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spk04: Greetings and welcome to the Tayshia Gene Therapy's first quarter 2024 earnings 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 press star and then zero on your telephone keypad. As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Hayley Collins. Thank you. You may begin.
spk08: Thank you. Good afternoon and welcome to Tayshia's first quarter 2024 financial results and corporate update conference call. Earlier today, Tayshia issued a press release announcing financial results for the first quarter ended March 31st, 2024. A copy of this press release is available on the company's website and through our SEC filings. Joining me on today's call are Sean Nolan, Tayshia's CEO, Sukumar Nagandran, President and Head of R&D, and Cameron Alam. Chief Financial Officer. We will hold a question and answer session following our prepared remarks. Please note that on today's call, we will be making forward-looking statements, including statements relating to the therapeutic and commercial potential of TASHA 102, including the reproducibility and durability of any favorable results initially seen in our first and second patient's dose in the reveal trial to positively impact quality of life and the course of disease in the patients we seek to treat. our research, development, and regulatory plans for our product candidates, including the timelines for our clinical trials and reporting results therefrom, and our current cash resources supporting our planned operating expenses and capital requirements into 2026. These statements may include the expected timing and results of clinical trials for our product candidates and other clinical and regulatory plans, and the market opportunity for those programs. This call may also contain forward-looking statements relating to 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. Various risks may cause the actual results to differ materially from those stated or implied in such forward-looking statements. These risks include uncertainties related to the timing and results of clinical trials and regulatory interactions for our product candidates, our dependence upon strategic alliances and other third-party relationships, our ability to obtain patent protection for our discoveries, limitations imposed by patents owned or controlled by third parties, and the requirements of substantial funding to conduct our research and development activities. For a list and description of the risks and uncertainties that we face, please see the reports that we have filed with the Security and Exchange Commission, including in our annual report on Form 10-K for the full year ended December 31, 2023, and our quarterly report on Form 10-Q for the quarter ended March 31st, 2024, that we filed today. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, May 14th, 2024. TASHA undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities laws. With that, I would now like to turn the call over to our CEO, John Nolan.
spk10: Thank you, Haley, and welcome, everyone, to our first quarter 2024 financial results and corporate update conference call. Today, I will begin with a brief update on our recent activities. Then, Dr. Sukundagendran, President and Head of R&D of TASHA, will provide an update on our lead TASHA 102 program and clinical evaluation for the treatment of Rett syndrome. Cameron Alam, our chief financial officer, will follow up with a financial update. I will provide closing remarks and open the call up for questions. We are pleased with the recent progress that we've made to advance TASHA 102, our lead gene therapy program and clinical evaluation for the treatment of Rett syndrome. This includes reporting encouraging longer-term data for the first two adult patients dosed in the low-dose cohort and enrolling the first patient in the high-dose cohort of our Reveal Phase 1-2 adolescent and adult trial earlier than planned, dosing the second patient in our Reveal Phase 1-2 pediatric trial, and receiving regenerative medicine advanced therapy designation from the FDA for TASHA-102. We believe this progress reinforces the therapeutic potential of TASHA-102 across a broad population of patients with Rett syndrome and supports the continued clinical evaluation of our gene therapy program. We believe that we are well positioned for continued execution across our key upcoming value-creating milestones for our TASHA 102 program with the goal of generating critical longer-term clinical data across broad range of ages and stages of patients with Rett syndrome in multiple geographies that will guide the next phase of our studies. The unmet need and burden of care for Rett syndrome is high. As a rare neurodevelopmental disorder caused by mutations of the MECP2 gene, Rett syndrome afflicts an estimated 15,000 to 20,000 patients in the United States, European Union, and the United Kingdom. Currently, there are no approved disease-modifying therapies that treat the genetic root cause of the disease, and there is a significant unmet medical need. The random X inactivation and subsequent mosaic pattern of ME-CP2 expression results in a mixture of cells that are either deficient in ME-CP2 protein or express ME-CP2 protein normally, which makes Rett syndrome challenging to treat with traditional small molecule and gene therapy approaches. We believe our TASHA-102 gene therapy candidate, equipped with the novel MI-102 RNA-responsive autoregulatory element, or MIRAIR technology, has the potential to appropriately address this challenge by mediating ME-CP2 expression in the central nervous system on a cell-by-cell basis to overcome the risks associated with both under- and overexpression of ME-CP2 protein. We are evaluating TASHA-102 in two ongoing Phase I-II reveal trials. an adolescent and adult trial taking place in Canada and the U.S., and a pediatric trial taking place in the U.S. with clearance in the U.K. As a reminder, our Reveal Phase 1-2 Adolescent and Adult Trial is a first-in-human study assessing the safety and preliminary efficacy of TASHA-102 in females aged 12 years and older with Rett syndrome. We are currently enrolling patients in Part A, the dose escalation portion of the trial, which is evaluating two dose levels of TASHA-102 sequentially. Two patients have been dosed to date in cohort one with the low dose of TASHA-102 of 5.7 e to the 14 total vector genomes, and dosing in cohort one is now considered complete. Following review of the clinical data from the first three patients treated with TASHA-102 across the adolescent and adult trial and the pediatric trial, The Independent Data Monitoring Committee, or IDMC, approved our request to proceed to an early dose escalation in the adolescent and adult trial. Data from Part A of the trial will be assessed by regulatory agencies and the IDMC to provide guidance to determine final key elements of the Part B aspect of our trial, the dose expansion portion. including hierarchy of efficacy endpoints, study duration, and the maximum tolerated dose or maximum administered dose. Therefore, advancing to cohort two, evaluating the high dose of TASHA-102 of 1E to the 15 total vector genomes earlier than planned accelerates our ability to inform our clinical development and regulatory