In a recent earnings call, Taysha Gene Therapies provided an update on their TSHA-102 gene therapy program for Rett Syndrome, reporting significant progress in their Phase 1/2 trials, including positive safety and efficacy data from the low-dose cohort. The company has initiated the high-dose cohort and expanded the pediatric trial into Canada. Financially, Taysha has strengthened its balance sheet through a public follow-on offering and reported a cash runway extension into the fourth quarter of 2026. The company discussed its strategy for data presentation and future regulatory discussions, aiming to align with FDA expectations and provide robust data updates.
Key Takeaways
- TSHA-102 has shown improvements in Rett Syndrome patients' motor skills, communication, and socialization.
- Positive results from the low-dose cohort in adult and pediatric patients.
- High-dose cohort initiation and expansion of the pediatric trial into Canada.
- Financial results: $15.1 million in R&D expenses, a net loss of $20.9 million, and $172.7 million in cash.
- Cash runway extended to Q4 2026, with plans to report further data in the first half of 2025.
- Upcoming regulatory discussions to further refine trial design and endpoints.
Company Outlook
- Aim to develop a transformative therapy for Rett Syndrome with no approved disease-modifying treatments.
- Plan to share safety and efficacy data from high-dose cohorts and updates on low-dose cohorts in 2025.
- Anticipate discussions with the FDA, using the RMAT designation to facilitate updates.
Bearish Highlights
- Reported a net loss of $20.9 million for the quarter.
- Serious adverse event occurred, although unrelated to the treatment and resolved.
Bullish Highlights
- TSHA-102 showed promising safety and efficacy in the low-dose cohort.
- Strengthened balance sheet through a recent public follow-on offering.
- Cash runway extended, sufficient to support operations until late 2026.
Misses
- The exact timeline and data requirements for FDA discussions are still uncertain.
Q&A Highlights
- Company is transitioning from individual patient data reporting to cohort-based updates.
- Plans to complete Cohort 2 dosing and natural history analysis before FDA meeting.
- Considering changes to the dosing schedule to potentially accelerate the trial timeline.
Taysha Gene Therapies (ticker: TSHA) remains focused on advancing their TSHA-102 gene therapy candidate for Rett Syndrome, a rare neurodevelopmental disorder. The company has successfully made progress in the low-dose cohort of their Phase 1/2 trials and is actively working towards regulatory alignment for future trial designs and data sharing. Despite a net loss, Taysha's financial position appears stable with a cash runway into the fourth quarter of 2026. The company is committed to providing more consistent and comprehensive data updates in the future and is open to addressing any further questions offline.
InvestingPro Insights
Taysha Gene Therapies (ticker: TSHA) has demonstrated a commitment to advancing their gene therapy programs, with positive clinical developments and a strengthened financial position. Here are some insights from InvestingPro that could further inform investors about the company's current status:
- InvestingPro Data reveals a substantial 96.39% revenue growth** over the last twelve months as of Q1 2024, indicating a strong increase in the company's financial performance. However, this is tempered by a **quarterly revenue decline of 27.52%** in Q1 2024, suggesting some variability in the company's revenue streams.
- The company's **market capitalization** stands at **$413.83 million**, which, when paired with its **high Price / Book multiple of 7.74**, signals that investors may hold the company's assets in high regard, despite the current lack of profitability.
- An **InvestingPro Tip** highlights that Taysha holds **more cash than debt** on its balance sheet, which is a positive sign for financial stability and may provide some reassurance to investors about the company's ability to fund ongoing operations and research initiatives.
- Another **InvestingPro Tip indicates that analysts do not expect the company to be profitable this year, which aligns with the reported net loss but is a typical scenario for many biotech firms in the clinical trial phase.
For those looking for a deeper dive into Taysha Gene Therapies, InvestingPro offers additional tips and metrics that can provide a more comprehensive financial picture. There are 9 more InvestingPro Tips available at https://www.investing.com/pro/TSHA, which can help investors make more informed decisions.
Full transcript - Taysha Gene Therapies Inc (TSHA) Q2 2024:
Operator: Greetings and welcome to the Taysha Gene Therapies 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. [Operator Instructions]. As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Hayleigh Collins, Director and Head of Corporate Communications and Investor Relations. Thank you. You may begin.
