Q4 2024 Taysha Gene Therapies Inc Earnings Call
Speaker Change: Ladies and gentlemen, good morning and welcome to the Teja Gene Therapy's full year 2024 conference call. At this time, all participants are in a listen-only mode. A brief question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please signal the operator by pressing star and zero on your telephone keypad.
Speaker Change: 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.
Speaker Change: Thank you. Good morning and welcome to Tayshia's full year 2024 financial results and corporate update conference call. Earlier today Tayshia issued a press release announcing financial results for the full year ended December 31st 2024.
Speaker Change: A copy of this press release is available on the company's website and through our SEC filings.
Speaker Change: Joining me on today's call are Sean Nolan, TASIA's Chief Executive Officer, Sukumar Nagendran, President and Head of R&D, and Kamran Alam, Chief Financial Officer.
Speaker Change: We will hold a question and answer session following our prepared remarks.
Speaker Change: Please note that on today's call, we will be making forward-looking statements.
Speaker Change: including statements concerning the potential of Tayshia-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 our product candidates, including the timing of initiating additional trials and reporting data from our clinical trials.
Speaker Change: the potential for the product candidate to receive regulatory approval from the FDA or equivalent foreign regulatory agencies.
Speaker Change: The clinical potential of intra-fecal 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.
Speaker Change: This column may also contain forward-looking statements relating to TASHA'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.
Speaker Change: Various risks may cause TASIA's actual results to differ materially from those stated or implied in such forward-looking statements.
Speaker Change: 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.
Speaker Change: This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, February 26, 2025.
Tayshia: Tayshia undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. Acceptance 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 full-year 2024 Financial Results and Corporate Update Conference Call.
Speaker Change: I will begin with a brief update on our recent activities, then Dr. Sukumar Nagendran, president and head of R&D of Tayshia, will provide an update on our LEAD Tayshia 102 gene therapy program and clinical evaluation for Rett syndrome.
Speaker Change: 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
Speaker Change: has been marked by exceptional execution as we have focused on generating critical, longer term clinical data across our two reveal phase one, two trials.
Speaker Change: We are pleased with the pace at which our TATIA 102 program is advancing across a broad range of ages and stages of patients with Rett syndrome.
Speaker Change: Importantly, we believe the progress we have made has set the stage for a highly impactful 2025 as we focus on advancing Tatia 102 toward the pivotal phase of the reveal trials.
Speaker Change: I am pleased to share that both the high and low dose of Tayshia 102 continue to demonstrate an encouraging safety profile.
Speaker Change: Tayshia 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 two reveal trials as of the February 2025 data cutoff.
Speaker Change: Importantly, we have completed dosing of the 10 patients in Part A, the dose escalation portion of the REVEAL Phase 1-2 Adolescent Adult and the REVEAL Phase 1-2 Pediatric Trial.
Speaker Change: This includes 6 patients in Cohort 2 evaluating the high dose of Tayshia-102 at 1 e to the 15 total vector genomes.
Speaker Change: and four patients in Cohort 1 evaluating the low-dose Ceptatia 102 of 5.7 e to the 14 total vector genomes.
Speaker Change: This maturing data set continues to support our advancement toward the pivotal Part B trial as part of our ongoing discussions with the FDA.
Speaker Change: 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.
Speaker Change: 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 Tayshia 102 with the FDA.
Speaker Change: Previously, we announced that following regulatory meetings with the FDA regarding our ongoing Tayshia 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 revealed trials.
Speaker Change: Recall, the clinical data presented from the adult and pediatric patients with varying genotypes and disease severity.
Speaker Change: including those with the most advanced stage of Rett syndrome, treated with the low dose of Tayshia 102, consistently showed clinical improvements and functional gains across multiple domains as early as four weeks post-treatment that persisted and strengthened over time.
Speaker Change: This included improvements and functional gains across the domains of fine and gross motor function, socialization and communication, autonomic function, and seizure events.
Importantly...
Speaker Change: 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
Speaker Change: To further assess the therapeutic potential of Tayshia 102, 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
Speaker Change: are the most relevant, objective, and clinically meaningful assessments of the treatment effect of Tayshia 102 in patients with Rett syndrome, where functional gains or restoration of loss in function are not expected to occur in the untreated population.
