Taysha Gene Therapies, Inc. (TSHA) Earnings Call Transcript & Summary

Ladies and gentlemen, good morning, and welcome to the Taysha Gene Therapies Full Year 2024 Conference Call. [Operator Instructions] As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Hayleigh Collins, Director, Head of Corporate Communications and Investor Relations. Please go ahead.

Thank you. Good morning, and welcome to Taysha's full year 2024 financial results and corporate update conference call. Earlier today Taysha issued a press release announcing financial results for the full year ended December 31, 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 Chief Executive Officer; 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 concerning the potential of TSHA-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 quality of life and alter the course of disease in the patients we seek to treat our research development and regulatory plans for product candidates, including the timing of initiating additional trials and reporting data from our clinical trials, the potential for the product candidate to receive regulatory approval from the FDA, or equivalent foreign regulatory agencies, clinical potential of intrathecal administration, the market opportunity for our programs and the current cash resources supporting our planned operating expenses and capital requirements into the fourth quarter of 2026. 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. For a list and description of the risks and uncertainties that we face, please see the reports we have filed with the Securities and Exchange Commission, including in our annual report on Form 10-K for the full year ended December 31, 2024, that we filed today. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, February 26, 2025. 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.

Thank you, Hayleigh, and welcome, everyone, to our full year 2024 financial results and corporate update conference call. I will begin with a brief update on our recent activities. Then Dr. Suku Nagendran, President and Head of R&D of Taysha will provide an update on our lead TSHA-102 gene therapy 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. The past year has been marked by exceptional execution as we have focused on generating critical longer term clinical data across our two REVEAL Phase I/II trials to further elucidate the therapeutic potential of TSHA-102 and inform the development plan for the next phase of the trials. We are pleased with the pace at which our TSHA-102 program is advancing across a broad range of ages and stages of patients with Rett syndrome. Importantly, we believe the progress we have made has set the stage for a highly impactful 2025 as we focus on advancing TSHA-102 toward the pivotal phase of the REVEAL trials. I am pleased to share that both the high and low dose of TSHA-102 continue to demonstrate an encouraging safety profile. TSHA-102 was generally well tolerated with no treatment related serious adverse events or dose-limiting toxicities in the 10 pediatric, adolescent and adult patients dosed across our 2 REVEAL trials as of the February 2025 date of cutoff. Importantly, we have completed dosing of the 10 patients in Part A. The dose escalation portion of the REVEAL Phase I/II, adolescent/adult, and the REVEAL Phase I/II pediatric trial. This includes 6 patients in cohort 2, evaluating the high dose of TSHA-102 at 1E to the 15 total vector genomes and 4 patients in cohort 1, evaluating the low dose of TSHA-102 of 5.7E to the 14 total vector genomes. This maturing data set continues to support our advancement toward the pivotal Part B trial as part of our ongoing discussions with the FDA. From the outset, our strategy has been to utilize part A of our trials to generate a data set that informs our development plan for Part B, which is the pivotal phase of the trials. With dosing of the 10 patients in Part A complete, we believe we have a strong maturing data set in hand that enables us to further solidify the regulatory pathway for TSHA-102 with the FDA. Previously we announced that following regulatory meetings with the FDA regarding our ongoing TSHA-102 development plan, we intend to focus on objective measures that clinically capture improvements in the core features of Rett syndrome in Part B of our REVEAL trials. Recall the clinical data presented from the adult and pediatric patients with varying genotypes and disease severity, including those with the most advanced stage of Rett syndrome treated with the low dose of TSHA-102 consistently showed clinical improvements and functional gains across multiple domains as early as 4 weeks post treatment, that persisted and strengthened over time. This included improvements in functional gains across the domains of fine and gross motor function, socialization and communication, autonomic function and seizure events. Importantly, the functional gains consistently seen in the treated patients that we've reported to date directly represent improvements in activities of daily living that are meaningful to caregivers. Since then, to further assess the therapeutic potential of TSHA-102, we have continued to evaluate the 4 patients in the low dose cohort and have expanded our dataset by completing dosing of the 6 pediatric, adolescent and adult patients in the high dose cohort. We continue to believe that functional outcome are the most relevant, objective and clinically meaningful assessments of the treatment effect of TSHA-102 in patients with Rett syndrome. For functional gains or restoration of loss in function are not expected to occur in the untreated population. As such, based on our ongoing discussions with the FDA and the totality of the clinical data we have collected, our goal is to advance TSHA-102 toward a pivotal trial design that objectively assesses functional gains across key clinical domains impacted in Rett syndrome to bring TSHA-102 to patients as expeditiously and as safely as possible. We remain encouraged by our productive ongoing discussions with the FDA through the regenerative medicines advanced therapy or RMAT mechanism, and the strong maturing data set we have in hand that provides us the further ability to solidify the regulatory pathway for TSHA-102. We look forward to providing an update on the pivotal Part B trial design in the first half of 2025. We also expect to provide an update on the clinical data from the low- and high-dose cohorts across our adolescent adult trial, as well as our pediatric trial in the first half of 2025. As we prepare for these critical milestones, we remain highly confident in our differentiated gene therapy candidate, which we believe has the potential to provide meaningful benefit to a broad population of patients with Rett syndrome using a minimally invasive delivery approach. I will now turn the call over to Suku to provide more context on these advancements that further support our development approach for TSHA-102. Suku?

