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spk15: Greetings and welcome to the Tayshia Gene Therapy's second quarter 2024 earnings call. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Haley Collins, Director and Head of Corporate Communications and Investor Relations. Thank you. You may begin.
spk10: Thank you. Good morning and welcome to Tayshia's second quarter 2024 financial results and corporate update conference call. Earlier today, Tayshia issued a press release announcing financial results for the second quarter ended June 30th, 2024. A copy of this press release is available on the company's website and through our SEC filing. Joining me on today's call are Sean Nolan, Tayshia's CEO, Sukumar Nagandran, 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 relating to the therapeutic and commercial potential of TASHA-102, including the reproducibility and durability of any favorable results initially seen in the patient's dose to date in clinical trials to positively impact the 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 timelines for our clinical trials and reporting results therefrom, and our current cash resources supporting our planned operating expenses and capital requirements into the fourth quarter of 2026. These statements may include, but are not limited to, the expected timing and results of clinical trials for our product candidates and other clinical and regulatory plans, and the market opportunities for those programs. This call may also contain forward-looking statements relating to Tayshia'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 Tayshia's actual results to differ materially from those stated or implied in such forward-looking statements. These risks include uncertainties related to the timing, and results of clinical trials of and regulatory interactions for our product candidates, our dependence upon strategic alliances and other third-party relationships, our ability to obtain patent protection for our discoveries, limitations imposed by patents owned or controlled by third parties, and the requirements of substantial funding to conduct our research and development activities. For a list and description of the risks and uncertainties that we face, please see the reports we have filed with the SEC including in our annual report on the Form 10Q, the full year ended December 31st, 2023, in our quarterly report on Form 10Q for the quarter ended June 30th, 2024 that we filed today. This conference call contains time sensitive information that is accurate only as of the date of this live broadcast, August 12th, 2024. TASHA undertakes no obligation to revise or update any forward looking statements to reflect events or circumstances after the date of this conference call. except as may be required by applicable securities laws. With that, I would now like to turn the call over to our CEO, Sean Nolan.
spk14: Thank you, Haley, and welcome, everyone, to our second quarter 2024 Financial Results and Corporate Update conference call. Today, I will begin with a brief update on our recent activities and then, Sukku, Our president and head of R&D will provide an update on our lead TASHA 102 program in clinical evaluation for Rett syndrome. Cameron Alam, our chief financial officer, will follow up with a financial update, and I will provide closing remarks and open the call up for questions. In the second quarter of 2024, we made strong progress across the TASHA 102 program in clinical evaluation for pediatric, adolescent, and adult patients with Rett syndrome. This included reporting encouraging safety and efficacy data from the low-dose cohort in both our Reveal Phase 1-2 trials, initiating the high-dose cohort, expanding our pediatric trial into Canada, and strengthening our balance sheet. With this progress, we believe we are well-positioned to execute across key value-creating milestones in our CASIA 102 program. Our goal is to develop potentially transformative therapy options for all patients suffering from Rett syndrome. We remain steadfast and focused on clinical trial execution and data collection across a broad range of ages and stages of patients with Rett syndrome, which will further inform our discussions with regulatory authorities on the development plan for the next phase of our studies. As a reminder, Rett syndrome is a rare neurodevelopmental disorder that afflicts an estimated 15 to 20,000 patients in the United States, European Union, and United Kingdom. Currently, there are no approved disease-modifying therapies that 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 results in the neural network dysfunction and leads to multi-system complications. It's characterized by loss of communication and hand function, slowing and or regression of development, motor and respiratory impairment, 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. Artesia 102 gene therapy candidate is a one-time intrathecally delivered treatment designed to address