Hayleigh Collins: Thank you. Good morning and welcome to Taysha's second quarter 2024 financial results and corporate update conference call. Earlier today, Taysha issued a press release announcing financial results for the second quarter ended June 30, 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, Taysha's CEO; Sukumar Nagendran, President and Head of R&D; and Kamran 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 TSHA-102, including the reproducibility and durability of any favorable results initially seen in the patients dosed to date in clinical trial to positively impact the quality of life and also 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, in 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 opportunity for those programs. This call may also contain forward-looking statements relating to Taysha's growth, forecasted cash runway and future operating results, discovery and development of product candidates, strategic alliances and intellectual property as well as matters that are not historical facts or information. Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements. These risks include uncertainties related to the timing and results of clinical trials of and regulatory interactions for our product candidates, our dependence upon strategic alliances and other third-party relationships, our ability to obtain patent protection for our discoveries, limitations imposed by patents owned or controlled by third parties, and the requirements of substantial funding to conduct our research and development activities. For a list and description of the risks and uncertainties that we face, please see the reports we have filed with the SEC, including our Annual Report on Form 10-K for the full year ended December 31st, 2023 and our quarterly report on Form 10-Q for the quarter ended June 30, 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 12, 2024. Taysha undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities laws. With that, I would now like to turn the call over to our CEO, Sean Nolan.
Sean Nolan: Thank you, Hayleigh 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 Suku, our President and Head of R&D will provide an update on our lead TSHA-102 program and clinical evaluation for Rett Syndrome. Kamran 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 TSHA-102 program and 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 TSHA-102 program. Our goal is to develop potentially transformative therapeutic option 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 15,000 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 MECP2 gene, which results in the neural network dysfunction and leads to multi-system complications. It's characterized by loss of communication in the 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 24x7 care and lifelong assistance with daily activities, resulting in high caregiver burden and significant impact on quality of life. Our TSHA-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 TSHA-102 equipped with the novel MIRARE 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 over-expression of MECP2. Recall, we have two ongoing Phase 1, 2 REVEAL trials evaluating TSHA-102. An adolescent and adult trial taking place in Canada and the U.S. for patients 12 and older with Stage 4 Rett Syndrome, which is the most advanced stage of the disease. And a pediatric trial taking place in the U.S. and UK with recent clearance in Canada for patients five to eight 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 TSHA-102. Part B of the pediatric trial, the dose expansion portion, will evaluate TSHA-102 in two age cohorts, an expanded five to eight years of age cohort and the three to five years of age cohort. Two patients have been dosed in Cohort 1, which is evaluating the low dose of TSHA-102, 5.7x1014 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 1 in our pediatric trial and longer term data from Cohort 1 in our adolescent and adult trial, 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 TSHA-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 TSHA-102 over time. Following a 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 1 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 to the next phase of our studies. With Cohort 1 complete, we turned our focus to dosing patients from the high dose cohort across both our REVEAL trials and building on our promising preliminary low dose data set from both adult and pediatric populations. We dosed the first patient in Cohort 2 of our adolescent and adult trial, which is evaluating the high dose of TSHA-102, which is one use of 15 total vector genomes. We are pleased to share that the high dose of TSHA-102 was generally well tolerated with no serious adverse events or dose limiting toxicities as of the patient's initial six-weeks assessment. Following a review of these data, the IDMC provided clearance to proceed with the dosing the second patient in Cohort 2 of the adolescent and adult trial and the first patient in Cohort 2 of the pediatric trial earlier than planned. Subsequently, we enrolled the second adolescent adult patient and the first pediatric patient in Cohort 2 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 TSHA-102 program. Importantly, this capital infusion allows us to build on our preliminary TSHA-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 Suku to provide a more in-depth discussion of our TSHA-102 program. Suku?
Sukumar Nagendran: Thank you, Sean and good morning, everyone. I'm pleased to provide an update on our TSHA-102 gene therapy program in clinical evaluation for Rett Syndrome. We will start with our REVEAL Phase 1/2 adolescent and adult trial. As Sean mentioned, we have completed dosing in Cohort 1, which included two adult patients who received low dose of TSHA-102. TSHA-102 demonstrated an encouraging safety profile with no serious adverse events related to TSHA-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 demand and efficacy measures at week 52 following the completion of the steroid and sirolimus taper for the first patient and at week 25 following the completion of the sirolimus 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 deferred 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 improvements. 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 TSHA-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 TSHA-102 in females, 5 to 8 years of age with Stage 3 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 present with hallmark symptoms and many advanced manifestations. Enrollment criteria require patients to be post regression, and have entered the stage of stabilization, meaning there have not been any identified list of skills as in the last six months prior to treatment. Cohort 1, evaluating the low dose of TSHA-102 to complete -- TSHA-102 demonstrated an encouraging safety profile with no serious adverse events as to TSHA-102 or dose-limiting toxicities as of the week 22 assessment for the first pediatric patients 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 improvements across the same clinical domains we observed in the adult patients with early evidence of developmental gains following treatment at week 12 and 8 respectively. This included improvements in autonomic function, seizures, gross motor skills, fine motor skills, and health 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. 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 TSHA-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 REVEAL 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 Kamran to discuss our financial results. Kamran?