Thank you, Sean, and good morning, everyone. As Sean mentioned, we have made significant progress on the advancement of our TSHA-102 program. TSHA-102 is a onetime intrathecally delivered gene therapy that was strategically designed to enable optimal and controlled transgene expression on a cell-by-cell basis across the central nervous system. Recall, we have 2 ongoing Phase I/II REVEAL trials evaluating TSHA-102 and adolescent and adult trial taking place in Canada and the U.S. for patients aged 12 and older with Stage 4 Rett syndrome and a pediatric trial taking place in the U.S., the U.K. and Canada for patients 5 to 8 years of age with Stage 3 Rett syndrome. We are currently evaluating TSHA-102 in Part A, the dose escalation portion of both trials, evaluating 2 dose levels. As Sean mentioned, our approach from the outset has been to utilize Part A to generate a dataset that will inform the key elements of the Part B pivotal trial. We previously announced that following regulatory meetings with the FDA regarding our ongoing TSHA-102 development plan, we intend to focus on objective measures that clinically capture improvements in the core features of Rett syndrome. To put this in perspective, I will review key characteristics of Rett syndrome. Rett syndrome is a rare progressive neurodevelopmental and neural network disease that inhibits neuronal development and leads to complication across multiple domains, including fine and gross motor function, socialization and communication, autonomic function and seizures. It is a heterogeneous condition, so individuals experience different levels of clinical severity based on their distinct genetic background. However, despite differences in disease severity, patients generally follow a common trajectory regarding the achievement of functional developmental skills. Rett syndrome typically begins with normal development during the first 6 to 18 months of life. Individuals acquire some skills and reach certain developmental milestones in fine motor, gross motor and communication and socialization such as the ability to grasp and hold objects, sit independently and use single words. However, this progress is followed by a period of regression where individuals use many of these previously acquired functional skills and milestones, typically resulting in the loss of purposeful hand function, motor coordination, and verbal communication. They also start to develop new disease features such as hand stereotypies, seizures, and autonomic dysfunction, including breathing, sleep, and cardiac abnormalities. Following this regression, affected individuals typically enter a plateau period during the ages of 5 to 6, during which they are highly unlikely to gain new functional skills or developmental milestones or regain skills that have been lost due to disease progression. Individuals will continue to experience a decline over time. These functional impairments and disease features typically result in the loss of independence as patients are unable to perform daily activities or communicate needs. They usually require 24/7 care and lifelong assistance in daily tests, placing a significant burden on caregivers that impact their quality of life. There is a high unmet need for this devastating disease. Patients being evaluated in our REVEAL Phase I/II trials are in the post-regression phase of the disease where functional gains or restoration of loss function are not expected to occur in the untreated population. In our REVEAL trial, we have reportedly or reported clinical data from the low dose cohort showing pediatric and adult patients with advanced disease gaining functional skills across the domain of fine motor, gross motor, and socialization and communication, which directly represent improvement in activities of daily living. This included beginning to use eating utensils, sitting independently, standing up from a chair independently, and the ability to use an eye gaze communication device. These outcomes have shaped our interaction with the FDA regarding the optimal regulatory pathway for TSHA-102. Based on our data-driven findings and ongoing discussions, we continue to believe that functional outcomes are the most relevant, objective and clinically meaningful assessments of the treatment effect of TSHA-102 in patients with Rett syndrome. As a result, we anticipate that our pivotal trial design will be distinct from previously approved treatments for Rett syndrome. We continue to work closely with the FDA to further solidify the regulatory pathway for TSHA-102 based on the maturing safety and efficacy dataset from Part A that we now have in hand. I will now turn the call over to Kamran to discuss financial results. Kamran?