strategy for part B. We're pleased to share the first patient in a high-dose cohort has been enrolled in the study, and dosing is scheduled to take place here in the second quarter of 2024. Earlier this year, we announced encouraging longer-term data for the first two adult patients treated in the low-dose cohort with late motor deterioration, stage four Rett syndrome, and different genetic mutations and severity of disease. Recall, when we initiated and revealed Our focus was primarily on safety, with little expectation of efficacy for the adult population among key opinion leaders in the Rett syndrome community due to the advanced stage of the disease. Therefore, it was very exciting last November to announce the encouraging initial impact of TASHA-102 appeared to have across multiple clinical domains in the first two adult patients as early as four weeks following treatment, despite the trial participants having very different genetic mutations and disease severity. We presented longer-term follow-up data in the first quarter of this year, including a six-month follow-up assessment for the first adult patient, showing a continued durable response with sustained and new improvements in the absence or reduction of steroid levels. As of the six-month assessment, patient one showed sustained improvement across key efficacy measures at decreased steroid levels, with new improvements observed in the red Syndrome Behavioral Questionnaire, or RSVQ. Additionally, the second adult patient demonstrated sustained improvements across key efficacy measures, with new improvements observed in certain measures, including the Revised Motor Behavior Assessment, or RMBA, as of the 12-week assessment, and significantly reduced seizures as of the 19-week assessment following treatment. The longer-term clinical observations reported by the principal investigator showed that both patients had sustained and new improvements across multiple clinical domains impacting activities of daily living, including motor skills, socialization and communication, autonomic function, and seizures, compared to earlier post-treatment assessments. Importantly, these continued improvements were reported at week 35. following completion of the steroid taper for the first patient, and at week 19, at decreased steroid levels for the second patient. Sukhu will discuss these observations in more detail. The longer-term safety profile is also encouraging. Data from the first two adult patients showed that TASHA-102 was well tolerated with no treatment emerging serious adverse events as of week 35 assessment for patient 1 and as of the 19-week assessment for patient 2. We believe the safety profile and continued improvement across multiple clinical domains, even at reduced steroid levels in both adult patients with advanced stage 4 Rett syndrome treated with the low dose of TASHA-102, supports the durability and transformational potential of TASHA-102 across multiple genotypes of Rett syndrome and further validates our construct. We are also focused on evaluating the therapeutic potential of TASHA-102 in the pediatric population, where we hope to see a similar safety profile and a consistent pattern of response across clinical domains in the pediatric patients with different genotypes treated with the low dose of TASHA-102. Our ongoing Reveal Phase 1-2 pediatric trial is evaluating the safety and preliminary efficacy of TASHA-102 and female patients with Rett syndrome age five to eight years old. We are currently enrolling pediatric patients in part A of the trial, which will evaluate two dose levels of TASHA-102 sequentially. We have dosed the second pediatric patient in cohort one, the low dose cohort of 5.7 e to the 14 total vector genomes, following the IDMC's review of the initial six week data from the first pediatric patient dose. While this trial captures a younger patient population with an earlier stage of disease compared to our adolescent and adult trial, it is important to understand that most patients with stage 3 Rett syndrome have already developed the hallmark symptoms of the disease and therefore present with many advanced disease manifestations. Patients typically approach stage 3 disease, known as the pseudo-stationary symptom stage, after a period of deterioration and rapid regression of learned skills. particularly relating to language and hand movement. The regression period is also characterized by partial or complete loss of acquired purposeful hand skills and spoken language, gait abnormalities, and stereotypic hand movements, which results in the loss of independence and in most cases leads to lifelong caregiver dependence. Many patients in this age group also suffer from seizures that can significantly impact their quality of life. Similar to the adult population, the heterogeneity among pediatric patients is high due to the broad spectrum of genetic backgrounds that result in variable phenotypic symptoms and severity in Rett syndrome. Part A of the pediatric trial is intended to include patients across a broad spectrum of genetic backgrounds, which will help us generate a robust data set to inform our development plan for the next phase of the study. We hope to see a consistent pattern of response across key clinical domains in the pediatric patients with different genotypes treated in the low-dose cohort, which we believe will bring us closer to our goal of bringing a potentially transformative treatment to all patients with Rett syndrome. Recently, we were pleased to receive Regenerative Medicines Advanced Therapy, or RMAT, designation from the FDA following review of available safety and efficacy data from the first two adult patients and the first pediatric patient dose with a low dose of TASHA-102. A regenerative medicine therapy is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious condition, and preliminary clinical evidence indicates the therapy has the potential to address unmet needs for such a condition. Sponsored companies receiving RMAT designation can benefit from increased interactions with FDA involving senior managers to help expedite drug development. We believe receiving RMAT designation is important recognition from the FDA that reinforces the high unmet need in Rett syndrome and the therapeutic potential of patient 102 to bring meaningful change to patients and families with Rett syndrome. We will work closely with the FDA and other regulatory agencies as we continue to advance our TASHA 102 program. We look forward to the year ahead as we remain focused on further expanding into pediatric patients, executing trials in multiple geographies, evaluating the high dose across age groups, and generating critical longer-term clinical data across a broad population of patients with Rett syndrome that will guide the next phase of our studies. We expect to provide an update on clinical data from the completed low-dose cohort of our Reveal adolescent and adult trial and initial available data from the low-dose cohort of our Reveal pediatric trial in mid-2024. Additionally, we expect to report initial available data from the high-dose cohort for both of our Reveal trials in the second half of 2024. I will now turn the call over to Sukhu to provide a more in-depth discussion of TASHA-102. Sukhu?
