Taysha Gene Therapies Inc - Earnings Call - Q4 2024

Executive Summary

• Completed dosing of all 10 Part A patients (high dose n=6; low dose n=4) across both REVEAL Phase 1/2 trials; TSHA-102 remained generally well tolerated with no treatment‑related SAEs or DLTs as of the February 2025 cutoff.
• Regulatory path continued to progress: ongoing RMAT-enabled FDA dialogue with an update on pivotal Part B design and primary endpoint planned for 1H 2025; management emphasized objective functional gains as the core of the pivotal strategy.
• Financially, FY 2024 revenue was $8.33M vs. $15.45M in FY 2023, net loss improved to $89.30M vs. $111.57M in 2023, and year-end cash was $139.04M with runway into 4Q26 (maintained).
• Near-term stock catalysts: (1) pivotal Part B design/endpoints alignment with FDA, (2) Part A high- and low-dose clinical data updates (adolescent/adult and pediatric) in 1H 2025, (3) clarity on immunosuppression for Part B (potential to simplify to short-course steroids).

What Went Well and What Went Wrong

What Went Well

• Clean safety/tolerability across both dose levels: “no treatment‑related serious adverse events (SAEs) or dose‑limiting toxicities (DLTs)” (n=10) and recent IDMC review supportive; management reiterated typical IT gene therapy LFT elevations are mild and controlled with steroids.
• Regulatory engagement constructive and consistent; FDA has encouraged continued dataset maturation and use of natural history to contextualize functional gains; pivotal design update targeted for 1H 2025.
• CMC readiness remains a relative strength (from prior quarter): FDA previously endorsed commercially intended process; pivotal product released for use in trials based on analytical comparability, supporting readiness for Part B.

Quotes

• “TSHA-102 continues to be well tolerated… With dosing of the 10 patients in Part A… we have a strong, maturing dataset in hand to further solidify the regulatory pathway…” — Sean P. Nolan, CEO.
• “We intend to focus on objective measures that clinically capture improvements in the core features of Rett Syndrome in Part B…” — Management on pivotal approach.

What Went Wrong

• Topline still largely non-commercial: FY revenue declined to $8.33M from $15.45M in FY 2023, reflecting dependency on collaboration/deferral mechanics; quarterly revenue lens shows modest variability (see Financial Results).
• Operating spend increased y/y on R&D (GMP/commercial process and clinical activities), with an impairment charge; although net loss improved y/y, burn remains meaningful pre-pivotal.
• Regulatory endpoint specifics not yet finalized; while FDA dialogue is positive, investors remain focused on endpoint choice/thresholds and competitor read‑throughs; company will disclose once alignment is achieved.

Transcript

Operator (participant)

Ladies and gentlemen, good morning, and welcome to the Tayshia Gene Therapies Full Year twenty twenty four Conference Call. At this time, all participants are in a listen only mode. A brief question and answer session will follow the formal presentation. As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Haley Collins, Director, Head of Corporate Communications and Investor Relations. Please go ahead.

Hayleigh Collins (Director & Head - Corporate Communications & Investor Relations)

Thank you. Good morning, and welcome to Tayshia's full year twenty twenty four financial results and corporate update conference call. Earlier today, Tayshia issued a press release announcing financial results for the full year ended 12/31/2024. 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 Shawn Nolan, TACHA's Chief Executive Officer Sukhumarna Gandran, President and Head of R and D and Cameron Lam, 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 TAYSHA one hundred and two, including the reproducibility and durability of any favorable results initially seen in the patient's dose to date and clinical trials to positively impact quality of life and alter the course of disease in the patients we seek to treat our research, development and regulatory plans for our product candidates, including the timing of initiating additional trials and reporting data from our clinical trials the potential for the product candidate to receive regulatory approval from the FDA or equivalent foreign regulatory agencies the 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 twenty twenty six. This call may also contain forward looking statements relating to Tayshia's growth, forecasted cash runway and future operating results, discovery and development of product candidates, strategic alliances and intellectual property, as well as matters that are not historical facts or information. Various risks may cause Tayshia's actual results to differ materially from those stated or implied in such forward looking statements.