the underlying cause of the disease. Rett syndrome is challenging to treat with traditional small molecule and gene therapy approaches due to the random X inactivation and subsequent mosaic expression pattern of MECP2 that results in a mixture of cells that are either deficient in MECP2 or express MECP2 normally. We believe TASHA-102, equipped with the novel MI Rare technology, has the potential to appropriately address this challenge by mediating MECP2 expression in the central nervous system on a cell-by-cell basis to overcome the risks associated with both under- and overexpression of MECP2. Recall, we have two ongoing Phase 1-2 reveal trials evaluating TASHA-102, an adolescent and adult trial taking place in Canada and the U.S. for patients 12 and older with stage 4 RUT syndrome, which is the most advanced stage of the disease, and a pediatric trial taking place in the U.S. and U.K. with recent clearance in Canada for patients 5 to 8 years of age with stage 3 Rett syndrome. We are currently enrolling patients in Part A, the dose escalation portion of both trials, which is evaluating two dose levels of TASHA-102. Part B of the pediatric trial, the dose expansion portion, will evaluate TASHA-102 in two age cohorts, an expanded five to eight years of age cohort and a three to five years of age cohort. Two patients have been dosed in cohort one, which is evaluating the low dose of TASIA-102, 5.7 e to the 14 total vector genomes in each trial. At the 2024 Rett Syndrome Foundation Rett Syndrome Scientific Meeting in June, we reported encouraging preliminary data from cohort one in our pediatric trial and longer-term data from cohort one in our adolescent and adult trials. which demonstrated a well-tolerated safety profile and improvements across consistent clinical domains impacting daily activities in the adult and the pediatric patients treated with the low dose of TASHA-102. We are pleased by the consistent clinical response demonstrated across multiple areas of disease, including autonomic function, seizures, gross motor skills, fine motor skills and hand function, and communication and socialization in both adult and pediatric patients with different genetic mutation severity. We look forward to continuing to evaluate the clinical impact of the low dose of TASHA-102 over time. Following review of these data, the Independent Data Monitoring Committee, or IDMC, approved our request to dose escalate early in both reveal trials. Therefore, dosing in cohort one of both trials is complete. Expediting dose escalation is an important step in our development plan as advancing earlier to the high dose accelerates our ability to further inform our clinical development and regulatory strategy for the next phase of our studies. With cohort one complete, we've turned our focus to dosing patients in the high dose cohort across both are reveal trials, and building on our promising preliminary low-dose data set from both adult and pediatric populations. We dose the first patient in cohort two of our adolescent and adult trial, which is evaluating the high dose of TASHA-102, which is 1E to 15 total vector genomes. We are pleased to share that the high dose of TASHA-102 was generally well-tolerated with no serious adverse events for dose-limiting toxicities as of the patient's initial six weeks assessment. Following review of these data, the IDMC provided clearance to proceed with the dosing the second patient in cohort two of the adolescent and adult trial and the first patient in cohort two of the pediatric trial earlier than planned. Subsequently, we enrolled the second adolescent adult patient and the first pediatric patient in cohort two across both trials. Dosing of both patients is scheduled to occur in the third quarter of 2024. Lastly, we strengthened our balance sheet with the recent completion of a public follow-on offering that resulted in total net proceeds of $76.8 million. We expect the net proceeds to extend our anticipated cash runway into the fourth quarter of 2026 to support the continued development of our TASHA 102 program. Importantly, this capital infusion allows us to build on our preliminary TASHA 102 clinical data set in the adult and pediatric patients and enables us to focus on execution as we endeavor to deliver on key value-creating milestones. We are moving forward reporting cohort-based updates with more mature data sets in order to provide more fulsome updates on our clinical data. In line with this decision, we plan to report safety and efficacy data from the high-dose cohorts and an update on the safety and efficacy from the low-dose cohorts in both our adolescent and adult trial and our pediatric trial in the first half of 2025. With our balance sheet strengthened and cash runway extended, we believe we are in excellent position to execute on our key upcoming milestones. I will now turn the call over to Sukhu to provide a more in-depth discussion of our TASHA-102 program.
spk09: Sukhu?