spk09: Thank you, Sean, and good afternoon, everyone. I'm pleased to provide an update on our TASHA-102 gene therapy program in clinical evaluation for the treatment of Rett syndrome. is a rare neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene, which encodes the MECP2 protein, an essential regulator of neuronal and synaptic function in the brain. The disorder is characterized by loss of communication and hand function, slowing and or regression of development, motor and respiratory impairment, seizures, intellectual disabilities, and shortened life expectancy. Rett syndrome progression is divided into four key stages, beginning with early onset developmental stagnation at 6 to 18 months of age, followed by rapid regression, plateauing, and late water deterioration. As a reminder, TASHA-102 is a self-complementary intrathecally delivered AAV9 gene transfer therapy designed as a one-time treatment. Because of the risks associated with both under and over expression of MECP2, we have combined high-throughput microRNA profiling and expression to create MI rare. Our novel miRNA target panel designed to mediate MECP2 expression in the central nervous system on a cell-by-cell basis controls the therapeutic levels of ME-CP2. With mRNA, endogenous mRNA are activated in the presence of ME-CP2 protein and are thought to base pair with targets in the viral genome-encoded microRNA to ultimately decrease protein expression levels through RNA interference. Thus, TASA-102 is expected to provide the necessary function of the ME-CP2 protein in cells lacking MECP2 while protecting against toxic overexpression of MECP2 in healthy cells. Clinical and preclinical data continue to support the ability of ASIA-102 to produce and maintain safe transgene expression levels in the central nervous system. As Sean mentioned, we observed a similar pattern of response across multiple clinical domains, impacting activities of daily living in both Adult patients treated in the low-dose cohort of our Reveal Phase 1-2 adolescent and adult trials. These patients have very different genetic mutations and associated disease severity. The first patient is a 20-year-old female with a large deletion within her ME-CP2 gene that manifests in a more severe disease phenotype and was completely non-ambulatory at baseline. While the second patient is a 21-year-old female It's a myosin mutation in her ME-CP2 gene that manifests as a mild phenotype and could walk with prompting at baseline. Further protocol, prophylactic immunosuppression therapy begins prior to TASIA-102 administration. The steroid paper was initiated at week 17 and completed by week 33 for the first patient. At the 35th week post-treatment assessment, the principal investigator observed that the initial improvements across multiple clinical domains had been maintained following completion of the seride taper and new improvements observed compared to earlier post-treatment assessments. Specifically, 35 weeks following treatment, the first patient showed sustained improvement in motor function, including restored leg movement and the ability to sit unassisted for the first time in over a decade, and in hand function, including the gained ability to grasp objects with a non-dominant hand and transfer them to a dominant hand for the first time since infancy. Progressive loss of hand function is a hallmark characteristic of Rett syndrome and a key area of concern for caregivers given It limits communication, daily activities, and independence. We believe the sustained improvements in hand function, which are not typically observed in the natural history of Rett syndrome, support the therapeutic potential of TASIA-102 to bring meaningful change to patients and caregivers. Sustained improvements in autonomic function were also observed in the first patient, including improved breathing patterns, circulation, and sleep quality. while they gained the ability to sleep through the night for the first time in 20 years, resulting in the patient being more alert and interactive during the day. At week 35 post-treatment, the principal investigator observed new improvements in the first patient in socialization and communication, including increased vocalization and the enhanced ability to use an IG-1 communication device. Difficulty in communication, including loss of speech, is also a prominent symptom of Rett syndrome and a key area of concern for caregivers as it directly interferes with the patient's ability to communicate their needs and express their interests. Based on caregiver input, we believe the ability to communicate could give patients a sense of control and greater independence. The first patient's seizures were overall well-controlled with a stable seizure event through week 35 at lower levels of anti-seizure medication relative to baseline, and the patients now no longer experience unprovoked seizures. Now let's turn to the second patient, second adult patient. At the 19-week post-treatment assessment, while the patient was on decreased steroid levels, the patient showed sustained improvement in motor skills with improvement in hand stereotypes for the first time since regression at age three and in socialization and communication with increased interest in social communication and activities including increased response to spoken words and eye contact. The patient also showed improvement in autonomic function with sustained improvement in breathing presence and circulation. The principal investigator also observed new improvements in the second patient's seizures frequency at week 19, with a significant reduction