Thank you, Suku. Research and development expenses were six $66 million for the full year ended December 31, 2024, compared to $56.8 million for the full year ended December 31, 2023. The $9.2 million increase in the year ended December 31, 2024, was driven by good manufacturing practices or GMP batch activities for the intended commercial manufacturing process for TSHA-102 and additional clinical trial activities across the 2 REVEAL Phase I/II clinical trials in 2024. General and administrative expenses were $29 million for the full year ended December 31, 2024, compared to $30 million for the full year ended December 31, 2023. The decrease of $1 million was primarily due to the decrease in issuance costs allocated to the liability classified 2023 pre-funded warrants associated with the August 2023 financing. Net loss for the full year ended December 31, 2024, was $89.3 million or $0.36 per share compared to a net loss of $111.6 million or $0.96 per share for the full year ended December 31, 2023. As of December 31, 2024, Taysha had $139 million in cash and cash equivalents. We continue to expect that our 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?

Thank you, Cameron. This is an exciting time for our TSHA-102 clinical development program with critical progress made that we believe strongly positions us for success as we work to bring TSHA-102 to the Rett syndrome community as expeditiously as possible. In what we expect to be a transformative year ahead, we are focused on advancing TSHA-102 toward the pivotal phase of the REVEAL trials. With the dosing of the 10 patients in Part A for both of our trials complete, we have a strong maturing data set in hand to further solidify the regulatory pathway for TSHA-102 with the FDA. We remain encouraged by our productive ongoing discussions with the FDA and are focused on execution as we prepare for key late-stage milestones expected in the first half of 2025, including providing an update on the pivotal trial design for TSHA-102 and clinical data across the high- and low-dose cohorts in both our REVEAL trials. With that, I will now ask the operator to begin our Q&A session. Operator?

[Operator Instructions] The first question comes from the line of Kristen Kluska from Cantor Fitzgerald.

Congrats on completing the enrollment of Part A. Given that you've had recent several FDA interactions to your RMAT designation, can you generally speak to the number of people that are involved in the conversations? Essentially, what I'm trying to get at is, is it one person that's been supportive of talking about this path forward? Or is it several? I think this is something that investors are just focusing on given some of the recent layoffs we've seen in the FDA.

Thanks for the question, Kristen. I could say that consistently in our discussions subsequent to having RMAT, where we've had multiple meetings in 2024, we started off with meetings in 2025 with the FDA. We're generally talking 15 to 20 people in attendance from the FDA, both senior level, I would say, consistently, Nicole Verdun has been included in all those meetings. And we have not thus far seen any impacts from the new administration as related to our program. So we've seen consistent broad attendance from the FDA across clinical, CMC, preclinical, et cetera.