spk12: Thank you, Sean, and good morning, everyone. I'm pleased to provide an update on our TASHA-102 gene therapy program in clinical evaluation for REC syndrome. We will start with our reveal phase one, slash two, adolescent and adult trial. As Sean mentioned, we have completed dosing in cohort one, which included two adult patients who received low dose of TASHA-102. TASHA-102 demonstrated an encouraging safety profile with no serious adverse events related to TASHA-102 or dose-limiting toxicities as of the week 52 assessment for the first patient and the week 36 assessment for the second patient. Additionally, long-term efficacy data showed a continued durable response with sustained and new improvement across multiple clinical domains and efficacy measures at week 52, following the completion of the steroid and serolimus taper for the first patient, and at week 25, following the completion of the steroid taper for the second patient. Both adult patients demonstrated partial restoration of function or improvement in areas of disease that were lost in early childhood, which is not typically observed in the natural history of Rett syndrome. While the disease severity differed between the two adult patients, the improvements were demonstrated in consistent clinical domain as early as four weeks post-treatment in both patients, which was sustained through longer-term assessments. This included improvements in autonomic function, seizures, gross motor skills, fine motor skills, and hand function, and communication and socialization which can translate to beneficial impacts on quality of life and daily activities for patients and caregivers. We look forward to continuing to evaluate the patients over time for potential further improvement. These improvements are supported by clinical observations reported by the principal investigator, video evidence, and multiple clinical and caregiver reported efficacy measures. The well-tolerated safety profile and durable response in both adult patients with the most advanced stage of disease is encouraging and supports the transformative potential of TASHA-102 across multiple genotypes of patients with stage 4 Rett syndrome. Now let's turn to our ongoing reveal phase 1-2 pediatric trial, evaluating the safety and preliminary efficacy of TASHA-102 in females five to eight years of age with stage three Rett syndrome. While this trial captures an earlier stage of disease, it is important to understand that most of these patients require lifelong caregiver dependence and they're present with hallmark symptoms and many advanced manifestations. Enrollment criteria require patients to be post-regression and have entered a stage of stabilization meaning there have not been any identified loss of skills as in the last six months prior to treatment. Quote one, evaluating the low dose of TASHA-102 to complete TASHA-102 demonstrated an encouraging safety profile with no serious adverse events related to TASHA-102 or dose-limiting toxicities as of the week 22 assessment for the first pediatric patient and week 11 assessment for the second pediatric patient. Similar to the adult patients, the pediatric patients possess different disease severity and genetic backgrounds. Importantly, both pediatric patients demonstrated initial improvement across the same clinical domains we observed in the adult patients, with early evidence of developmental gains following treatment at weeks 12 and 8, respectively. This included improvements in autonomic function, seizures, gross motor skills, fine motor skills, and hand function, and communication and socialization, which can translate to beneficial impacts on quality of life and daily activities for patients and caregivers. We look forward to continuing to evaluate the patients over time for potential further improvements. These improvements are supported by clinical observations reported by the principal investigator, video evidence, and multiple clinical and caregiver reported efficacy measures. Rett syndrome is a highly complex syndromic disease. The critical takeaway is that we believe these early improvements and signs of developmental gain observed across consistent areas of disease in the adult and pediatric patients are very encouraging and support the potential of TASHA-102 to bring meaningful benefit to patients and caregivers. We look forward to collecting longer-term data on the low-dose and moving to the high-dose cohort across both revealed trials, where the totality of the data we collect will further inform our developmental plan for the next phase of the study. I will now turn the call over to Cameron to discuss our financial results. Cameron?
spk08: Thank you, Sukhu.
spk13: Research and development expenses were $15.1 million for the three months ended June 30th, 2024, compared to $19.8 million for the three months ending June 30th, 2023. The $4.7 million decrease was primarily due to a milestone fee payable to Abiona Therapeutics during the three months ended June 30th, 2023, following the dosing of the first patient and the reveal phase one to adolescent and adult trial. General and administrative expenses were $7.3 million for the three months ended June 30th, 2024, compared to $6 million for the three months ended June 30th, 2023. The increase of $1.3 million was primarily due to $0.9 million of higher non-caste stock-based compensation expenses and $0.4 million of higher consulting, professional fees, and other expenses. Net loss for the three months ended June 30th, 2024 was $20.9 million or 9 cents per share compared to a net loss of $24.6 million or 38 cents per share for the three months ended June 30th, 2023. As of June 30th, 2024, Caesha had $172.7 million in cash and cash equivalent. The company 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 Sean for his closing remarks. Sean?
spk09: Thank you, Cameron.
spk14: Overall, we are encouraged by the well-tolerated safety profile in patients who receive the low dose of HACIA-102 and the clinical effect being demonstrated across consistent clinical domains in the pediatric and adult patients with stage 3 and 4 disease treated with a low dose of TASHA-102. We believe these cohort 1 data validate our novel construct and support the potential of TASHA-102 to address the significant unmet medical need in Rett syndrome for a broad range of ages and stages of patients. We are pleased the high dose of TASIA-102 was generally well tolerated as of the initial six-week assessment in the first patient treated in cohort two of the adolescent and adult trial. IDMC approval to proceed with dosing the second adolescent adult and the first pediatric patient earlier than planned in the high dose cohort of our revealed trials enables us to build on the promising preliminary low dose data that demonstrated relevant clinical effect across key clinical domains impacting activities of daily living in the adult and pediatric patients treated with TASHA-102. As we move to the high dose, we continue to look for a similar pattern of consistent improvement across adult, adolescent, and pediatric patient populations. Looking ahead, we remain focused on clinical trial execution and data collection. The totality of of the data we collect from the low and high dose in Part A will inform further our discussions with regulatory authorities on our development plan for the next phase of the trials. We look forward to reporting safety and efficacy data from the low-dose and high-dose cohorts in both adolescent and adult trials and the pediatric trial in the first half of 2025. With that, I will now ask the operator to begin our Q&A session. Operator?
