FDA has generally been looking at, you know, keep empty capsids from, you know, going above 30, percent or so, you know, and we want to be, you know, way, way less than that. And so we focused a little bit more on the downstream. And, you know, that's where we did our work. And so when you look at the actual attributes of the product, you know, the potency and infectivity and those kinds of things, you know, the data were very, very consistent. And the improvements that we made were were clear and we identified those and obviously where we landed with the FDA was in a very positive fashion. So we're pleased with where we are and look forward to, I guess what I'd make the point that we're at scale. We've got our final process and we've got product in the freezer that we're planning to use in Part B. And we're looking forward to that. So having CMC lined up at this point in time is a big step for the program because generally it turns out that CMC gets on the critical path. And that's not the case for us.

Okay. And that's very helpful. And another follow-on as it relates to potential designs for, you know, pivotal studies here. Yeah, it sounds like we're looking more at, you know, natural history here, but would you guys still consider a randomized study in adult patients, for example, or does the disease heterogeneity make that very complicated? Thank you.

I mean, the heterogeneity is,

really there in all patient ages and stages. So that's one of the reasons that we're thinking about multiple trial designs. But ultimately, if you can come up with a construct where it's dependable to use the patient as their own control, regardless of age, would be an optimal setting. because the patients are so heterogeneous that, you know, using a delayed treatment group, you know, that really isn't taking care of the issue either. So, you know, I think we've, I can tell you we've given a great deal of time and effort around this. We've had discussions with the FDA on multiple occasions, and, you know, we've basically said we'll continue to bring forward both clinical data as well as, you know, the final assessment of our The work we did in natural history to make our case for why we think a certain approach makes the most sense. And I can just say the agency has been very open to that. There's been no pushback. There's, I would say, a very good understanding by the agency of the disease and the inherent challenges that you would have. And so that's where we've been thinking a lot about the combination of the trial design and the endpoints to allow us to facilitate getting this drug approved in the most expedited fashion possible with the greatest scientific rigor. And it's our view that the natural history work that we've done will be helpful in facilitating that. Well, you know, we have to certainly get there in final form with the FDA, but that's where we're thinking at this point in time, and we're encouraged by previous discussion.

Thank you very much.

The next question comes from from Jeffries. Please proceed with your questions.

Hi. Congrats on the progress, and thanks for taking my questions. Just clarifying, it sounds like you could have that alignment on a registrational study design and endpoints ahead of the data update first half of 25. So would that be part of your first half 25 disclosure?

You know, in a perfect world, yes. We would like to basically come out with, you know, the feedback from the FDA and do the data update, you know, simultaneously would be fantastic. So, Just to be clear that what I was pointing at, we are going to have another meeting with the FDA end of this year or very beginning of next year. That's a next step in the discussion. We would expect that more final discussion to happen in the first half of next year. And it's our goal, our preference to align it. So we'd love to come out and tell you guys, here's where we landed with the FDA. here's the data update, and here's the next steps in the program is how we've drawn it up. And hopefully we're able to execute and make that happen.

Got it. Okay. That's all pull in. Maybe just a quick one. Wondering if you discussed with FDA the potential to dose a younger cohort of patients at three to five-year-olds in Part B? Or is this part of longer-term plans? I guess just based on the safety and profile that you have so far, could you potentially get into those younger patients in Part B?

Yeah, I mean, right now, Part B does include three- to five-year-olds. And I would just say, Maury, that our intent is ultimately to make sure that this is available, you know, for patients newly diagnosed, you know, throughout adulthood. So we are contemplating all of that in our whole clinical program, and we'll step through it accordingly. We've got the plan in place, and we're in concert in discussion with the FDA about that and how to best step through that.

Got it. Okay, thanks for taking my questions.

All right.

Thank you. The next question comes from Yanan Zhu from Wolf Fargo. Please proceed with your questions, Yanan.

Hi. This is Jeff Han for Yanan. Thanks for taking our questions. Can you just give us your overall thoughts on the NeuroGene data and how you see it comparing to TASHA-102? And then secondly, is dosing above the high dose of 1 times 10 to the 15 vector genomes with TASHA-102 possible? Do you think there's safety room to dose higher? Thanks.