in seizures and a 25% lower level of anti-seizure medicine relative to baseline. The patient's pre-treatment seizure frequency is approximately 2 to 4 seizures per week, and the patient has been seizure-free for 17 weeks as of the 19-week post-treatment assessment. Additionally, both patients demonstrated continued improvement across consistent key clinical and caregiver-reported efficacy measures based on a six-month assessment at decreased steroid levels for the first patient and 12-week assessment for the second patient. This includes sustained improvement in clinical global impression improvement, or CGII, parent global impression improvement, or PGII, revised motor behavior assessment, or RMBA, Rett syndrome behavior questionnaire, or RSBQ, and in seizure diaries. The first patient also demonstrated a sustained improvement in CGIS and the Rett syndrome hand function scale. at six months post-treatment relative to earlier post-treatment assessments. These similar assessments across key efficacy measures observed in both adult patients reinforces the clinical observations from their principal investigator. Overall, we are highly encouraged by the consistent and early responses that were sustained through long-term follow-up assessments and the new improvements that developed in the two adult patients with different disease stability. We believe these improvements, even at reduced steroid levels, completed with a well-tolerated safety profile, supports the durability and transformative potential of TASHA-102 across multiple genotypes for Rett syndrome. With the low-dose cohort complete in the adolescent and the adult trial, We are currently focused on collecting data with the high dose to further explore the clinical impact of TASHA-102. We enrolled the first patient in the high dose cohort, and dosing is scheduled to take place in the second quarter of 2024. Now let's turn to the first pediatric trial. It's titled Reveal Phase 1-2 Pediatric Trials Similar to the Reveal Phase 1-2 Adolescent and Adult Trials. It was designed primarily as a safety study. Efficacy data being collected across a variety of measures is hypothesis-generating and will inform our thinking relative to Part B of the trial. Therefore, Part A of the trial is intended to include patients with diverse genetic backgrounds to evaluate the clinical impact of TASHA-102 broad range of pediatric patients. As Sean mentioned, similar to the adult population, the heterogeneity amongst pediatric patients is high due to the broad spectrum of genetic backgrounds that result in different phenotypic symptoms and several in patients with Rett syndrome. Phenotypic variation commonly occurs between individuals with the same ME-CP2 mutation and is attributed to different in the random X chromosome inactivation that results in a miniature mixture of cells with different levels of MECP2 protein expression. Because of this, the baseline status and overall disease severity of the patient will continue to be of importance to consider when interpreting the data, regardless of age or stage of disease. Our hope is that the pediatric patients with different genotypes who are treated with the low dose of TASIA-102 will show consistent safety profiles and recapitulate the meaningful improvement across clinical domains that we have observed in the adult patients. We have discussed the first two pediatric, we have dosed the first two pediatric patients in cohort one, evaluating the low dose of TASIA-102, and expect to report the initial available safety and efficacy data from cohort one in mid-2024. We remain focused on completing dosing and part A of both revealed trials and anticipate significant data collection in 2024. Our efforts to expand our clinical trials remain underway, and we are currently focused on additional site activation in the U.S. for our revealed adolescent and adult trials with the goal of expanding the ongoing trial in Canada into the U.S. in our review pediatric trial as we have focused on site activation in the UK with the goal of expanding our ongoing pediatric trial in the US into the UK as well. I will now turn the call over to Cameron to discuss our financial results. Cameron?
spk03: Thank you, Sukhu.
spk11: Research and development expenses were $20.7 million for the three months ended March 31, 2024, compared to $12.5 million for the three months ending March 31, 2023. The $8.2 million increase was primarily driven by an increase in good manufacturing practice or GMP batch activities during the three months ended March 31, 2024, which is representative of the intended commercial manufacturing process for TASHA 102. Additionally, clinical trial expenses increased primarily due to ongoing activities in the Reveal adolescent, adult, and pediatric trial. General and administrative expenses were $7.1 million for the three months ended March 31st, 2024, compared to $8.8 million for the three months ended March 31st, 2023. The decrease of $1.7 million was due to reduced general and administrative compensation as a result of lower headcount and a reduction in consulting and professional fees. Net loss for the three months ended March 31st, 2024 was $24.1 million or 10 cents per share as compared to a net loss of $17.6 million or 28 cents per share for the three months ended March 31st, 2023. As of March 31st, 2024, Tayshia had $124 million in cash and cash equivalents. The company continues to expect that its current cash resources will support planned operating expenses and capital requirements into 2026. I will now turn the call back over to Sean for his closing remarks. Sean?