Speaker Change: As such, based on our ongoing discussions with the FDA and the totality of the clinical data we have collected,
Speaker Change: Our goal is to advance Tayshia 102 toward a pivotal trial design that objectively assesses functional gains across key clinical domains impacted in Rett syndrome. To bring Tayshia 102 to patients as expeditiously and as safely as possible.
and others.
Speaker Change: We remain encouraged by our productive, ongoing discussions with the FDA through the Regenerative Medicines Advanced Therapy, or RMAP, mechanism and the strong, maturing data set we have in hand that provides us the further ability to solidify the regulatory pathway for Tayshia 102.
Speaker Change: We look forward to providing an update on the Pivotal Part P trial design in the first half of 2025.
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: I will now turn the call over to Suku to provide more context on these advancements that further support our development approach for TASIA 102. Suku?
Suku: Thank you Sean and good morning everyone. As Sean mentioned, we have made significant progress on the advancement of our TESA 102 program.
Suku: KeSHA-102 is a one-time 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.
Suku: Recall, we have two ongoing Phase 1, 2 reveal trials evaluating TESHA 102, an 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.
Suku: the UK and Canada for patients 5 to 8 years of age with stage 3 Rett syndrome.
Suku: We are currently evaluating TESLA-102 in Part A, the dose escalation portion of both trials evaluating two dose levels.
Suku: 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.
Suku: We previously announced that following regulatory meetings with the FDA regarding our ongoing TESHA 102 development plan, we intend to focus on objective measures that clinically capture improvements in the core features of Rett syndrome.
Suku: To put this in perspective, I will review key characteristics of Rett syndrome.
Suku: Rett syndrome is a rare progressive neurodevelopmental and neural network disease
Suku: that inhibits neuronal development and leads to complication across multiple domains including fine and gross motor function, socialization and communication, autonomic function and seizures.
Suku: It is a heterogeneous condition, so individuals experience different levels of clinical severity based on their distinct genetic background.
Suku: 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
6-18 months of life
Suku: 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.
Suku: where individuals lose many of these previously acquired functional skills and milestones, typically resulting in the loss of purposeful hand function, motor coordination, and verbal communication.
Suku: They also start to develop new disease features, such as hand stereotypies, seizures, and autonomic dysfunction, including breathing, sleep, and cardiac abnormalities.
Suku: 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.
Suku: or regain skills that have been lost due to disease progression.
individuals will continue to experience a decline over time.
Suku: These functional impairments and disease features typically result in the loss of independence as patients are unable to perform daily activities or communicate needs.
Suku: They usually require 24-7 care and lifelong assistance in daily tasks.
Suku: placing a significant burden on caregivers that impact their quality of life.
There is a high unmet need.
for this devastating disease.
Suku: Patients being evaluated in our REVEAL Phase 1-2 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.
Suku: 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.
Thank you.
Suku: 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.
Suku: These outcomes have shaped our interaction with the FDA regarding the optimal regulatory pathway for TESA 1 or 2.
Suku: 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 TESA-102 in patients with Rett syndrome.
Suku: As a result, we anticipate that our favorable trial design will be distinct from previously approved treatments for Rett syndrome.
Suku: We continue to work closely with the FDA to further solidify the regulatory pathway for K702 based on the maturing safety and efficacy dataset from Part A that we now have in hand.
Suku: I will now turn the call over to Kamran to discuss financial results. Kamran?
Thank you very much.
Kamran Alam: Thank you, Suku. Research and development expenses were $66 million for the full year ended December 31st, 2024, compared to $56.8 million for the full year ended December 31st, 2023.
Kamran Alam: The $9.2 million increase in the year ended December 31, 2024, was driven by good manufacturing practices or GMP batch activities.
Kamran Alam: for the Intended Commercial Manufacturing Process for Tayshia-102 and additional clinical trial activities across the two revealed Phase I-II clinical trials in 2024.
Kamran Alam: 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.
Kamran Alam: 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.
Kamran Alam: Net loss for the full year ended December 31st, 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 31st, 2023.
Kamran Alam: As of December 31st, 2024, Tayshia had $139 million in cash and cash equivalents.
Kamran Alam: We continue to expect that our current cash resources will support planned operating expenses and capital requirements into the fourth quarter of 2026.
Sean Nolan: I will now turn the call back over to Sean for his closing remarks. Sean?
Thank you, Kamran.