The next question comes from the line of Salveen Richter from Goldman Sachs.

With regard to the ongoing discussions with the FDA, has there been any change here with regard to what they're looking for from functional gains since the last update? And are there any additional details you can share about what functional gains and key domains they're most interested in here?

Yes, Salveen. I will say that the FDA discussions that we've had through 2024 and into 2025 have been very consistent. And I think if you go back to our disclosures in 2024, we've generally, since we started reporting data, have focused on functional outcomes, gains of function, restoration of function. That's always been our lead. And in our discussions with the FDA, we've taken a similar approach. Again, if you keep in mind what we're trying to do, if you take into account the disease and what we're talking about a gene therapy program, we've always stated that we felt that the best put forward will be to show very clinically meaningful objective improvements. And we think we've reported, at least to date, those across all the patients that we've seen regardless of age, stage or genotype. So in our discussions with the FDA, we've been consistent about how we think about potentially a trial design and also about what endpoints would be relevant. I can say that they have been constructive and positive in those discussions. They have not tried to steer us down a different path. And they've continued to encourage us to do 2 things. One is continue to let the data sets mature, dose more patients. And also, we've talked about work we've done on natural history that we think would further contextualize the data that we're putting in front of them. And so all that has been very consistent. We've recently shared our natural history data assessments with the FDA, and that is part of the ongoing discussion. So I think everything has been very, very consistent in that regard. To the second part of your question, the domains that we listed that Suku kind of outlined are the ones that the FDA and also, frankly, caregivers really emphasize. It's communication and socialization, it's fine motor function, gross motor function. And of course, the seizure aspect of the disease is very important as well. So the FDA has not, at this point, talked about any kind of a hierarchy. They've acknowledged the fact that these are all very clinically meaningful based on what is happening to an individual patient. Hope that helps.

The next question comes from the line of Chris Raymond from Piper Sandler.

Congrats from us on the progress as well. Just on the competitive setup and sort of the broader Rett gene therapy competitive setup. So your competitor is forging ahead with their low dose, which is similar to your high dose. So far with this update, it seems your high dose looks pretty good. Maybe just -- I know this is maybe a horse -- cart before the horse kind of question, but talk about the differentiating factors, I think, that we should be looking for as the clinical pictures of both therapies start to emerge.

Yes, Chris, I think that I'll point you to what's been publicly disclosed at this particular point in time. And I'll start with the fact that, look, we ultimately want improvements available therapeutic options for the Rett community. The more options they have, the better, right? And that's what we're working towards. I think everyone who's in the space is trying to do the same thing. What we have -- and I don't want to get into the details of the construct unless you'd like to. But we feel that because of the fact that we've taken a choice to use self-complementary technology, we're making protein much, much quicker than somebody who would be using a single strand. And if you're able to mediate the production of MeCP2 on a cell-by-cell basis, so you're producing protein in sufficient and robust quantities in the cells that are deficient and you're not producing them in the healthy normal cells, then we should be seeing clinical effects happening sooner and faster with our construct. And I would point you to the data that we released back in the summertime where within 4 weeks we've seen improvements in functional gains or restoration of function in patients. And they've been in all the patients that we've reported regardless of the stage or the age of the patient. So I think in our view, onset is very important because the sooner you can start to restore function or improve a gain, our view is that, that should improve over the course of time. So getting better faster certainly makes sense. I think the second thing is regardless of disease severity, when you take a look at our data set, all patients did have improvements in functional gains. And I would encourage you to take a look at -- from a competitive perspective, it seems like maybe there's a better response to some of the less severe patients based on what was reported by others. We're seemingly viewing that we're seeing response across genotypes and across disease severities. And the last piece would be, again, that based on what we're seeing so far from a safety perspective, having a route of administration that's less invasive is certainly beneficial to the patient themselves and the caregivers given it's much less invasive. Hopefully that gives you some perspective.