spk10: Thank you, Cameron. Throughout the first quarter of 2024, we have made important progress on the clinical development of TASHA-102. The sustained and new improvements in both adult patients with advanced stage four Rett syndrome are very encouraging. And we look forward to moving to the high dose and further evaluating TASHA-102 across a broad population of ages and stages of patients with Rett syndrome. We are focused on completing dose escalation for both, of our reveal trials and collecting data to inform the next phase of our studies. We will continue to look for similar patterns of improvement across adult, adolescent, and pediatric patient populations. In the year ahead, we have many clinical milestones expected, and we look forward to providing additional updates including reporting initial clinical data from our Reveal pediatric trial and providing an update on the completed low-dose cohort from our Reveal adolescent and adult trial in mid-2024. With that, I will now ask the operator to begin our Q&A session.
spk03: Operator?
spk04: Thank you. We will now be conducting a question-and-answer session. If you would like to ask a question, please press star and then 1 on your telephone keypad. Confirmation tone will indicate your line is in the question queue. You may press star and then two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. It is requested that you ask one question and one follow-up question. The first question we have is from Kristen Kluska of Cantor Fitzgerald. Please go ahead.
spk07: Hi, everyone. Congrats on the RMAT designation. So you've been very transparent providing all the data you've collected to the street, but we continue to get a lot of questions about expectations for the younger patients in the trial. So how should we be thinking about ways to measure some anecdotes since this population isn't as far advanced? I know it's heterogeneous with different genetic backgrounds, but for younger patients, are there any domains in particular that stand out? Thank you.
spk10: Thanks for the question, Kristen. I'll take a stab at that and ask Sufu to further opine on it. But I think what's important is, again, that we recognize the fact that the pediatric patient population that we're studying, ages five to eight, has very advanced disease. And they have generally all the hallmark symptoms that people who are adults have. They may not have had it very long, but again, They may have had it for six or seven years or something along those lines. So it's a very entrenched disease, and the severities can be different based on the genotypes. So from our perspective, what would be, I think, a dramatic response in the low dose would be a consistent response to what we're seeing in the adults, meaning that there's clinical impact occurring across multiple domains. and that it's occurring very rapidly post-treatment. And I think that would further reinforce our belief that we're potentially dealing with a transformational therapy here. And I think with pediatric patients, it stands to reason that it could be that over the course of time, they have ultimately a better outcome than let's say an adult, But just remember, it takes time for people to make such dramatic improvements. I mean, if you put it in the terms that probably most on the call can appreciate it, if you have children, the first words may be coming at 8 to 10 to 12 months post-birth. So it takes time to developmentally get there. And so if you've had the disease and you haven't been able to speak, as an example, for multiple years, to expect that there's gonna be a transformational occurrence happening in the first three months, I don't think is reasonable. But I think if you see consistently that gross motor function's improving, fine motor function's improving, the hands are becoming more efficient in what they can do, the socialization and the attempt at communication improves, seizure improvement, Those are the things that I think are going to tell us if we've got, you know, effect happening from a clinical perspective. And again, keeping in mind that we're at the low dose. Let me pause there and ask Sukhu, is there anything you would add to that for perspective for Chris?
spk09: So, Sean, I mean, you've, I think, laid it out very clearly. And what I would also just, I mean, remind Kristen and the audience, is that given that we are treating the root cause of the disease with our gene replacement therapy, the duration of the disease, whether it's in a younger patient or older patient, the severity of the genotype and the actual severity of the clinical presentation with this complex syndromic presentation that these patients have, that I think will also drive, at times, the consistent response efficacy that we've shown so far in the adult patients. So what I'm saying is I think this gene therapy I think will treat the patients across the age ranges fairly efficaciously, but we have to see as we recruit the patients into the pediatric trial and gather that data to confirm this as well.
spk07: Thank you so much. That was very helpful. And then for my follow-up, For the RMAT designation, I appreciate you can't share any data from the third patient yet, but can you comment to us the length or the amount of data that the FDA had from this patient when they gave you that designation? Thanks so much again.
spk10: Yeah, thank you, Kristen. Sukhu, do you want to take that question? Yeah, sure.
spk09: Absolutely, Sean. So when we filed For the RMAG designation system, we filed with the data from the two adult patients who were dosed in Canada and one pediatric patient who was dosed in the U.S. And the FDA reviewed the data set and found that our product has what they would consider significant clinical impact to qualify to receive the RMAC designation. And then as you know, once you get the RMAC designation, the FDA obviously then commits a lot more time in working with the sponsor on its product and program because there is commitment now that this disease that we are trying to address has significant unmet medical needs and justifies very close collaboration between the sponsor and the FDA. Overall, we are very excited that we received it, and it's a good thing for patients.
spk04: Thank you. The next question we have is from Salveen Richter of Goldman Sachs. Please go ahead.
spk05: Good afternoon. Thanks for taking my questions. With regard to the midyear update from the low-dose cohort, Can you just frame this for us in the context of what we've seen so far where you've had new benefits or basically maintained the benefit thus far? And then secondly, with regard to RMAT, help us understand how you're thinking about the regulatory process from here on the forward. Thank you.