Yeah, I mean, I can say that in our non-human primate tox, we were clean at 2E to the 15. So we could potentially go higher if we wanted to. Based on the preclinical data, it looks like 1E to the 15 is the right choice at the higher dose. But it's something that we could certainly contemplate. We have the ability to go higher. So I think that's a I think as it relates to the NeuroGene data, you know, I think number one, I would just say that it's a positive for the RET community that the NeuroGene data was, you know, demonstrating benefit to patients. And I think what it highlights is that utilizing gene therapy to target MECP2 is a good target and that there's a benefit that's been derived now from two different constructs. And I think we have to look at, you know, over time, you know, how things elapse. I don't think it's appropriate to get into the details of how one may be better than the other at this particular point in time. But I think that the win, if you will, is for the community and that, you know, hopefully there's options available. for the family suffering from RAP.

Okay, thanks very much.

Thank you. Ladies and gentlemen, if I may just ask, if you could please just limit your questions to just one question per end list. The next question comes from Jack Allen from Bayard. Please proceed with your question.

Great. Thanks so much for taking the questions, and congratulations on the progress made over the course of the quarter. I wanted to ask about the four patients that have been dosed with a high dose. How should we think about those patients and the centers at which they've been dosed? I'm trying to understand if there's a broadening footprint here and if additional physicians are getting hands-on experience with Keisha-102. Thanks for any context you provide.

Yes, Suku, don't make sure I get this right, but we have seven total sites available five sites available right now to dose in the two protocols. And so of the four patients that were dosed at the high dose, it's at least two different sites. So right now we've had a total, when you look at the total, the both reveal programs, there's at least three sites that have dosed patients. And hopefully Hopefully that makes sense.

Three different sites. Got it. And then three sites, I guess, just to clarify across both the low and the high dose is the way to think about it? Yes.

Okay. Thanks so much for the call.

Thank you. The next question comes from Julie from Tourist Securities. Please proceed with your questions.

Hey, thanks for taking our questions. As we look forward to Part A data in first half of next year, will you be providing updates on RSPQ, or are you no longer sharing RSPQ as part of your assessment? And for the endpoint you are considering for Part B, can you at least share if that's something that you're already tracking in Part A?

Thank you. Yeah, June, we are not going to give updates on RSPQ anymore, given the fact that in our discussions with the FDA, it's very clear that they didn't see it as a viable option as a primary endpoint or a secondary endpoint for that matter. And we completely are on board with that. We see no value to continue to show it. Yeah. And so, you know, for those reasons, we're focused more on, you know, And most importantly to us are really what are the functional gains and clinical observations that are being demonstrated? We still think CGI is something that's relevant to look at. But again, that's not a primary endpoint in our view and discussions with the FDA. So we will consistently give updates on the other aspects of the program that we have, but we just felt RSPQ, given that it's been completely ruled out and given the focus that people have put on it, makes no sense. We're trying to be very clear that it has no effect on the program going forward from a regulatory perspective, and it's not a good assessment of clinical effectiveness. As it relates to your question about Part A, yes, I mean, we are collecting milestone data. We've reported on a lot of milestones over the course of time. You know, that'll certainly go into the discussion that we're having with the FDA in terms of endpoints. We've already had several discussions about that, as well as hand function and and gross motor function. So, you know, when we give our update in the first half of next year, you know, we're, we're hopefully it can be very comprehensive for everyone in terms of where we landed from trial design and end points. How did that correlate to what we've seen in part a, and then what is your high dose data look like? Um, so we're, we're excited. I think we're exiting the year with a ton of momentum. Um, we're in a good place and you know, what we have to do as a team is execute across the board. generate clinical data, and continue our dialogue with regulators to put us in a great position that we plan to share in the first half of 2025.

All right. Thank you. You bet.

Thank you. The next question comes from from Citizens JMP. Please proceed with your questions.

Good evening, and thanks for taking my questions. I just want to ask about the doses and how you view the equivalency between your dosing exposure and that of NeuroGene, given you've also recently presented data of EGC-T on biodistribution. Thank you.