The next question comes from the line of Gil Blum from Needham & Company.

Congrats on the progress here. So I may have missed this earlier, but did you guys discuss the kind of data disclosures that we should expect in the first half given today you updated enrollment and dosing?

Yes, Gil, no, we didn't. So it's a good question. So in the first half, we'll give -- there's 2 kind of, I would say, buckets of an update, right? The first would be we plan to give an update in the first half on the regulatory side with more specifics around the trial design and primary endpoint in particular. And on the clinical data side, we plan to give an update on the low-dose longer-term data. So all those patients will have over a year of time on therapy. And at the high dose, what we've guided to is that, that would be a total of 6 patients across pediatrics, adolescents and adults. And we've stated that we'd like to have the majority of those patients have a minimum of 6 months of time on drug with the idea that it would give you all and the investors a robust data set to evaluate through the lens of what our clinical trial design would be. So that's the plan. If all that comes together, we'd like to do it all at the same time. And that's what we're working towards at this particular juncture. The other thing I would say, Gil, is that we also would give an update based on our analysis of the natural history because I think that's a key component in really understanding the data and then contextualizing the effects that we believe that we're seeing.

All right. Very helpful. And as a follow on to a prior question, how open-minded do you feel the FDA is as it relates to endpoints here? Do you feel like the agency may stick to something established or known or like CGI-I and CGI-S? Or is this a completely open-ended question?

Yes. I can say, and Suku, feel free to jump in here, but the FDA has never guided us towards an endpoint. In fact, I think we reported -- it was probably around the spring time of last year in one of our first RMAT meetings where we talked about endpoints. The FDA pointed to RSBQ and said this is nothing but an exploratory endpoint. And if you want to do a single-arm trial, you want to use things that are clinically objective and you're able to assess them. So CGI-I and CGI-S can be informative, but those are also very subjective in how they're being measured. You're generally looking at the overall health of the patient, and you wouldn't set up a single-arm trial, at least in our view, to use those as a primary endpoint. So the FDA has been very, I would say, open-minded to the data and being informed by that data. And they understand that the path we're going down, again, assuming we get full alignment there would make a lot of sense for the reasons that I've essentially outlined. So I would say there is definitely an open-mindedness driven by the evidence, and there is not a preconceived idea of what's the right thing for a gene therapy in terms of trial design and endpoints.

Yes, Sean, if I can add something for Gil. What I've noticed over the years is that if you have an effective therapy, especially a truly effective gene therapy for a clinical condition and it impacts an outcome that is truly clinically meaningful or transformative, then the FDA tends to wear towards that because that justifies approving that product rapidly so that patients can have hopefully a better life. But if you have a product that is not as effective, but still makes somewhat of a difference, then I've noticed that what they do is they will use subjective or other measures that have already been out there for a while that gives you some sense of disease impact of the product, even though the product -- I mean, those measures like CGI-I, S and RSBQ have never truly been validated, right, to look at the impact of a therapy until they did it [indiscernible]. Then they'll use that because that still justifies them getting an approval if they think the product makes a difference. But for a transformative product, I think they probably won't use these scales. They'll be secondary, I'm sorry. They could be secondary, not primary.

The next question comes from the line of Maury Raycroft from Jefferies.

I'll add my congrats on the progress. Just clarifying, as of the February '25 cutoff for safety, just wondering if you can provide more perspective on whether you think you're past a critical point for SAEs or DLTs in these patients.

I'll ask Suku to opine on this. But I would say, historically, when you look at gene therapy trials, if you're going to see something that's treatment related that's an SAE or a DLT, it's generally within the first 2 to 6 weeks. And we recently had an IDMC meeting and these patients data were all reviewed. And so thus far, we feel very encouraged by the safety profile that we're seeing. But Suku, I don't know if there's more you'd add given all your experience across gene therapy companies.