spk10: Sure thing, Selvi. So in terms of what to expect, so we're going to give an update mid-year on the two adult patients that we've dosed. So we'll work to share the most recent clinical observations and evaluations that have been done. And again, at this time, both patients would be off of steroids as an example. So we'll make sure we highlight the endpoints that we've shared to date. the clinical observations that we've shared today, and try to give a very fulsome update on how they are, you know, tracking over the course of time. And with the pediatrics, you know, think of it in the same terms relative to the endpoints. You know, it's possible we could show some additional data that wasn't collected in the adult study as part of this, you know, midyear update as well. and we'll provide the most recent available information we have for both of these patients. And so what we want to do is really give all of you a good landscape shot over the course of time in adults what have we seen. And, you know, again, today what we've been able to outline is that there's been consistent effect across multiple clinical domains. So the gross and fine motor function, the socialization and communication aspects, seizures, hand function, you know all of that we seem to have movement going in the right direction for both patients regardless of their genotype. We want to provide that same type of an overview for the first two pediatric patients and you know in our view a win at the low dose would be seeing consistent type effect across these domains for the pediatric patients. As it relates to to RMAT We're excited about this for a number of reasons. First of all, what's fantastic is that you get very ready access to the FDA, including folks at a senior level. So what's the good of that? You can be very much more collaborative just because you've got the opportunities to talk through things such as what we're seeing and what we think we might want to do with endpoints and trial design and get their feedback early on. And that obviously can help dramatically in terms of reducing the amount of time and increasing the probability of success. you know, in a potentially registrational trial. So, you know, we are very thankful, you know, to the agency for granting, you know, that particular designation to us. You know, what you do is within about 60 days is your initial meeting with them. You know, so again, as we're generating, you know, this data, very early on we'll be able to have nice pulse checks with the FDA relative to our thinking and their thinking And, you know, we think we're pretty aligned going into it, but this will further enhance things. So I think that the communication aspect and who you're able to talk to are probably, you know, the most critical aspects of garnering the RMAT designation. But let me ask Suku, you know, if there's additional considerations that I didn't outline that you think are important.
spk09: Well, Sean, I mean... based on what you've already discussed with Salveen. And as I said earlier, the RMAT obviously gives you much closer contact with senior officials within the FDA CBER, and it also actually allows the company, the sponsor, to understand as far as the FDA, what they are thinking when it comes to the initial data of our product and the program and what else could be done to accelerate the program if necessary. So essentially, I mean, it's a process designation that the FDA has created that allows the sponsor to truly accelerate a program that we think is going to make a significant difference in this patient population, especially when there's a significant unmet medical need. So as I said, you know, my teams will work very closely with the FDA when it comes to the clinical and CMC meetings and so forth. to move this program forward in an appropriate but rapid manner.
spk10: Yeah, the only other thing I would add is that, you know, we highlighted it in our remarks, but the other thing I think that's important about RMAT is that it's granted based on the preliminary clinical data that you're sharing. And so, you know, we share the two adult patients' worth of data, and I think Kristen asked the question about the pediatric patient. I believe it was four-week data. from the pediatric patient. So it's also an indicator that a very objective third party is sensing that there could be a potential benefit to the patient population that's suffering from the disease. So again, we're pleased we have it and look forward to the first interaction under RMAT with the agency.
spk03: Next question, please.
spk04: The next question we have is from Whitney Jim of Canaccord Genuity. Please go ahead.
spk06: Hey, guys. I'll add my congrats on our map. And I guess my question is around a cellist. Can you remind us how they are being – or to what extent they are being kept in the loop on the data? Is there sort of like a regular quarterly data sharing session, or what does that communication look like?
spk10: Sure, Whitney. I mean, there's formal – you know, structure around, you know, quarterly updates, you know, to the ASTELLAS team. But I would also just remind everybody that, you know, we do have Richard Wilson, you know, as an observer on our board. So he obviously is, you know, in real time, anything we're updating the board on, he's very aware of that. I can say that if we're having regulatory interactions, You know, members from the ASTELLAS team are participating in that. So, you know, I would say there's very clear transparency with ASTELLAS about the data that's being generated and key strategic aspects of the program and communications with regular authorities that are being shared.
spk03: Hopefully that helps you out, Whitney. Yep, very helpful. Thank you. Sure. The next question we have is from Chris Raymond of Piper Sandler. Please go ahead. Chris, your line is live. You may ask your question.
spk04: It seems to have no response from that line. The next question we have is from June Lee of Truist Securities. Please go ahead.
spk16: Hey, congrats on the data and the progress, and thanks for taking our question. You're scheduled to present data on June 19th at a RETS conference. Is that when we can expect initial pediatric data to load those, and do you have any plans to host a webcast around the event for the investors? Thank you.
spk10: Yeah, that would be the platform where we'd like to give the update on the pediatric data and the update on the the adult cohort one. And, you know, we haven't decided the specifics around further investor communication, but there will be some, yes.
spk03: Looking forward. Thank you. Thank you.
spk04: The next question we have is from Maureen Raycroft of Jefferies. Please go ahead.