So can you kind of restate that question? I want to make sure I understand it and be accurate in giving the answer.

Basically, you know, like your low dose is a little bit below what neurogen is administering, and now you escalated at the higher dose to approximately the same dose. Obviously, the route of administration is differently. So I just wanted to get an idea of, you know, if you have any sense of what the exposure around the critical part of the brain is in terms of the two gene therapies and what that means for the efficacy we've seen so far with the two products.

Well, Suku and I can tackle this together, but I think, number one, you know, the data that we reported out at ESGTC was hopefully giving good context to the question of what's the bioavailability look like when you go direct to brain versus intrathecally. And so we had over 29 non-human primates across all the ATB9 programs that we had. And when we looked at the biodistribution data, there really wasn't a difference between intrathecal levels of transduction versus what happens with ICM or direct-to-brain. So I think the first point is the biodistribution appears to be equal. And number two, when you look at the clinical data, that makes sense because, you know, when we reported our data initially, we were seeing effects occur across clinical domains. And so as you know, autonomic function, socialization communication, gross and fine motor function, seizures, all those happen in different parts of the brain. Sleep, you know, so that lines up well with the biodistribution data that I talked about that you have to be getting to all parts. And then when you look at the data that was announced later this week, you know, There seems to be similar effects, you know, one- to two-point improvements in CGII. You know, so it looks like the roots of administration are, you know, relatively, you know, equal in terms of delivering, you know, the effect across clinical domains. And I would just point to the fact that, you know, our dose is about 50% less than what was used at 1E to the 15th. And part of that can also be the construct design. And so we've talked about the fact that having a double strand and self complementary generally leads to greater levels of transduction efficiency than versus using a single strand. So I think all the data kind of line up with what we've been saying for the last couple of years. And so we're encouraged by what we've seen at the low dose. Even in the pediatrics at early time points, you know, within four weeks, we were seeing effects across, you know, breathing, sleep. We were seeing impacts on fine motor skills, gross motor skills, seizure activity. And, you know, that was in as little as four to 12 weeks. So from our perspective, that's super exciting, and we think that sets the trajectory for how these patients are going to do over time. So, you know, it's our anticipation that as longer-term data unfolds at the low dose, and we believe hopefully even at a better magnitude at the high dose, that we see the data strengthen over the course of time, and we see sustained and new gains emerge over time as well.

Sean, I would also add to that question. It appears, right, both the ICB approach and the typical approach, the proof of concept now has been proved. So that is number one. Number two is, yes, the urethane does use a high dose. And the other thing is, you know, from an overall safety standpoint, It's pretty well known in gene therapy, the higher the dose, even small changes from a logarithmic standard sometimes can impact certain types of safety figures. So this is the recent safety issue. I think there's a lot of curiosity as to what is going on. The third is about distribution, as you pointed out. There was a lot of questions around if you go into fecal via number puncture, do you get the same amount of equivalent by distribution to ICM or ICV? What we've shown now is a pretty large cohort of non-human primates. that we have equal biodistribution, we activate the nuclear network quite effectively, and we work quite rapidly when it comes to clinical efficacy, much quicker than a single-stranded construct. That is very clear. And then if you don't use the right dosage from a single-stranded construct, your efficacy is slow, it takes a while, and it may not even process. So those are some of the questions I think that have to be answered between the two constructs over time.

Thank you so much.

Thank you. The next question comes from Keith Tapper from BMO Capital Markets. Please proceed with your questions.

Hey, guys. Thanks for taking my questions and appreciate the execution across the program. Just trying to frame for investors the motivation for the high-dose co-work given the potential safety trade-off and really an absence of mature low-dose data in pediatric patients. Maybe could you remind us of expectations for the higher dose? Are we looking for upside to efficacy, durability, biodistribution, or a broadening of the patient population with two doses possibly moving to approval? And then from where we are today, I guess could you characterize the higher dose as experimental, exploratory, or necessary for competitiveness? Thanks.