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 12/31/2024, that we filed today. This conference call contains time sensitive information that is accurate only as of the date of this live broadcast, 02/26/2025. Tayshia 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 (CEO & Chairman)

Thank you, Haley, and welcome, everyone, to our full year twenty twenty four financial results and corporate update conference call. I will begin with a brief update on our recent activities, then Doctor. Sooku Nagendran, President and Head of R and D of TASIA will provide an update on our lead TASIA-one hundred and two 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 onetwo trials to further elucidate the therapeutic potential of TAYSHA-one hundred and two and inform the development plan for the next phase of the trials.

We are pleased with the pace at which our TAYSHA-one hundred and two 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 TATIA-one hundred and two toward the pivotal phase of the REVEAL trials. I am pleased to share that both the high and low dose of TATIA-one hundred and two continued to demonstrate an encouraging safety profile. TATIA-one hundred and two 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 two REVEAL trials as of the February 2025 data cutoff. Importantly, we have completed dosing of the 10 patients in Part A, the dose escalation portion of the REVEAL Phase onetwo adolescent adult and the REVEAL Phase onetwo pediatric trial.

This includes six patients in Cohort two evaluating the high dose of TASIA-one hundred and two at 1e15 total vector genomes and four patients in Cohort one evaluating the low dose of TASIA-one hundred and two of 5.7 to the 14 total vector genomes. This maturing dataset 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 dataset 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 dataset in hand that enables us to further solidify the regulatory pathway for TASIA-one hundred and two with the FDA. Previously, we announced that following regulatory meetings with the FDA regarding our ongoing TAYSHA-one hundred and two 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 TAYSHA-one hundred and two consistently showed clinical improvements and functional gains across multiple domains as early as four 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 TAYSHA-one hundred and two, we have continued to evaluate the four patients in the low dose cohort and have expanded our data set by completing dosing of the six 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 TASIA-one hundred and two 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 TAYSHA-one hundred and two toward a pivotal trial design that objectively assesses functional gains across key clinical domains impacted in Rett syndrome to bring TASIA-one hundred and two 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 TASIA-one hundred and two. We look forward to providing an update on the pivotal Part P trial design in the first half of twenty twenty five. 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 twenty twenty five. 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 Sooku to provide more context on these advancements that further support our development approach for TASIA-one hundred and two. Sooku?

Sukumar Nagendran (President & Head - Research & Development)

Thank you, Sean, and good morning, everyone. As Sean mentioned, we have made significant progress on the advancement of our TACE-one hundred and two program. TACE-one hundred and two is a one time intratheically delivered gene therapy that's strategically designed to enable optimal and controlled transgene expression on a cell by cell basis across the central nervous system. Recall, we have two ongoing Phase onetwo REVEAL trials evaluating TASIA-one hundred and two, an adolescent and adult trial taking place in Canada and The U. S.

For patients aged 12 and older with Stage four X syndrome and a pediatric trial taking place in The U. S, The UK and Canada for patients five to eight years of age with Stage three Rett Syndrome. We are currently evaluating TASIA-one hundred and two in Part A, the dose escalation portion of both trials evaluating two 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 TAYSHA-one hundred and two 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 and developmental skills. RECT syndrome typically begins with normal development during the first six to eighteen 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 five to six, 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 20 fourseven care and lifelong assistance in daily tasks, 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 onetwo trials are in the post regression phase of the disease where functional gains or restoration of lost 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 heating 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 TASIA-one hundred and two. Based on our data driven findings and ongoing discussions, we continue to believe that functional outcomes are the most relevant, objective and clinically meaningful assessment of the treatment effect of TASIA-one hundred and two in patients with Rett Syndrome. As a result, we anticipate that our pivotal trial design will be distinct from previously approved treatment for Rett Syndrome. We continue to work closely with the FDA to further solidify the regulatory path pathway for TASIA-one hundred and two 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 Cameron to discuss financial results. Cameron?