Sean Nolan: This is an exciting time for our Tayshia 102 clinical development program, with critical progress made that we believe strongly positions us for success as we work to bring Tayshia 102 to the Rett syndrome community as expeditiously as possible.
Sean Nolan: In what we expect to be a transformative year ahead, we are focused on advancing Tayshia 102 toward the pivotal phase of the reveal trials.
Sean Nolan: 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 Tayshia-102 with the FDA.
Sean Nolan: 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.
Sean Nolan: including providing an update on the pivotal trial design for Tayshia 102 and clinical data across the high and low-dose cohorts in both our revealed trials.
Sean Nolan: With that, I will now ask the operator to begin our Q&A session. Operator?
Thank you.
Speaker Change: Ladies and gentlemen, we will now begin the question and answer session. If you would like to ask a question, please press star and 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star and 2 if you would like to remove your question from the queue.
Sean Nolan: For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys.
Sean Nolan: Ladies and gentlemen, we request you to limit to one question and one follow-up question per participant.
One moment please, while we poll for questions.
Sean Nolan: The first question comes from the line of Christian Kluska from Cantor Fitzgerald, please go ahead.
all three seen in the FDA.
Sean Nolan: Thanks for the question, Kristen. I could say that, you know, consistently...
Sean Nolan: in our discussions, you know, 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.
Sean Nolan: both 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.
Sean Nolan: from the new administration as related to our program. So we've seen consistent broad attendance from the FDA across clinical, CMC, preclinical, etc.
Very helpful. Thanks. I'll get back in the queue.
Thanks, Kristen.
Speaker Change: Thank you. The next question comes from the line of Salveen Richter from Goldman Sachs. Please go ahead.
Speaker Change: and many more. Thank you. Thank you. Thank you. Thank you.
Salveen Richter: 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?
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Salveen Richter: Yes, Alvin. 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.
Salveen Richter: 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
Salveen Richter: The best put forward would be to show very clear, clinically meaningful, objective improvements. And we think we've reported, you know, at least to date,
Salveen Richter: 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...
Salveen Richter: constructive and positive in those discussions. They have not tried to steer us down a different path.
and they've continued to encourage us.
Salveen Richter: to do two things. One is, you know, continue to let the data sets mature, dose more patients.
Salveen Richter: And also, you know, we've talked about work we've done on natural history, you know, that we think would further contextualize the data that we're putting in front of them. And so all that has been very consistent.
Salveen Richter: 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, you know consistent in that regard
Salveen Richter: To the second part of your question, you know, the domains that we listed that Suku kind of outlined
Salveen Richter: you know, are the ones that the FDA and also, frankly, caregivers
really emphasize.
It's communication and socialization.
Salveen Richter: 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.
Salveen Richter: They've acknowledged the fact that these are all very clinically meaningful based on what is happening to an individual patient. Hope that helps.
Thank you very much.
Yes, thank you.
You're welcome.
Speaker Change: Thank you. The next question comes from the line of Chris Raymond from Piper Sandler. Please go ahead.
Chris Raymond: Thanks and 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.
Chris Raymond: You know so far with this update it seems you know your high dose looks pretty good You may be just you know. I know this is maybe a horse crap for the horse kind of question, but
Chris Raymond: You know talk about the differentiating factors I think that we should be looking for you know as the clinical pictures of both therapies start to emerge
Yeah, Chris, I think that, you know...
Speaker Change: 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, you know, improvements available, therapeutic options for the rec community. You know, 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.
Chris Raymond: 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, you know,
Chris Raymond: taken a choice to use self-complementary technology, we're making protein much much quicker than somebody who would be using a single strand.
Chris Raymond: And if you're able to mediate the production of MECP2 on a cell-by-cell basis, so you're producing protein
Chris Raymond: 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
Chris Raymond: with our construct. And I would point you to the data that we released back in the summertime, where within four weeks,
Chris Raymond: You know, 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
Chris Raymond: you know, the stage or the age of the patient. So I think, in our view, onset's 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, you know, certainly makes sense.
Chris Raymond: 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.
Chris Raymond: And I would encourage you to take a look at, you know, from a competitive perspective, you know, it seems like, you know, maybe there's a better response to some of the less severe patients based on what was reported.