Yeah, we decided to, when we picked the doses,

we see in preclinical data that there should be benefit to go to the 1D to the 15, based on all the preclinical work that we've done. And given the fact that we have, you know, double that, 2X that safety margin in our tox studies, you know, we feel, you know, we feel encouraged about the benefit risk. And I think that utilizing the intrathecal approach, assuming that you have equal biodistribution, in our view, the data that we put out preclinically and more importantly clinically support the biodistribution, intrathecal is, if not the safest, one of the safest ways to administer therapy to target the benefit and minimize the risk. So, you know, we're very pleased with what we've seen at the low dose. And it's our view that at the high dose, there is a relatively very low likelihood of any type of safety issue. And there is a better than, you know, there is a good chance that we're going to see incremental benefit that the patients are going to get derived by going to that dose. So for us, it's a very easy calculus to say, let's go to the high dose. And I can tell you, you know, in the IDMC meetings, you know, we continue to show high versus low dose, looking at all of the different, you know, parameters that are collected, whether it's liver function, platelets, all that kind of stuff. And, you know, we've seen essentially no difference in the two. So, again, that's why we feel good about things and have decided to, you know, to move the high dose even, you know, earlier than we were supposed to based on the protocol. And, of course, the IDMC supported that recommendation.

Okay, great. That's helpful. And just one follow-up, if I could. Just how should we think about the more mature adult clinical data that we have in terms of translatability to the pediatric cohort? just maybe in context of baseline characteristics and the original goals of the adult trial, and then considering differences in brain development and disease stage for the adults. Another way, do you have different expectations for pediatric versus adult responses to treatment? Thanks.

Well, I think, keep in mind, when we started the adult trial, I think the consensus view was we wouldn't see any efficacy. That was kind of what the KOL community felt, and You know, within four, actually within two weeks, you know, sleep normalized. Seven days. Seven days was, okay, seven days. And, you know, within six weeks, gross motor function improving were milestones being achieved that, you know, hadn't occurred in over eight years, essentially. And, you know, what we've seen when we look at the high-dose data is that the patients do seem to strengthen over the course of time, right? And so sometimes, like the CGIIs, you know, sometimes the scale will get better, and the adults, sometimes it might stay the same. But what's happening to the patient, the activities of daily living, the functional gains, those are improving over time. seizure reduction. That's improving over the course of time. And so the way we've described it is that in the adult population, you see early benefits, early clinical improvements and functional gain. And then over time, those are either sustained or they get better. And so it's our expectation in the pediatric group that that should also be the case. It should follow a similar pattern. And so we were very encouraged with the early data that we put out in June. You know, in eight weeks, we had, you know, a patient with a two-point improvement in CGI. You know, that's fantastic. And so 50% of the patients had a two-point improvement. 50% had a one-point improvement. And then we were seeing changes occur in terms of function, right? I mean, one of the girls got her ability to use her thumb and pincer grasp back after having not had it for five years. Like that's incredible. And so it's our view that those patients should get better over the course of time as they get stronger, they get used to having certain skills. The socialization aspect also, you know, with what we've seen in the adults, And even in the early data of the pediatrics got better over the course of a few months, we would expect that to do the same. So, you know, it's kind of like you think about two possibilities, you know, with the pediatric patients that I feel pretty good about is I would hope, and I'm hoping based on what I've seen in the adults, that the pediatric low-dose data looks even better over the long term, and then that the high dose looks even better, both in the short and the long term than the low dose. So again, that's why we're so excited about 2025, because I think the teams worked hard to put us in a position with regulators, with opening multiple sites. I mean, we're not just getting our data from one site. You know, we've now got five sites that are active and enrolling, and we've dosed you know, patients at three of those five with the other two coming online here, well, they're online. It's just getting to the dosing that we've got scheduled already. So we feel good about where we are and where the program's going.

We look forward to the game continuing to be played.

Thank you very much. Ladies and gentlemen, we have reached the end of the question and answer session. And I'd now like to hand the call back to Mr. Sean Nolan for closing remarks. Thank you, sir.

I just want to thank everyone for taking the time this evening to hear the update and look forward to any follow-up questions. Take care and have a good night.

Thank you. Ladies and gentlemen, that does conclude today's conference. Thank you very much for joining us. You may now disconnect your lines.