spk15: Thank you. If you'd like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. To allow for as many questions as possible, we ask that you each keep to one question and one follow-up. Thank you. Our first question comes from the line of Kristen Kliska with Cantor Fitzgerald. Please proceed with your question.
spk01: Hi, good morning, everyone. Thanks for taking my questions. So when you report the high-dose data next year, what, in your opinion, is going to be the best way to determine if there is a dose response? We already did see some profound changes from the low dose, and the definition of improvement really differs from patient to patient, given the heterogeneity and different domains impacted sometimes. But is there a clear way that you're looking to try to measure this?
spk14: Thanks, Kristen. I'll take that initially, and Suku, feel free to jump in on this. But I would say, first of all, when you take a look at the preclinical data, at the high dose, there was an increase in survival. There was an improvement in gait abnormalities, which is kind of a surrogate for overall health. And obviously, when you go into the high dose, you're going to be pushing more volume, should have greater biodistribution, greater transduction. And, you know, we would expect, you know, first and foremost, that we see consistent effect across all the clinical domains that we've talked about. I mean, I think at this point, the low dose is established. Frankly, it's established a high hurdle bar. I think we're in a good place with the high dose, and we expect that this would effectively build on that. I would say, you know, based on the preclinical data and the translation, the always difficult translation of it, you know, exactly what's that going to look like in adults, you know, it's difficult to predict both, I would say, the overall magnitude and the temporal aspect of things. So, you know, we expect that there should be an observed improvement, and the question is really, do we see it early on, or does it take more time to manifest? You know, ultimately, we're going to have to run the experiment, you know, to really fully answer your questions. Again, I would say that from a comparative perspective, we're utilizing the same endpoints, the same clinical observation mechanisms, the same ways to capture the data. So we're trying to keep all that as consistent as possible. And, you know, once we have enough data in patients over a longer course of time, you know, we feel confident we'll be able to make the determination, you know, of if there is a drug effect. But with that, I'll turn things over to Suku just to see if there's anything else he would add.
spk12: Yeah, thanks, Kristen and Sean. So, you know, you've raised a very interesting question. Usually in drug development, right, you do look for the highest dose that gives you the greatest efficacy and safety, and that seems to apply for gene therapy. And in Rett syndrome, I guess the question is there is a drug on the market. It's a small molecule. there's still significant unmet medical need. And as you point out, Kristen, with such a heterogeneous disease, a low dose is actually showing consistent response that I think that parents and patients will appreciate. But at the same time, though, if you look at some of our preclinical data, if you look at some of the work Sir Adrian Bird and others have done, there is justification to go to the high dose and see if the high dose will also give us a consistent and further better response than the lower dose. And I'll leave it open-ended like that because it's only the data that will eventually drive us to eventually the endpoints, the ideal dose that we're going to get approved by the regulator, and a dose that will truly make a difference in this very complex disease and patient population.
spk08: Thank you. Thanks, Kristen.
spk15: Thank you. Our next question comes from the line of Salveen Richter with Goldman Sachs. Please proceed with your question.
spk11: Hey, good morning and thank you for taking our question. This is Elizabeth on for Salveen. Wondering on the regulatory front if you could comment on how the dialogue is going with the regulatory authorities and if there's any additional color you can share about the nature of those conversations to date. Thank you.
spk14: Thanks, Elizabeth. What I would say on the regulatory front is that we do have an upcoming Type B meeting as a result of the RMAT designation. So I would say there would be subsequent updates on that in the future. Our goal at this meeting, there are several goals, but I would say, you know, one of them is to basically align around the cadence of how we're going to interface with the agency. you know, focus on some of the priorities that we're going to want to continue the dialogue that we've had historically. So that would be the data that we have as it comes in. You know, we want to make sure that they're seeing the data in an appropriate fashion, but they're seeing it as real time as possible. And that, plus the additional work that we're doing on natural history, it will be information that we share with them that ultimately will inform you know, more thinking on both sides and our alignment around trial design and endpoints for Part B. So the next step in that journey is actually coming up in the relatively near future, and we will certainly provide updates on that, you know, in the coming quarter.
spk08: Thank you. Thank you.
spk15: Thank you. Our next question comes from the line of Chris Raymond with Piper Sandler. Please proceed with your question.