Chris Raymond: by others. We're seemingly viewing that we're seeing response across genotypes and across disease severities. And the last piece would be
Chris Raymond: Again, that based on what we're seeing so far from a safety perspective, you know, having a route of administration that's less invasive is certainly beneficial, you know, to the patient themselves and the caregivers, given that it's much less invasive. Hopefully that gives you some perspective.
Yes, that's perfect. Thank you.
Speaker Change: Thank you. The next question comes from the line of Gil Bloom from Needham and Company. Please go ahead.
Speaker Change: Hi everyone and thanks for taking our questions and congrats on the 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 in a dosing?
Speaker Change: Yeah Gil, no we didn't, so it's a good question. So in the first half we'll give
Speaker Change: There's two kind of, I would say, buckets of an update, right? The first would be, you know, we plan to give an update in the first half on the regulatory side with
Speaker Change: with more specifics around the trial design and primary endpoint in particular. And on the clinical data side, you know, 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.
Speaker Change: across pediatrics adolescents and adults 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
Speaker Change: through the lens of what our clinical trial design would be.
Speaker Change: So that that's the plan, you know, if all that comes together, we'd like to do it all at the same time
Speaker Change: And, you know, that's what we're working towards at this particular juncture. The other thing I would say, Gil, is that...
Speaker Change: 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.
Speaker Change: All right, very helpful and as a follow-on to a prior question
Speaker Change: How open-minded do you feel the FDA is as it relates to endpoints here?
Speaker Change: Do you feel like the agency may stick to, you know, something
Speaker Change: established or known or you know it's like CGI and CGI or is this a completely open-ended question?
Yeah, I can...
Speaker Change: 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
Suku: It was probably around the springtime of last year, one of our first RMAT meetings where we talked about endpoints.
subjective in how they're being measured.
Suku: 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.
Suku: and being informed by that data and they understand that the path we're going down, again, assuming...
Suku: we get full alignment there you know would make a lot of sense for the reasons that I've that I've essentially outlined so I would say there's a definitely an open-mindedness driven by the evidence
Suku: 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.
Suku: 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
truly clinically meaningful or transformative.
then the FDA tends to wear towards that because that
justifies approving that product.
Suku: rapidly, so that patients can have, you know, hopefully a better life.
Thank you very much.
Speaker Change: That gives you some sense of disease, the impact of the product, even though the product, I mean those measures like PHCGIS and RSVQ have never truly been validated, right? To look at the impact of a therapy until they did it for their book.
Speaker Change: 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, you know.
Speaker Change: Oh, they'll be secondary, I'm sorry, they could be secondary, not primary.
All right. All right, guys. Very helpful. Thank you.
Thanks Gil.
Speaker Change: Thank you. The next question comes from the line of Maury Raycroft from Jefferies. Please go ahead.
Maury Raycroft: Hi, good morning. I'll add my congrats on the progress and thanks for taking my questions. Just clarifying, as of the February 25th 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?
Speaker Change: 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, you know, two to six weeks.
Speaker Change: and we recently had an IDMC meeting and these patients' data were all reviewed.
Speaker Change: And so, you know, 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, you know, gene therapy companies.
Yes, Sean, just to make sure I heard you correctly.
Suku: You were referring to our program, right, when it comes to the intrathecal.
Speaker Change: Proud of administration, whether we've seen anything of safety concern, correct?
Speaker Change: Yes, yeah, correct. As of the safety cutoff, or the February 25th cutoff, just if you think you're past a critical point for safety issues.
Speaker Change: just to kind of lay the framework in a practical approach.
Speaker Change: seems to be very safe across the board. When it has been developed for many diseases, it applies to our program in RECT as well. There has been no treatment related or DLTs of any concern.
Speaker Change: And what you find, again, I mean, I'm sure you've seen the literature, whether it's systemic or whether it's in tracheal,
Speaker Change: It's actually, in general, very mild. You see some LFTs that go up marginally, which are controlled 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.
Thank you for watching!
Got it. Okay, that's...
Paul Poern
Speaker Change: 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?
Speaker Change: Well, Maury, I would say that we've been having those those conversations on an ongoing basis, you know, 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.
Speaker Change: So, you know, I would say we're not limited right now. The discussions are ongoing and, you know, we're on pace to give the updates that we've laid out in terms of first half disclosures.
Got it. Okay, thanks for taking my questions.
Speaker Change: Thanks, Maureen. The next question comes from the line of Yan and Sue from Belfargo. Please go ahead.