Yes, Sean. Maury, just to make sure I heard you correctly, you were referring to our program, right, when it comes to the intrathecal route of administration, whether we've seen anything of safety concern, correct?

Yes. Yes, correct. As of the safety cutoff or the February '25 cutoff, just if you think you're past a critical point for safety issues?

Yes, sure. So overall, just to kind of lay the framework, intrathecal approach seems to be very safe across the board when it has been developed for many diseases, it applies to our program in Rett as well. There has been no treatment related or DLTs of any concern. And what you find, again, I mean, I'm sure you've seen the literature is whether it's [ systemic ] or whether it's intrathecal, and intrathecal is actually in general very mild. You see some LFTs that go up marginally which control with the prednisolone and then other minor things that happen that one would say may be related to an immune response, but that's about it. We haven't seen anything else.

Got it. Okay. That's helpful. And then just as a follow-up question, you mentioned the 6 months follow-up that you'd like to have for patients in the next data update. How much follow-up do you need for the high-dose patients to meet with the FDA to discuss the Part A data and pivotal path design and endpoints? And when do you estimate that meeting will occur?

Well, Maury, I would say that we've been having those conversations on an ongoing basis for the last year. So we're always sharing updated information, clinical data with the FDA in all of these meetings. So they're very well informed as to how things are pacing as we're having the discussions about trial design and endpoints. So I would say we're not limited right now. The discussions are ongoing, and we're on pace to give the updates that we've laid out in terms of first half disclosures.

The next question comes from the line of Yanan Zhu from Wells Fargo.

Wondering how close are you to an agreement on the endpoint? Will the alignment come before the first half data update?

Yanan, I would say, again, we feel very positive about the discussions that we've had because we have not really at all deviated from our position for over a year. So we have not introduced any new concepts to the FDA since we began our discussions, and we've continued to have constructive discussions along the way. So we feel good about that. I'll just tell you like a preference of ours would be that we would be able to provide the regulatory update coincident with the clinical data update just because I think it would be the most informative way for analysts and investors to fully assess what's the path forward and then what does your data look like in that type of a setting once you've outlined what your trial design and your endpoint looks like. So that's the preference. We'll have to see just based on how things completely sequence, but that's what we're working towards.

Great. Also wondering that in terms of the functional gain primary endpoint, would you be able to comment on the bar for the level of change and the time point at which those change changes can be achieved at this point?

Yes. I think for competitive reasons, we won't get into a lot of the detail. I think that some of the -- if you go back and look at our disclosures of where we've reported functional gains, things ranging from sitting unassisted, improvements in communication, the ability to use words with meeting, going from a -- being able to sit unassisted, going from a sit to a stand, all of those things are meaningful from a clinical perspective, they're meaningful from a caregiver perspective. And so those are the types of things that we would be looking at. We've got a much more detailed and specific plan in terms of how to assess those and things of that nature. But I think it's a little premature for us to come out and say anything until we've got the final agreement with the FDA, which we believe we're on track to do.

The next question comes from the line of Jack Allen from Baird.

Congrats on all the progress. I know there have been a number around the regulatory interactions with the FDA. But my first one I just wanted to ask was what are the gatekeeping aspects as it relates to reaching alignment with the FDA? Is there a specific type of meeting you want to have? Is there a new data that you want to present to them? Or is this all being done on a rolling basis and you'll just know when you reach alignment that you're at alignment? Or is there a catalyst that you're looking for in the next 3 months here to reach regulatory alignment? And then I have a quick follow-up as well on the dosing, the high dose cohort.

Yes. Jack, I mean, we use the words ongoing for a purposeful reason. I mean they really are ongoing discussions. I think I alluded to earlier in the call that we did recently share our analysis of the natural history with the FDA. So that's the first time they've seen that. So they're digesting that. We're doing some discussions and back and forth on that. In the background, what's percolating is we continue to have data mature, right, as we've dosed patients and gain more time. And that also helps support the case in our view that we're making. So it's really the confluence of those things. And it's kind of like you said, we'll know it when we see it, when we get there. We haven't put a stake in the ground. There's not one major hurdle that we're trying to overcome. It's really, I think, just the introduction of data that we just recently did, and we're working through the natural back and forth with that to make sure that we're both fully seeing things the same way. So we feel very encouraged by where we are right now. And again, we believe we're on the path to give that first half update.