spk07: Hey, thank you. Just a question on what you're going to present, I guess, in the first half of next year in terms of time on therapy. Just looking back at the last update, I think the low-dose pediatric update, you had some variability. I think one patient was 12 weeks post-dose. Another one was eight weeks post-dose. Are you looking to standardize that follow-up, and what is that time point, if you can tell us? Thanks.
spk14: Yeah, Chris, I would say this. Number one, I think the fact that even at those early time points, we were seeing signs of preliminary efficacy is super encouraging to us. And we felt the right thing to do to really provide more line of sight and clarity was is generate more data over the course of time so that we can give you guys a more fulsome update. So I think the easiest way to answer that sitting here today would be that we would like, you know, so the way things are right now for the high dose, right, we would have three patients in each cohort, right, so the pediatric cohort and the adolescent adult cohort, and that that For the majority of those patients, there's a minimum of six months would be the way that I would think of it. I think that would be the minimum data set that we would plan to go out with. And I think that hopefully would give everyone a better line of sight, more consistency, et cetera. So that's how we're thinking of it right now. We can certainly work to refine our thinking as time moves on, but that's the minimum bar that we see right now. Hopefully that's helpful.
spk08: Yep. Very much, thank you very much. You bet.
spk16: Thank you.
spk15: Our next question comes from the line of Gil Bloom with Needham & Company. Please proceed with your question.
spk03: Good morning and thanks for taking our question. So, as it relates to discussions that you are going to have with the FDA over time, is there a situation in which, you know, a potential endpoint may depend on what the patients have at baseline, you know, for example, If patients have a significant seizure burden, could they be assessed on that? Just trying to understand how to view a heterogeneous disease like that.
spk09: Thanks. Gil, great question.
spk14: I would say a couple things and certainly turn it over to Suku for his thinking. You know, it's an evolving situation is probably the best way to say it. I think when you do have a disease that's heterogeneous, you are always trying to think of a way that how do you best standardize what you're capturing? So, you know, while I really do believe that the point you're making is something that we, I can just tell you, we are taking into our calculus, and I can see a world where if you're able to restore or partially restore a lost function, like we've seen in the low-dose data, right? We've seen an adult There was no expectation of having an effect sit unassisted after not being able to do that for 10 years. We clearly saw in those videos, at least in our opinion, that there was much greater communication and socialization in that same patient. Or as you point out, reduction in seizures, the ability to grasp in the pediatric patients, the improvements in the breathing. Those clinical effects are there. I think what we're working to refine is there may be a situation where a primary or co-primary endpoint is more standardized. You might focus more on really consistently measuring improvements, let's say, in fine motor function, looking at the hands or gross motor function. But I do think also capturing the data on the what I call the restoration of function or, you know, regaining of a milestone, I think that would be at a minimum, you know, very supportive data that I think would be highly impactful to the agency, the payers, et cetera. So, you know, we've been pretty consistent, I would say, in how we're trying to think about ultimate endpoint selection. And when I step through, right now is just a high level view of strategically how we're thinking of it. And we're working as we collect the data, both in terms of our patient data at the high dose, also in terms of natural history data that we've been analyzing. I think that should help further put a fine point on what would be the best primary or potentially co-primary and also allowing us to, you know, include, you know, potentially as a secondary or supportive, you know, these ideas of capturing the restoration of effect. So, Sukhu, would you add anything to that?
spk12: Yeah, what I would add, Sean, is that as we all know, it's a complex heterogeneous disease, but we've shown so far over a timeframe in the patients treated with the low dose in the pediatric study and the adult study, there are consistent positive clinical impact of our gene therapy. But then the question that I think Gil brought up is a really important one because as we get our natural history data from our databases back, and there are certain clinical features that actually could be good comparisons for us regardless of clinical trial design when we have our Part B meetings, those variabilities within a clinical feature that our gene therapy is consistently helping to treat is, I think, also going to be important because in our studies so far, we've shown that these patients have seizures, right? 80% to 90% of patients, I think, have seizures. But there is a range of seizures. I mean, some patients may have three seizures a day. Others may have one seizure a quarter. So the question becomes, how do you assess the clinical impact of a seizure based on frequency and medication dose versus, let's say, hand function, which is consistently lost to the extreme. So I think these are things that we have to continue to gather data on, and hopefully our clinical trial design for the Part B component will allow us to assess them hopefully over a shorter period of time to show that we can actually have a positive clinical impact for this patient population. So I guess what I'm really saying, Sean, is we, are gathering the data and hopefully we can put it all together for a very complex disease where I think we have a pretty good gene therapy.