Kamran Alam (CFO)

Thank you, Sooku. Research and development expenses were $66,000,000 for the full year ended 12/31/2024, compared to $56,800,000 for the full year ended 12/31/2023. The $9,200,000 increase in the year ended 12/31/2024 was driven by good manufacturing practices or GMP batch activities for the intended commercial manufacturing process for CATIA-one hundred and two and additional clinical trial activities across the two REVEAL Phase onetwo clinical trials in 2024. General and administrative expenses were $29,000,000 for the full year ended 12/31/2024 compared to $30,000,000 for the full year ended 12/31/2023. The decrease of $1,000,000 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 12/31/2024 was $89,300,000 or $0.36 per share compared to a net loss of $111,600,000 or $0.96 per share for the full year ended 12/31/2023. As of 12/31/2024, Tayshia had $139,000,000 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 twenty twenty six. I will now turn the call back over to Sean for his closing remarks. Sean?

Sean Nolan (CEO & Chairman)

Thank you, Cameron. This is an exciting time for our TAYSHA-one hundred and two clinical development program. With critical progress made that we believe strongly positions us for success as we work to bring TAYSHA-one hundred and two to the Rett syndrome community as expeditiously as possible. And what we expect to be a transformative year ahead, we are focused on advancing TASIA-one hundred and two 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 TASIA-one hundred and two 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 twenty twenty five, including providing an update on the pivotal trial design for TASIA-one hundred and two 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 and A session. Operator?

Operator (participant)

Thank The first question comes from the line of Kristian Kluska from Cantor Fitzgerald. Please go ahead.

Kristen Kluska (Equity Research Analyst)

Hi, good morning. 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.

Sean Nolan (CEO & Chairman)

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, etcetera.

Kristen Kluska (Equity Research Analyst)

Very helpful. Thanks. I'll get back in the queue.

Sean Nolan (CEO & Chairman)

Thanks, Kristen.

Operator (participant)

Thank you. The next question comes from the line of Salveen Richter from Goldman Sachs. Please go ahead.

Salveen Richter (Biotechnolgy Equity Research)

Good morning. Thanks for taking my questions. 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?

Sean Nolan (CEO & Chairman)

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 would be to show very clear 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 two things. One is continue to let the datasets 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's 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 is 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.

Salveen Richter (Biotechnolgy Equity Research)

Yes. Thank you.

Sean Nolan (CEO & Chairman)

You're welcome.

Operator (participant)

Thank you. The next question comes from the line of Chris Raymond from Piper Sandler. Please go ahead.

Christopher Raymond (MD & Senior Biotechnology Analyst)

Yes. Thanks and congrats from us on the progress as well. Just on the competitive setup and sort of the broader RET 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 for 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.

Sean Nolan (CEO & Chairman)

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 rec community. The more options they have, the better, right? And that's what we're working towards. I think everyone who's in this 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 on 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 four 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 or 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 that's much less invasive. Hopefully that gives you some perspective.

Christopher Raymond (MD & Senior Biotechnology Analyst)

Yes, that's perfect. Thank you.

Operator (participant)

Thank you. The next question comes from the line of Gil Blum from Needham and Company. Please go ahead.

Gil Blum (Senior Analyst)

Hi everyone and thanks for taking our questions and congrats on the progress here. So I may have missed this earlier, but do you guys discuss the kind of data disclosures that we should expect in the first half given today you updated enrollment and dosing?

Sean Nolan (CEO & Chairman)

Yes, Gil, no, we didn't. So it's a good question. So in the first half, we'll give there's two 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 six patients across pediatrics, adolescents and adults. And And we've stated that we'd like to have the majority of those patients have a minimum of six 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.

Gil Blum (Senior Analyst)

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 and CGIS or is this a completely open ended question?