Kamran Alam: Thank you, Suku. Research and development expenses were $15.1 million for the three months ended June 30, 2024 compared to $19.8 million for the three months ending June 30, 2023. The $4.7 million decrease was primarily due to a milestone fee payable to Abeona Therapeutics (NASDAQ:ABEO) during the three months ended June 30, 2023 following the dosing of the first patient in the REVEAL Phase 1/2 adolescent and adult trial. General and administrative expenses were $7.3 million for the three months ended June 30, 2024 compared to $6 million for the three months ended June 30, 2023. The increase of $1.3 million was primarily due to $0.9 million of higher noncash stock-based compensation expenses and $0.4 million of higher consulting, professional fees, and other expenses. Net loss for the three months ended June 30, 2024 was $20.9 million or $0.09 per share compared to a net loss of $24.6 million or $0.38 per share for the three months ended June 30, 2023. As of June 30, 2024, Taysha had $172.7 million in cash and cash equivalents. 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?
Sean Nolan: Thank you, Kamran. Overall, we are encouraged by the well tolerated safety profile in patients who received the low dose of TSHA-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 the low dose of TSHA-102. We believe these Cohort 1 data validate our novel construct and support the potential of TSHA-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 TSHA-102 was generally well tolerated as of the initial six-week assessment in the first patient treated in Cohort 2 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 REVEAL 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 TSHA-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 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?
Operator: Thank you. [Operator Instructions]. Our first question comes from the line of Kristen Kluska with Cantor Fitzgerald. Please proceed with your question.
Kristen Kluska: Hi, good morning everyone. Thanks for taking my question. 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 in different domains impacted sometimes but is there a clear way that you're looking to try to measure this?
Sean Nolan: 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, just kind of a surrogate for overall tough. And obviously, when you go into the high dose, you're going to be pushing more volume, should have greater bio-distribution, greater transduction, and we would expect, first and foremost, that we see consistent effect across all the clinical domains that we've talked about. And 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 based on the preclinical data and the translation that always difficult translation of exactly what's that going to look like in adult it's difficult to predict both, I would say, the overall magnitude and the temporal aspect of things. So 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. Ultimately, we're going to have to run the experiment 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 once we have enough data in patients over a longer course of time, we feel confident we'll be able to make the determination 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.
Sukumar Nagendran: Yeah thanks Kristen and Sean. So you've raised a very interesting question because 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 but still significant unmet medical need. And as you point out, Kristen, with such a heterogeneous disease, a lower dose is actually showing consistent response. 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 higher dose and see if the higher 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 eventually the endpoints, the ideal dose that you'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.
Kristen Kluska: Thank you.
Sean Nolan: Thanks Kristen
Operator: Thank you. Our next question comes from the line of Salveen Richter with Goldman Sachs (NYSE:GS). Please proceed with your question.
Elizabeth Webster: Hey, good morning and thank you for taking my 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.
Sean Nolan: 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 one of them is basically align around the cadence of how we're going to interface with the agency, 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. We want to make sure that they're seeing the data in an appropriate batching, but they're seeing it as real time as possible. And that, plus the additional work that we're doing on natural history will be information that we share with them that ultimately will inform 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 in the coming quarter. Thank you.
Elizabeth Webster: Thank you.
Operator: Thank you. Our next question comes from the line of Chris Raymond with Piper Sandler. Please proceed with your question.
Christopher Raymond: 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 8 weeks. Are you looking to standardize that follow-up and what is that time point if you can tell us? Thanks.
Sean Nolan: Yes, 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, it was super encouraging to us. And we felt the right thing to do to really provide more line of sight and clarity 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 -- so the way things are right now for the high dose, right, we would have three patients in each cohort, so the pediatric cohort and the adolescent adult cohort and 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, etcetera. 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.
Christopher Raymond: Yes, very much. Thank you very much.
Operator: Thank you. Our next question comes from the line of Gil Blum with Needham & Company. Please proceed with your question.
Gil Blum: 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 a potential endpoint may depend on what the patients have at baseline, 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? Thanks.