Speaker Change: Great, thanks for taking the questions. I'm wondering how close are you to an agreement on the endpoint? Will the alignment come before the first half data update?
Speaker Change: Jan and I would say that again we feel you know very
Speaker Change: 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, you know, constructive
Speaker Change: discussions along the way so you know we feel 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
Speaker Change: the clinical data update just because I think it would be the the most informative way for
Speaker Change: 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.
Speaker Change: That's the preference, you know, we'll have to see just based on how things completely sequence, but but that's what we're working towards
Great. Also wondering...
Speaker Change: 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.
Speaker Change: Yeah, I think for competitive reasons we won't get into a lot of the detail.
Speaker Change: If you go back and look at our disclosures of where we've reported functional gains.
Speaker Change: things ranging from sitting unassisted, improvements in communication, the ability to use words with meaning, going from a...
Speaker Change: being able to sit unassisted, going from a sit to a stand.
Speaker Change: You know, all of those things are meaningful from a clinical perspective or meaningful from a caregiver perspective. And so
Speaker Change: 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.
Thank you.
Great. Thanks for all the coverage.
Thanks, y'all.
and many more. Thank you. Thank you.
Jack Allen: Thank you. The next question comes from the line of Jack Allen from Baird. Please go ahead.
Jack Allen: 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...
Speaker Change: What are the gatekeeping aspects as it relates to reaching alignment with FDA? Is there a specific type of meeting you want to have?
Speaker Change: 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 reach alignment that you're at alignment, or is there a catalyst that you're looking for in the next?
Speaker Change: I'll three months here to reach regulatory alignment, and then I have a quick follow-up as well on the dosing, the high dosing.
Speaker Change: Jack, I mean, we use the words ongoing for a purposeful reason. I mean, they really are ongoing discussions.
Speaker Change: I think, you know, I alluded to earlier in the call that, you know, 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, you know, they're digesting that. We're doing some discussions and back and forth.
Speaker Change: on that. You know, 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, you know, helps, you know, support the case in our view, you know, 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...
Speaker Change: 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.
Speaker Change: 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.
Thank you very much.
Speaker Change: 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.
Speaker Change: I guess you mentioned on the call previously that the the window for acute SAEs for gene therapies is two to six weeks
Speaker Change: 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?
Speaker Change: two to six week window, how should we think about interpreting the timing of dosing and where we are as it relates to acute toxicity?
and many more. Thank you. Thank you.
Speaker Change: Yeah, so that's a good question. So in the first, okay, so the commonest clinical observation you see with intrathecal gene therapy,
Speaker Change: 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.
Speaker Change: The elevation is very mild, I mean, again, if you've seen gene therapy, you know, you can get the enzymes and systemic
Speaker Change: interventions or administration where it can go 10, 15, 20 times upper limits of normal or more, but prednisone almost always controls it and it's the same.
Speaker Change: 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, you know, TESHA 102,
Speaker Change: 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?
Yeah. Yeah. In the chat.
Speaker Change: Jack, the other thing I would say to Suku's point is that, you know, we did recently just have an IDMC meeting and the IDMC reviewed 10 patients' worth of safety data that's all available, and, you know, we obviously just disclosed that we've seen no treatment-related SAEs or DLTs.
Speaker Change: You know, you can never say never, but, you know, we've got 10 patients worth of data, and, you know, so far everything looks to be very encouraging on the tolerability profile.
Speaker Change: That's great. Thank you so much for the call and congrats on all the progress.
Thanks, Jack.
Speaker Change: Thank you. The next question comes from the line of June Lee from Truist Securities. Please go ahead.
Speaker Change: Hi, good morning and congrats on the progress. This is Maydeon for June. A couple for us. So could you provide some color on the latest or final steroid, serolimus dosing and taper regimen that you have and is this something that you need to also align with FDA or not?
Yeah, the FDA really has had no...
Speaker Change: They gave us no direction on their recommendations from the beginning on immune suppression, you know, they left that up to the company.
Speaker Change: And to your point, you know, we've got right now a combination of steroids and serolimus. The serolimus is a six-month paper.
at this point.
Speaker Change: And, you know, we'll be evaluating that for Part B just because, you know, we've been encouraged by the safety profile we see and there can very well be a case that we may not use that.