Sean Nolan (CEO & Chairman)

Yes, I can say in that, 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 springtime of last year, '1 of our first RMAT meetings where we talked about endpoints. The FDA pointed to RSPQ 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 and CGIS can be informative, but those are also very subjective in how they're being measured.

You're generally looking at the overall gestalt 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.

Sukumar Nagendran (President & Head - Research & Development)

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 veer 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 some part 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 THC GI SN RSV care never truly been validated, right, to look at the impact of a therapy until they did it for debut, 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. Or they'll be secondary, I'm sorry. They could be secondary, not primary.

Gil Blum (Senior Analyst)

All right. All right guys, very helpful. Thank you.

Sean Nolan (CEO & Chairman)

Thanks Gil.

Operator (participant)

Thank you. The next question comes from the line of Maury Raycroft from Jefferies. Please go ahead.

Maury Raycroft (Equity Research Analyst)

Hi, good morning. I'll add my congrats on the progress and thanks for taking my questions. Just clarifying as of the February 25 cut off for safety, just wondering if you can provide more perspective on whether you think you're past a critical point for SAEs or DLPs in these patients?

Sean Nolan (CEO & Chairman)

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 two to six 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 Sooku, I don't know if there's more you'd add given all your experience across gene therapy companies.

Sukumar Nagendran (President & Head - Research & Development)

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

Maury Raycroft (Equity Research Analyst)

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.

Sukumar Nagendran (President & Head - Research & Development)

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 RECA 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.

I mean intrathecal is actually in general very mild. You see some LFTs that go up marginally, which shut control with prednisolone and then other minor things that happen that one would say maybe related to an immune response, but that's about it. We haven't seen anything else.

Maury Raycroft (Equity Research Analyst)

Got it. Okay. That's helpful. And then just as a follow-up question, you mentioned the six 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?

Sean Nolan (CEO & Chairman)

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 those 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.

Maury Raycroft (Equity Research Analyst)

Got it. Okay. Thanks for taking my questions.

Sean Nolan (CEO & Chairman)

Thanks, Maury.

Operator (participant)

Thank you. The next question comes from the line of Yanan Zhu from Wells Fargo. Please go ahead.

Yanan Zhu (Analyst)

Great. Thanks for taking the questions. Wondering how close are you to an agreement on the endpoint? Will the alignment come before the first half data update?

Sean Nolan (CEO & Chairman)

Jan, and I would say that 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.

Yanan Zhu (Analyst)

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 changes can be achieved at this point? Thank you.

Sean Nolan (CEO & Chairman)

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 meaning, going from being able to sit unassisted, going from a sit to a stand, all of those things are meaningful from a clinical perspective or 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.

Yanan Zhu (Analyst)

Great. Thanks for all the color.

Sean Nolan (CEO & Chairman)

Thanks, Amit.

Operator (participant)

Thank you. The next question comes from the line of Jack Allen from Baird. Please go ahead.

Jack Allen (Senior Research Analyst)

Hey, thank you so much for taking the questions and 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 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 you reach alignment that you're at alignment?

Is there a catalyst that you're looking for in the next three months here to reach regulatory alignment? And then I have a quick follow-up as well on the dosing, the high dose?

Sean Nolan (CEO & Chairman)

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 as 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 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 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.

Jack Allen (Senior Research Analyst)

Got it. That makes a lot of sense.

And then just a brief follow-up on the completion of the dosing, the high dose cohort. I guess, you mentioned on the call previously that the window for acute SAEs for gene therapies is two to six 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 two to six week window, how should we think about interpreting the timing of dosing and where we are as it relates to acute toxicities?

Sukumar Nagendran (President & Head - Research & Development)

Sean, do you want to take that?

Sean Nolan (CEO & Chairman)

Yes, go ahead please.

Sukumar Nagendran (President & Head - Research & Development)

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 four to six 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, as you've seen in gene therapy, you can get the enzymes in systemic interventions or administration where it can go ten, fifteen, 20 times 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 TAYSHA one hundred and two, I have no concern of from a safety standpoint because it's pretty standard and routine. So I guess what I'm saying is the benefit outweighs the risk. Does that make sense?