Sean Nolan: Gil, great question. I would say a couple of things and certainly turn it over to Suku for his thinking. 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 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 loss function like we've seen in the low-dose data, 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 video, 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 on 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 a 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 redeeming of a milestone, I think that would be at a minimum, very supportive data that I think would be highly impactful to the agency, to payers, etcetera. So we've been pretty consistent, I would say, in how we're trying to think about ultimate endpoint selection. 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 include potentially as a secondary or supportive these ideas of capturing the restoration of effect. So Suku, would you add anything to that?
Sukumar Nagendran: Yes. 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 time frame 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 database is back, and there are certain clinical features that actually could be good comparisons for us regardless of the clinical trial design when we have our Part B meeting. Those variabilities within a clinical future that our gene therapy is consistently helping to treat is, I think, also going to be important because in our study 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, pan function, which is consistently blocked to the extreme. So I think these are things that we have to continue to get the data on and hopefully, our clinical trial design for the Part B component will allow us to assist 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.
Operator: Thank you. Our next question comes from the line of Joon Lee with Truth Securities. Please proceed with your question.
Joon Lee: Hey, thanks for taking our questions. So can you help us understand your 180-degree on the data disclosure strategy as we can see from your first patient, the patient with the best efficacy so far was shared at week six, yet the data from the second -- the high dose cohort passed the six-week mark but you're reserving that for later. Any sort of -- anything you can share on efficacy will be helpful there? And also, help us understand what you mean by fulsome, like how many patients worth of data do you think is sufficient to get a clear picture and how much data would you have by 1Q that passes that definition of fulsome data? Thank you so much.
Sean Nolan: So Joon, just to be clear, you're talking about the fact that the very first patient we reported on was at six weeks and now we're seeing we're going to longer-term data set. I just want to make sure that's what you're...
Joon Lee: Yes, yes. My understanding is that the first patient, that person -- that patient's efficacy were shared around that six-week mark. I am just curious, I understand the need to hold off until you have some fulsome data, but -- and your change in data strategy -- data disclosing strategy, but anything you can share on the high dose cohort?
Sean Nolan: Yes, sure. I would say a couple of things. First of all, one major change is the status and the fortune of the company in terms of balance sheet. I mean when we reported the first patient out to be totally frank, I think you all know this, the company was in an essential situation. And we were fortunate, frankly, 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 in a more traditional fashion the easiest thing to do and the more robust way to present the data would be to present information on a cohort-by-cohort basis. And I felt an obligation to the investors that came in on the one patient worth of data. They supported us. Many of you supported us with that data because it was so transformational for that patient. And so I personally felt an obligation to -- for a period of time to show data earlier than I normally would have. Fortunately, from my perspective, 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 IRS in the pediatric patients at 8 weeks and 12 weeks, I'll put that data up against anything that people have probably seen. I mean where have you seen video of people getting restoration of function. And we can argue on the margins, the standardization of the videos and things of that. And I acknowledge that, and that's what we're trying to work to standardize as we move forward. And in particular, we must have it all standardized for Part B. But the point is there was clearly an effect 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, now we're stepping in. We've demonstrated, I would say, very significant effect with the low dose. We got the okay from the IDMC to step to the high dose. And so now we have an opportunity to present more data over time. And I think people looking at something, 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 dose -- 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's a fulsome update. I mean that's -- you're starting to see if you're getting consistency, durability, etcetera, and we think that is a better way for everybody to be able to evaluate what we're seeing as we step into the high dose. So we felt it was a clean break going from the low dose to the high dose. We thought it was an evolution in how we've been reporting and that's why we think, ultimately, this is the best thing for all involved to see the data in a more cohort batch basis. So hopefully, that gets to what you're asking, Joon.
Joon Lee: 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 1Q.
Sean Nolan: Of course. Thank you.
Operator: Thank you. Our next question comes from the line of Maury Raycroft with Jefferies. Please proceed with your question.
Maurice Raycroft: Hi, thanks for taking my question. Does the time line change to your data impact your time line for an under Phase 1 meeting with FDA for the randomized pivotal I guess, could that still happen in first half 2025 or more likely the second half of the year? And do you anticipate the first half 2025 data would still be -- would be sufficient to bring to FDA for alignment on a randomized Phase 2 pivotal or would you need additional follow-up?