spk15: Hi. Congrats on the progress, and thanks for taking my questions. Just a clarification question initially. Are you saying which month you dose the second pediatric patient, or can you say how much total follow-up you'll have in the mid-year update for the pediatric patients?
spk10: You know, I don't believe we gave specific dosing date for the second pediatric patient. But, you know, what I would think about is that, you know, we would have four to eight weeks of data, most likely, for that second patient.
spk15: Got it. And also clarifying for the pediatric data, are there specific measures or any unique efficacy measures that you're going to show for the pediatrics like the MSELA measure in the mid-year update?
spk10: You know, we're still working through the presentation. I mean, so I can tell you the things that you've seen on the adults, you know, we'll do our best to share that information. I would say that they're We're still working through the presentation, but there could be some measures that are shown that we haven't to date because they're not part of the adult study. So I'd just say, you know, stay tuned on that. Again, simply because we're working through it all and collecting the data at this point. But stay tuned for more on that, Maury.
spk15: Okay. Okay. Thanks for taking my questions.
spk03: I'll hop back in the queue. Sure.
spk04: The next question we have is from Chris Raymond of Piper Sandler. Please go ahead.
spk01: Sorry about the technical issues earlier. If this got asked already, I apologize. I got disconnected. We've heard some market chatter around the relative advantages of intrathecal administration versus a competitor program which uses ICV. And we've heard some folks maybe positing that there might be a disadvantage for 102 in terms of impacting brain function. I guess I'm kind of curious about this because you guys have seen, you know, pretty clear early improvement in autonomic function, some communication improvement, even seizures. You know, so that maybe just in broad strokes, remind us of the data that you have that shows the vector gets into the brain and has broad distribution. And then I have a follow-up.
spk10: Yeah, you know, I'll ask Sukku to take this question. I would just say that the, you know, what I would point to, and Sukku can, you know, fill in any gaps or take it down a different path, but I think the most important thing is that you're, it's a combination of biodistribution and likely total MECP2 produced. There's some threshold you have to get over to where you really start to see the impact on the disease. And, you know, when you point to all of the preclinical work that's been done, right, I mean, I think other gene therapies here have done, you know, one clinical trial or one, you know, preclinical trial in P0, P2 mice in ICV. You know, we've done that, and I think the results are very striking. You know, for TASHA-102, you know, at a lesser dose given intrathecally, And importantly, we also did work in different ages of mice, right? You know, P7, P14, P28, looking, you know, you're trying to, those should be harder mice to affect the phenotype. And, you know, again, we saw very good, you know, outcomes there as well with the intrathecal route. But most importantly, I think it's looking at the clinical data, right? And one of the reasons we've reported like we have thus far is we wanted to share with everybody the different clinical domains that are being affected, right? So if you're looking at gross and fine motor function, you're looking at speech and socialization, you know, seizure impact, hand coordination, those are all different areas of the brain, So there has to be distribution and level enough to have the impact that we're seeing. And again, I point to the RMAT designation and the threshold to get it is demonstrating some preliminary clinical efficacy in a disease with very high RMAT need. So I understand the academic discussion of one route versus another but I think that the preponderance of the evidence would indicate, whether it's preclinical or, more importantly, clinical data, that 102 has a significant effect on the disease, and we're seeing that in real time. But, Sukri, you may have more to add. Please go ahead.
spk09: Well, Sean, I think you gave him quite a good explanation. The only other thing I would add is that Rett syndrome is thought to be not just a neurodevelopmental disorder, but it's a neural network or maintenance disorder. And the reason I point this out is the rapidity with which both adult patients responded to our gene therapy given by lumbar puncture. So especially when it comes to autonomic dysfunction, these are getting corrected 10 days post-dosing with our gene therapy. So this raises another question. that with, I guess, with gene therapy, regardless of product, you may never need perfect biodistribution. It's really trying to understand the pathophysiology of the disease. So my point is, when MECP2 gets in or is in the nucleus of every neuron or astrocyte, it activates, it appears, thousands of genes. Some of these genes are silenced or transcription is prevented, while other genes are actually activated. So I guess what I'm getting at is just think of this orchestra conductor-like picture where MECP2 is the sick orchestra conductor, and once you wake him up and restore him, the entire orchestra starts playing, and then your brain function starts getting restored. And that's kind of what we're seeing with the adult patients that we've dosed up to now.
spk01: Thanks. And just to follow up, I think When you guys gave your last update, you know, there was some discussion around the presence, the fact that you were tapering steroids and, you know, the impact of steroid tapering on the RSVQ improvement in patient one. You know, any progress here maybe or update on teasing that out as you continue dosing patients?