spk16: Thank you.
spk15: Our next question comes from the line of June Lee with Truist Securities. Please proceed with your question.
spk02: Thanks for taking our question. So, can you help us understand your 180-degree on the data disclosure strategy? You know, efficacy from your first patient, the patient with the best efficacy so far was shared at week six, yet the data from the high-dose cohort passed the six-week mark, but you're reserving that for later. Anything you can share on efficacy would be helpful there, and, you know, also, Help us understand what you mean by fulsome, like how many patients for data you think is sufficient to get a clear picture, and how much data would you have by one cue that passes that definition of fulsome data? Thank you so much.
spk14: So, June, just to be clear, you're talking about the fact that the very first patient we reported on was it six weeks? And now you're saying we're going to longer-term data set. I just want to make sure that's what you're... Yes, yes.
spk02: My understanding is that the first patient, that person, that patient's efficacy was shared around that six-week mark. And just curious, you know, I understand the need to hold off until you have some fulsome data, but, you know... and your change in data strategy, data disclosure strategy, but anything you can share on the high-dose cohort?
spk09: Yeah, sure. I would say a couple things.
spk14: First of all, one major change is the status and the fortune of the company in terms of balance sheet, right? I mean, when we reported the first patient out, to be totally frank, I think you all know this, the company was in an existential situation, and we were fortunate, frankly, that the first patient responded as quickly and as pronounced as they did. And that allowed us to go ahead and finance the company and put us in a much different situation. And then over the course of time, I think you can see that there's been an evolution of more patient data being presented. And we ultimately got to the point where we just felt that, you know, in a more traditional fashion, you know, the easiest thing to do and the more robust way to present the data would be to present, you know, information on a cohort by cohort basis. And, you know, I felt an obligation to the investors that came in on the one patient worth of data. They supported us. You know, many of of you, you know, supported us with that data because it was so, you know, transformational for that patient. And so I personally felt an obligation to, for a period of time, you know, show data earlier than I normally, you know, would have. You know, fortunately from my perspective, you know, the data that we've continued to share has shown early, just like that first patient, onset of action and consistent effects. I mean, even in the data that we just showed at IRSF and the pediatric patients at eight weeks and 12 weeks, you know, I'll put that data up against anything, you know, that people have probably seen, right? I mean, where have you seen video of people getting restoration of function? And we can argue on the margins, you know, the standardization of the videos and things like that, and I acknowledge that, and that's what we're trying to work to standardize you know, as we move forward. And in particular, we must have it all standardized for Part B. But the point is, you know, there was clearly an effect, you know, in both patients that I think anyone can see. And so, as we continue to think about it as a management team, we just felt, okay, you know, now we're stepping in, you know, we've demonstrated, I would say, you know, very significant effect with the low dose. We got the okay from the IDMC to stuff to the high dose. And so now we have an opportunity to present more data over time. And I think, you know, people looking at something, you know, I would say for us a minimum threshold would be if we have three patients in the high dose cohort in the pediatric patient and we would have three patients in the pediatric population, that at least the majority of those patients are over six months of time elapsed. In our view, we felt that that's a wholesome update, right? I mean, you're starting to see if you're getting consistency, durability, et cetera, and we think that is a better way for everybody to be able to evaluate you know, what we're seeing as we step into the high dose. So we felt it was a clean break, you know, going from the low dose to the high dose. We felt it was an evolution in how we've been reporting. And, you know, that's why we think ultimately this is the, you know, the best thing for all involved, you know, to see the data, you know, in a more, you know, cohort batch basis. So hopefully that gets to what you're asking, June.
spk02: Yes. Actually, that makes a lot more sense, and I really appreciate your responses. Thank you so much, and we look forward to data in one or two.
spk08: Of course. Thank you.
spk15: Thank you. Our next question comes from the line of Maureen Raycroft with Jefferies. Please proceed with your question.
spk05: Hi. Thanks for taking my question. Does the timeline change to data impact your timeline for an end-of-phase one meeting with FDA for the randomized pivotal? I guess, could that still happen in first half 25 or more likely the second half of the year? And do you anticipate the first half 25 data would still be sufficient to bring to FDA for alignment on a randomized phase two pivotal, or would you need additional follow-up?