Jack Allen (Senior Research Analyst)

Yes.

Sean Nolan (CEO & Chairman)

Jack, the other thing I would say to Sukru'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.

Jack Allen (Senior Research Analyst)

That's great. Thank you so much for the color and congrats on all the progress.

Sean Nolan (CEO & Chairman)

Thanks, Jack.

Operator (participant)

Thank you. The next question comes from the line of June Lee from Truist Securities. Please go ahead.

Mehdi Goudarzi (Biotech Equity Research Analyst)

Hi, good morning and congrats on the progress. This is Mehdi on for June. A couple for us. So could you provide some color on the latest or final steroid serolimus dosing and paper regimen that you have? And is this something that you need to also align with FDA on that?

Sean Nolan (CEO & Chairman)

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 it right now a combination of steroids and Sarah Limus. The Sarah Limus is a six 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 they 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 started with 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.

Mehdi Goudarzi (Biotech Equity Research Analyst)

Awesome. And as 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?

Sean Nolan (CEO & Chairman)

We have not disclosed MP 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 that 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.

Mehdi Goudarzi (Biotech Equity Research Analyst)

Thank you.

Sean Nolan (CEO & Chairman)

Thank you.

Operator (participant)

Thank you. The next question comes from the line of Selwyn Toukjan from Citizens. Please go ahead.

Silvan Türkcan (Managing Director)

Yes. Thanks for taking my question and congrats on all the updates here. Just a question sorry to harp on these two 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 two gene therapy RET trials that are ongoing there about to move into pivotal? And would any of that be gating any of these trials be gating for each other? And then I have a quick follow-up. Thank you.

Sean Nolan (CEO & Chairman)

Yes, Sylvan, 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 datasets, 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 competitors 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 timeline that we've essentially agreed to with the FDA.

Silvan Türkcan (Managing Director)

Great. Thanks. 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 their different weights?

Sean Nolan (CEO & Chairman)

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 eighty percent, eighty five percent of each other. So it's pretty similar, which allows for the fixed dose to be the same.

Silvan Türkcan (Managing Director)

Great. Thank you. Congrats again.

Sean Nolan (CEO & Chairman)

Thanks, Sylvain.

Operator (participant)

The next question comes from the line of Evan Seagavan from BMO Capital Markets. Please go ahead.

Malcolm Hoffman (Senior BioPharma Equity Research Associate)

Hi, Makkum Hoffman on for Evan. Appreciate you taking our question. Focusing on dose limiting toxicities just once more, you had noted you had not seen any DLTs in patients just 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 three times the upper limit of normal or 5x maybe? Just trying to get your thoughts there. Thanks.

Sean Nolan (CEO & Chairman)

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 that they are suppressed by the time they get the drug. And so far things have been relatively low, not clinically meaningful, but Sooku, feel free to go ahead and give your perspective on that question.

Sukumar Nagendran (President & Head - Research & Development)

Yes, Sean, as I said previously, usually what you see is the most up to three times upper limits of normal. Really it can go above that, but prednisolone completely controls it. And I would say that the particular approach up to now is probably safer than many of the oral medications 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.

Malcolm Hoffman (Senior BioPharma Equity Research Associate)

Appreciate it. Thanks guys.

Sean Nolan (CEO & Chairman)

Sure. Thank you.

Operator (participant)

Thank you. The next question comes from the line of Whitney Ajim from Canaccord Genuity. Please go ahead.

Angela Qian (MD & Senior Biotechnology Analyst)

Hi. Thank you for taking your question. This is Angela on for Whitney. Can you just confirm quickly we'll be getting at least six 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 regular Tory update, how is that going to change? Thank you.

Sean Nolan (CEO & Chairman)

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 six patients, we've said that the majority of those patients would have at least six 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's 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.

Operator (participant)

Thank you.

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

Sean Nolan (CEO & Chairman)

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

Operator (participant)

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