Got it. That makes a lot of sense. And then just a brief follow-up on the completion of the dosing of the high-dose cohorts. I guess you mentioned on the call previously that the window for acute SAEs for gene therapies is 2 to 6 weeks. I guess any additional context you can provide as it relates to when the last high-dose patient was dosed and if we've made it out of that 2- to 6-week window? Or how should we think about interpreting the timing of dosing and where we are as it relates to acute toxicities?

Sean, do you want me to take that?

Suku, yes, go ahead, please.

Yes. So that's a good question. So in the first -- okay, so the commonest clinical observation you see with intrathecal gene therapy post dosing is usually in the first 4 to 6 weeks and it's liver enzymes going up, and it's thought to be due to an immune response. The elevation is very mild. I mean, again, if you've seen in gene therapy, you can get liver enzymes in systemic interventions or administration where it can go 10, 15, 20x upper limits of normal or more. But prednisolone almost always controls it, and it's the same case with our program as well. So I guess what I'm getting at is these patients are all on prednisolone. And once you give them the intrathecal TSHA-102, I have no concern from a safety standpoint because it's pretty standard and routine. So I guess what I'm saying is the benefit far outweighs the risk. Does that make sense?

Yes. Yes, that makes a lot of sense.

And Jack, the other thing I would say to Suku's point is that we did recently just have an IDMC meeting and the IDMC reviewed 10 patients' worth of safety data that's all available. And we obviously just disclosed that we've seen no treatment-related SAEs or DLTs. So you can never say never, but we've got 10 patients' worth of data. And so far, everything looks to be very encouraging on the tolerability profile.

The next question comes from the line of Joon Lee from Truist Securities.

Congrats on the progress. This is Mahdi on for Joon. A couple for us. So could you provide some color on the latest or final sirolimus dosing and taper regimen that you have? And is this something that you need to also align with FDA on that?

Yes. The FDA really has had no -- they gave us no direction on their recommendations from the beginning on immune suppression. They left that up to the company. And to your point, we've got right now a combination of steroids and sirolimus. The sirolimus is a 6-month taper at this point. And we'll be evaluating that for Part B just because we've been encouraged by the safety profile we see, and there can very well be a case that we may not use that in Part B. We don't think it's necessary. It's a discussion that we've had internally. So time will tell there. But I think with what we've generated to date, we have started out of an abundance of caution, but the data set really is leading us down a path where for Part B we may just be able to use steroids for a short course.

Awesome. And as a follow-up, like have you ever announced your full to empty capsid ratio for the product that you have? And given that your competitor is now limited to one fixed dose, what is the chance that you might consider going for even a little bit higher dose in your setting?

We have not disclosed empty to full ratio, and we will likely not do that. I would just say that from a CMC perspective, we're very comfortable. We've never had any -- I think if you look at our disclosures, the CMC discussions have always been quite constructive. We've never had an issue raised by the FDA relative to a purity type of a concern. So we feel good about where we are. And I'll just remind you that we are at scale. The FDA has effectively endorsed our commercially intended process. We've got product in the freezer that we can utilize. And so we feel very good from a CMC perspective.

The next question comes from the line of Silvan Tuerkcan from Citizens.

Congrats on all the updates here. Just a question, sorry to harp on these pivotal endpoints here. But do you think -- do you get a sense that the FDA wants to harmonize the trial design and specifically the endpoints across the 2 gene therapy read trials that are ongoing there about to move into pivotal? And would any of that be gating -- any of these trial designs be gating for each other? And then I have a quick follow-up.