spk14: Yeah, Maury, great question. I mean, the way we're thinking about it is that, you know, for us to sit down with the FDA and have a fulsome discussion around you know, what Part B design looks like. I would say, number one, we want to complete cohort two dosing, right? So we want to have that data. We want to complete our natural history analysis. And those are, I would say, those are key data points that we need. Now, how much data do you need? I would say it's early to say. You know, is it, you know, three months of data, six months of data. I think that's why we're guiding them more in our own mind. Can we sit down with the FDA in the first half? That's what we intend to do. But in terms of precisely what's the right level of data to bring them, I'd say it's a little bit early on that. And really what's going to help facilitate getting a better line of sight to that is going to be leveraging the RMAT process. So as I said, that starts this quarter with our clinical type B meeting that we have. And we'll actually be talking about things more broadly than just clinical. But the point is, you know, we will inform them with information as we have it. So as I said earlier, you know, as we have the natural history data completed, You know, we'll share that with the FDA and what we think that does to our clinical development plans and potential endpoints as we generate data from the high dose and longer-term data from the low dose. You know, we'll certainly share that with the FDA in a more real-time basis, leveraging the RMAT designation. So, you know, all that is leading and culminating to hopefully, you know, more detailed formal discussion in the first half. But again, I just want to caveat that exactly how much data we need and exactly when that happens, you know, I think it's a little early to tell, but we should have more line of sight, you know, in the next quarter or so. Hopefully that gives you a little perspective.
spk09: Yep. Yeah, very helpful. Thank you.
spk08: Thanks.
spk15: Thank you. Our next question comes from the line of Yanan Zhu with Wells Fargo. Please proceed with your question.
spk17: Great. Thanks for taking our questions. So based on what you just articulated about the maturity of the data, it feels like it's more the first half 25 guidance is probably going to be more second quarter than first quarter. Is that the right takeaway? And also given that you have dosed just one of the six patients today, one of the six across the two high dose cohorts today. Do you think you could have timely enrollment and dosing to ensure the data could be available in first half 25? And if you can comment on the safety waiting period, is that 42-day period true? across all six patients in those two cohorts. Thanks.
spk14: True thing, Yanen. So, again, we got into the first half to give ourselves flexibility. Your point on the stagger is a good one. And I would say this. I mean, per the protocol, at this time, the stagger is 42 days between patients. I would just simply say at this point in time that we have this topic very much in mind. And, you know, I would say the guidance that we've come up with we feel very comfortable with. And so it is possible that you could see some changes down the road to the frequency in which we might be able to dose patients. But that is a future-looking comment. So again, first half is the way we're thinking about it right now, and we're confident in stating that, given everything we know today.
spk08: Got it. Thank you. Thank you.
spk16: Thank you.
spk15: Our next question comes from the line of Jack Allen with Baird. Please proceed with your question.
spk06: All right. Thanks for taking the questions, and congratulations on the progress. My first one was on the high-dose patients that have been enrolled in the study today. It seems like there are about three patients that have been enrolled. In the low-dose cohorts, we noticed a difference in the severity of patients depending on their deletions. Somebody, you can comment as it relates to the baseline characteristics of these high-dose patients to some extent. And then my second question is around the low-dose data we expect in the first half of next year. I'd just love to hear the team's thoughts on any comments around how we think that data set should evolve over time. I think there had previously been some talk of, I guess, restoring MECP2 and regaining of skills over time and kind of a teaching bias over time. But I'd love to hear any thoughts you have around the long-term low-dose data as well.
spk09: Sure.
spk14: You know, Sukhu, I would ask you to take those two questions. You know, I think the first was, you know, are there any baseline characteristics that we can talk about in the high-dose patients that have been enrolled? We probably have to just stick to what CGISs are. I think that's all we've got to do, but you can talk about that. And then the second one is just expectations potentially on progress of low-dose patients over time.