Speaker Change: in Part B. We don't think it's necessary. It's a discussion that, you know, that we've had internally. So, you know, time will tell there, but I think with what we've generated to date, you know, 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.
Speaker Change: Awesome. And as a follow-up, 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?
and many more. Thank you. Thank you.
Speaker Change: We have not disclosed MP to full ratio and we will likely not do that. I would just say that from a CMC perspective, you know, we're very comfortable. We've never had any, I think if you look at our disclosures that the CMC discussions have always been
Speaker Change: quite constructive. We've never, you know, 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 just remind you that we are at scale. The FDA has as effectively, you know, 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.
Thank you.
Thank you.
Speaker Change: Thank you. The next question comes from the line of Selvin Turkcan from Citizens. Please go ahead.
Speaker Change: Thanks for taking my question and congrats on all the updates here. Just a question, sorry to harp on these pivotal endpoints here, but do you get a sense that the FDA wants to harmonize
Speaker Change: the trial design and specifically the endpoints across the two gene therapy red trials that are ongoing. They're about to move into pivotal and would any of them be gating, you know, any of these trial designs be gating for each other? And then I have a quick follow-up. Thank you.
Speaker Change: Yes, Sylvan, it's a good question. The short the short answer is I don't know. My view all along has been
Speaker Change: The premise of my view is based on the fact that
If you have
similar
Speaker Change: 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, you know, assumption.
But if you if you could then harmonize
Speaker Change: 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.
Speaker Change: I don't know that it would be necessarily exactly the same, but it could be similar.
Speaker Change: and all I can say is is that we 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
Speaker Change: 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.
Thank you.
Speaker Change: Great, thanks. And I don't know if I can comment on this, but is there any difference between the safety and tolerability in the pediatric versus the adolescent high-dose patients, you know, given their
different weights.
Speaker Change: No, no, we haven't seen any, you know, as we've reported, we've seen no treatment-related SAEs or DLTs. Keep in mind that the...
Speaker Change: The CNS volume of the kids that we're treating and the adolescents and adults is, you know, generally within 80, 85% of each other. So it's pretty similar, which allows for the fixed dose to be the same.
Great, thank you and congrats again.
Thanks, Sylvan.
Speaker Change: The next question comes from the line of Evan Segerwin from BMO Capital Markets. Please go ahead.
Speaker Change: I'm Malcolm Hoffman on for Evan. I appreciate you taking our question.
Speaker Change: Focusing on dose-limiting toxicities just once more, you had noted you had not seen any DLTs in patients' dose 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, you know, three, less than three times the upper limit of normal or 5x maybe? Just trying to get your thoughts there. Thanks.
Speaker Change: Yeah, I'll turn it over to Suku. I would just say keep in mind that immunosuppression starts a week before
Speaker Change: 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 Suku, feel free to go ahead and give your perspective on that question.
Suku: Yeah, Sean, as I said previously, usually what you see is the most up to three times upper limits of normal. Rarely it can go above that, but prednisone completely controls it.
Speaker Change: and I would say that the intrathecal approach up to now is probably safer than many of the oral medications out there in the marketplace, you know, for more primary care diseases. So that is also reassuring from a drug development standpoint and I hope that holds, you know.
Thank you.
Appreciate it. Thanks guys. Thank you.
Thank you.
The next question
Speaker Change: comes from the line of Whitney Agyem from Kennecott, Geneva. Please go ahead.
Speaker Change: I 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,
Speaker Change: 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? Thank you.
Speaker Change: Yeah, Angela, what we've said is that the update that we're planning, the low-dose patients would have a minimum of a year worth of data.
and the Heidos.
Speaker Change: which is a total of six patients, we've said that the majority of those patients would have at least six months of data.
Speaker Change: So that's the that's the clarification there. In terms of the disclosure, again I think you'll see the emphasis from us on functional gains.
Speaker Change: 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 on how the patients doing across the clinical domains.
and, you know,
Speaker Change: To us, any scales that we would show would be secondary, and I think that would be the purpose of doing things in concert with the regulatory update, because I think it would be evident to people, you know, why we put the emphasis where we did.
Speaker Change: And even if they were decoupled, I still think we would end up giving the clinical update as I outlined.
Thank you.
Speaker Change: Ladies and gentlemen, as there are no further questions, I will now hand the conference over to Sean Nolan for his closing comments.
Speaker Change: 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.