Sean Nolan: Good morning, great question. I mean the way we're thinking about it is that for us to sit down with the FDA and have a fulsome discussion around what Part B design looks like, I would say number one, we want to complete Cohort 2 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. Is it three months of data, six months of data, I think that's why we're guiding to more -- in our own mind, can we sit down with the FDA in the first half. That's what you 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 the clinical Type B meeting that we have and we'll actually be talking about things more broadly than just clinical. But the point is, we will inform them with information as we have it. So as I said earlier, as we have the natural history data completed, 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, we'll certainly share that with the FDA in a more real-time basis, leveraging the RMAT designation. So all that is leading and culminating to hopefully 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, I think it's a little early to tell, but we should have more line of sight in the next quarter or so. Hopefully, that gives you a little perspective.
Maurice Raycroft: Yeah, very helpful. Thank you.
Sean Nolan: Thanks.
Operator: Thank you. Our next question comes from the line of Yanan Zhu with Wells Fargo (NYSE:WFC). Please proceed with your question.
Yanan Zhu: 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 2025 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 2025 and if you can comment on the safety waiting period, is that 42-day period true for across all six patients in those two dose cohorts? Thanks
Sean Nolan: Two things Yanan. So again, we're guiding to 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 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.
Yanan Zhu: Got it, thank you.
Operator: Thank you. Our next question comes from the line of Jack Allen with Baird. Please proceed with your question.
Jack Allen: Hi, 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 low-dose cohorts, we noticed a difference in the severity of patients depending on their deletions. I was wondering if you could 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 just want to hear the team stop 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?
Sean Nolan: Sure. Suku, I would ask you to take those two questions. I think the first was, 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 CGIS are. I think that's all we've guided to, but you can talk about that. And then the second one is just expectations potentially on progress of low-dose patients over time.
Sukumar Nagendran: 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 4% to 6%. And as we 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 you know, is very common in a sense, loss of fine hand motor function and gross motor function and the repetitive movements, etcetera. 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 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 common commonalities in the clinical presentations that exist in Rett Syndrome patients, the hand function, I guess you could say social withdrawal, maybe seizures, etcetera, etcetera. So this will all be there. And then the other piece of the puzzle is when you have whatever the mutation is, missense mutation, [indiscernible] mutation or massive deletion, which then results in a horrible or severe clinical presentation. Then the question becomes any gene therapy due to -- the disease, what is the greatest impact it will have and on which clinical features. So these are things that we 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, the commonalities that the features will only see -- be seen in a few patients, because you're dosing five, six, seven patients to move into -- from Part A into Part B and then Part B into 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 -- and then the second question was I lost my trend there, Sean.
Sean Nolan: You answered the question on the baseline characteristics, right? It is going to be CGIS between 4 and 6. 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 initial patients that we've reported on over time, she did gain improvements, further improvements in different aspects whether it's getting stronger from a gross motor perspective; improvement in hand function over the course of time; improvements and ability to communicate. So I think, Jack, as you think about the low-dose patients in the pediatric that we just gave preliminary data on, our hope would be that we would see progress like that and hopefully, potentially, a little bit better just given the fact that they're younger in age. So 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 to what you're asking, Jack.
Jack Allen: Yes, definitely. Thanks so much for the color.
Sean Nolan: Thank you.
Operator: Thank you. Our final question this morning comes from the line of Silvan Tuerkcan with Citizens JMP. Please proceed with your question.
Silvan Tuerkcan: Hey, 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 -- haven't heard before? And then on the safety committee. Obviously, they accelerated your ability to dose into a higher dose. Could they -- at what point could they accelerate or get rid of the stagger, the 45-day waiting period between patients? Thank you so much.
Sean Nolan: Suku, 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 there's -- we haven't reported anything more on because there has been declared resolution of that from the PI. But just to make sure…
Sukumar Nagendran: Yes, Sean, if I can add, though, the whole issue of a stagger, I wanted to clarify, though, because lumber approach, I mean is intrathecal. I mean there are other approaches that IDMCs 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 risk is appropriate, right. So I just wanted to throw that out there because it's important. And that's what Dr. Peter Marks [ph] 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 is safe, you don’t necessarily have to do all the patients as the protocol had defined. The second question around stagger as 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 a product I don’t think there was any issue with the IDMC doing what it needed to do to move the program forward.
Sean Nolan: Yes. So there's been no additional disclosure on the SAE. It resolved and obviously, we've moved ahead, as Suku said, from a dosing perspective. Is that good for you, Silvan?
Silvan Tuerkcan: Perfect. Thank you.
Sean Nolan: Thank you.
Operator: Thank you. Ladies and gentlemen, that concludes our question-and-answer session. I'll turn the floor back to Mr. Nolan for any final comments.
Sean Nolan: Just appreciate everyone calling in and always happy to follow up with any additional questions offline. Thank you all and have a good day.
Operator: 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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