spk12: Yes. So, Sean, I mean, to answer the first question, So if you think about consistency, though, yes, the CGIS, right? I mean, these patients, for protocol, depending on which study they are, they tend to fall into a range of four to six. And as you all know, in Rett syndrome, the severity may sometimes drive the response, and there could be limitations to that as well. But what is more important is that there are clinical features, though, in the low-dose patients, which I think are consistent. So, autonomic dysfunction, I mean, for example, many of these patients have vascular abnormalities of the upper and lower extremities. Many of these patients did have respiratory abnormalities, the apneic spells and the hyperventilation. Seizures were pretty common. Loss of hand function, as we know, is very common. In a sense, loss of fine hand, motor function and gross motor function and the repetitive movements etc. I guess my point is there are certain clinical features that will always be there and I think when you talk to the experts they do confirm this but what we are doing is we have natural history databases that we're looking at which hopefully will also further support what we need to do for the future if this consistency is proven. So all I can say is that you know you have to stay tuned and Having said that, then if you look at the high-dose patients, I would anticipate you would see very similar commonalities in the clinical presentations that exist in Rett syndrome patients, the hand function, I guess you could say social withdrawal, maybe seizures, et cetera, et cetera. So these will all be there. And then the other piece of the puzzle is, you know, when you have whatever the mutation is, my sense mutation, a nonsense mutation or a massive deletion, which then results in a horrible or severe clinical presentation, then the question becomes, you know, any gene therapy due to the mosaic is not the disease. What is the greatest impact it can have and on which clinical features? So these are things that are still collecting. And I would say that, again, I would assume in gene therapy, if you have a product that has significant clinical impact, You know, the commonalities of the features will only be seen in a few patients, right, because you're dosing five, six, seven patients to move from part A to part B and then part B to other studies if that's what needs to be done. Sean, I mean, I don't know whether that helps answer the question, but the answer to the question for me is not, it's complex. And then the second question was, you know, I lost my trend there, Sean.
spk14: You answered the question on the baseline characteristics, right? It is going to be CGIS between four and six. That's really all the detail that we've provided thus far. There are going to be genetic differences in all these patients. And in terms of low-dose expectations, I think just at a high level to build on what you're saying is that over the course of time, at least the older patients, initial patient that we reported on, over time, you know, she did gain improvements, you know, further improvements in different aspects, whether it's getting stronger from a gross motor perspective, you know, improvement in hand function over the course of time, you know, improvements in ability to communicate. So I think, Jack, you know, as you think about the low-dose patients in the pediatric, you know, that we just gave preliminary data on, you know, our hope would be that we would see, you know, progress like that and hopefully, you know, potentially, you know, a little bit better just given the fact that, you know, they're younger in age. So, you know, we'll have to, again, we're running the experiment and we look forward to reporting that data out in the first half of next year. So hopefully that gets at what you're asking, Jack.
spk08: Yeah, definitely. Thanks so much for the call. Thank you.
spk15: Thank you. Our final question this morning comes from the line of Sylvain Turkin with Citizens JMP. Please proceed with your question.
spk04: Good morning and thanks for taking my question. Are there any more details on the SAE that you observed in the pediatric patient that was related to the immunosuppressive regimen that we haven't been or haven't heard before? And then on the safety committee, Obviously, they accelerated your ability to dose into a higher dose. At what point could they accelerate or get rid of the stagger, the 45-day waiting period between patients? Thank you so much.
spk14: Sukhu, maybe you can take the first one. The second one relative to the stagger is really I think it's a discussion between the company and the IDMC to talk about when they're comfortable making that type of a recommendation. So we have a view in our mind about what would be a sufficient and appropriate amount of data to potentially have that type of discussion, and it's predicated. of course, on having continued good safety results. So hopefully more to come on that in the future. And Suku, relative to the SAE that was not treatment-related, I don't know if there's more to add. I think the disclosure was pretty clear, and we haven't reported anything more, I think, because there had been a declared resolution of that from the PI. But just make sure I'm correct on that, please.
spk12: Yeah, Sean, if I can add, though, the whole issue of a stagger, I wanted to clarify, though, because remember our approach, I mean, is intrathecal. I mean, there are other approaches that IDMC and the FDA have been quite flexible on really shortening the stagger. For example, systemic gene therapy, where they are willing to consider it as long as the benefit of risk is appropriate, right? So I just wanted to throw that out there because it's important because, and that's what, you know, Dr. Peter Marks even wrote about last year. I think it was in Nature magazine because he was talking about why would you waste time on a first low dose in the sense as long as it's safe, you don't necessarily have to do all the patients as the protocol has defined. Then the second question around the safety, though, I think, Sean, I mean, as you said, we have given a fair amount of detail, and as it was not related to our product, I don't think there was any issue with the IDMC doing what it needed to do to move the program forward.
spk14: Yeah, so there's been no additional disclosure on the SAE. It resolved, and, you know, obviously we've moved ahead, as Sukru said, from a a dosing perspective.
spk08: Is that good for you, Sylvan? Perfect. Thank you. Thank you.
spk16: Thank you.
spk15: Ladies and gentlemen, that concludes our question and answer session. I'll turn the floor back to Mr. Nolan for any final comments.
spk14: Just appreciate everyone calling in and always happy to follow up with any additional questions offline. Thank you all and have a good day.
spk15: Thank you. This concludes today's conference call. You may disconnect your lines at this time. Thank you for your participation.
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