Yes. Silvan, it's a good question. The short answer is I don't know. My view all along has been -- the premise of my view is based on the fact that if you have similar data sets, meaning your efficacy is in the same zone, your safety is in the same zone, I think you can talk about harmonization, right? If they're not, then maybe that's not a logical assumption. But if you could then harmonize, I do think the FDA would not let one company go down a path that they didn't agree with if they felt the other company may have a more optimized trial design. I don't know that it would be necessarily exactly the same, but it could be similar -- and all I can say is that we don't feel at all that we've been guided along the way. I'm not saying that our competitor has been guided either. I'm just simply saying that I do think the FDA would try to keep things as aligned as they possibly could, but there are differences within the programs that they have to account for. So at this point, we don't feel that we're being paced. I would say our discussions are happening on the time line that we've essentially agreed to with the FDA.

Great. And I don't know if you can comment on this, but is there any difference between the safety and tolerability in the pediatric versus the adolescent high-dose patients given that they are different weights?

No. No, we haven't seen any -- as we've reported, we've seen no treatment-related SAEs or DLTs. Keep in mind that the CNS volume of the kids that we're treating and the adolescents and adults is generally within 80%, 85% of each other. So it's pretty similar, which was -- which allows for the fixed dose to be the same.

The next question comes from the line of Evan Seigerman from BMO Capital Markets.

[ Mack Martinen ] on for Evan. Focusing on dose-limiting toxicities, just once more. You noted you had not seen any DLTs in patients dosed so far, but maybe patients could see some minor liver enzyme elevations to start before the immunosuppression kind of takes hold. Can you just contextualize what those mild liver enzyme elevations could look like? Are they less than 3x the upper limit of normal or 5x maybe? Just trying to get your thoughts there.

Yes. I'll turn it over to Suku. I would just say, keep in mind that immunosuppression starts a week before gene transfer happens. So they are suppressed by the time they get the drug. And so far, things have been relatively low, not clinically meaningful. But Suku, feel free to go ahead and give your perspective on that question.

Yes, Sean, as I said previously, the -- usually what you see is the most up to 3x upper limits of normal. Really, it can go above that, but predisolone completely controls it. And I would say that the intrathecal approach up to now is probably safer than many of the oral indications out there in the marketplace for more primary care diseases. So that is also reassuring from a drug development standpoint. And I hope that holds.

[Operator Instructions] The next question comes from the line of Whitney Ijem from Canaccord Genuity.

This is Angela on for Whitney. Can you just confirm quickly, we'll be getting at least 6 months of data from all patients? Is that correct? And then in terms of endpoints, if there is no regulatory update with the data update, can you share what we might be able to expect? Is it the same efficacy measures and clinical improvements that we've seen previously? Or is it going to be something different? And then if you do have the regulatory update, how is that going to change?

Yes, Angela, what we said is at the low -- the update that we're planning, the low-dose patients would have a minimum of a year worth of data and the high dose, which is a total of 6 patients, we've said that the majority of those patients would have at least 6 months of data. So that's the clarification there. In terms of the disclosure, again, I think you'll see the emphasis from us on functional gains. We'll also talk about improvements in function that patients may have had at baseline. So they might have been able to have some level of hand function as an example, but that got better. So we're really going to focus on how the patient is doing across the clinical domains. And to us, any scales that we would show would be secondary. And I think that's the -- that would be the purpose of doing things in concert with the regulatory update because I think it would be evident to people why we put the emphasis where we did. And if they were decoupled, I still think we would end up giving the clinical update as I outlined.

Ladies and gentlemen, as there are no further questions, I will now hand the conference over to Sean Nolan for his closing comments.

We appreciate everyone taking their time this morning to listen to our update and ask your questions, and we look forward to a very exciting 2025. Thank you.

Thank you. The conference of Taysha Gene Therapies has now concluded. Thank you for your participation. You may now disconnect your lines.