spk10: Well, I would say, and Suku, feel free to jump in here, but But, you know, that N of 1 patient, I think, is interesting. We'll have to see as more time elapses with other patients if we see the same thing. But, you know, initially there was a thesis that the benefit that we were seeing efficacy-wise was because of the steroids. And, you know, what we've demonstrated is that, number one, we tried to highlight to everybody that no one uses steroids to treat this disease, number one. And I think we've dismissed that, but we wanted to show that after the steroids were gone, you know, there was no loss or diminution of effect. But with the flip side to it is, I think that we may see that there's a case to be made that steroids are actually masking some of the benefits of the therapy. And I think patient one is showing that, you know, she had reduced anxiety and irritability as a result of going off the steroids. And I can tell you, when you look at the patients that have been treated to date, the steroids are hard on them. I mean, they're on it for a long period of time at a very high dose. And if you think about it, a lot of these girls have very bad GERD or reflux. Well, the steroids can make you irritable, right? And it can be negative in terms of your ability to sleep, which then it's like a cycle, right? So I actually, like, I believe that as the steroids are backed down and eventually are removed, there may be, you know, positive, you know, outcomes that we see that we're being masked, particularly when you think about an RSPQ, where the caregivers having to provide an update on things, and they're probably tired and irritable, too, because they've been dealing with a child that doesn't feel well. So, you know, I think that's the distinction that we were trying to make. We'll have to see if more patients, you know, come off steroids if that's totally accurate, but that seems to be the case, and certainly, you know, I think patient one would help support that thesis. But, Sukhu, is there anything else you'd add to that one?
spk09: Not much else, Sean. I mean, as you pointed out, I think steroids and other immunosuppressants, what we are learning is the short-hand side of the use of them, the more effective it's going to be.
spk03: Yeah. Thanks, guys. The next question we have is from Gil Blum of Needleman Co.
spk04: Please go ahead.
spk13: Hi, everyone, and thanks for taking our questions. And again, congrats on the progress. So maybe harping a bit here, but just to help me understand, what do you guys mean by similar pattern of activity? I mean, is there multi-domain indications, right? Some of these patients are very heterogeneous. Just to help me understand that, I do have a follow-up.
spk10: Yeah, sure. I mean, I would say very simplistically, If you think about the endpoints like CGI, CGIS, RSVQ, and what those measure, yeah, we're going to give updates on those types of scales. But it's also thinking about the domains like the gross and fine motor function, hand function, speech and socialization. the seizure aspect of things. So, you know, we've always tried to paint a snapshot of, you know, the fact that disease just hits so many different areas, you know, for each patient. And each patient can have, you know, more or less severity in one area versus another. I mean, it's very, you know, heterogeneous, as you know. And so we're just trying to say that it's the same thing for the pediatric patients. They're going to present in a similar fashion in terms of multiple domains being affected. They've had the disease for, you know, for this group at least, you know, five, six years. And to us, it's important to show that we're affecting the disease across these domains similar to what we're seeing in the adults at the low dose. But Suku, again, if there's something there you want to highlight further, please do.
spk09: Now, Sean, I mean, I don't really have too much to add other than remind everyone this is a very complex syndromic disease where multiple aspects of, I guess, the human biology is made abnormal. And I think, as Gil pointed out, and as we know, the phenotypic presentation does vary quite a lot. So when it comes to the impact of a therapeutic intervention, I mean, look, my hope is that once you do the gene replacement to the intrathecal approach, you are able to restore function regardless of the syndromic presentation. So as we accumulate more data, then hopefully that proves our point, you know?
spk13: All right. That's very helpful. Now, is there any reason to believe that potential improvements in pediatrics will be larger than what was seen in adults? but maybe not in kind of the learned functions that you guys discussed before. How about autonomic functions? I mean, they are younger patients. Thank you.
spk03: Sukhu, you want to take that question?
spk10: Yeah, so was that Gil's show? Yeah, Gil was asking, you know, might autonomic function have a faster improvement or a greater improvement
spk03: in a pediatric patient versus an adult?
spk09: That is a tough question. I mean, I would assume at this point in time it's probably safer to say given that in the two adult patients we were rapidly correcting autonomic dysfunction within 10 days, if you're able to do those kind of autonomic corrections in the pediatric population also within 10 days, I think that will be a remarkable outcome for this therapeutic intervention. Now, the caveat, as you say, Gil, is can you do it in half the time? Honestly, I don't know. We have to dose the patients and see what happens. But at the same time, when it comes to autonomic dysfunction, at least the features we are aware of in Rett syndrome, rapidity of response, like say you get it addressed in two days versus eight or ten days, I don't think in the bigger picture, clinically, we make that much of a difference, you know?
spk03: Hope that helps you.
spk04: The next question we have is from Yanan Zhu of Wells Fargo. Please go ahead.
spk02: Great. Thanks for taking our questions. Since you mentioned the heterogeneity, a greater heterogeneity even in younger patients, I was wondering for the two patients you treated so far at baseline, what are the severity level like, i.e., could there be a very mild phenotype and therefore incurring the caveat of potential to see less of an effect. Yeah, and then I have a follow-up. Thanks.
spk03: Can you take that one, Sukum, please?
spk09: Yes, Sean. So I just want to make sure I heard the question, though. At the beginning, I think I heard you say that the pediatric population tends to be a lot more heterogeneous, I assume, compared to the adult population with Petson, right? Is that what you said?
spk02: Right. I'm just saying I thought I heard in a prepared remarks, you highlighted variability of disease for the pediatric patient population. So I was wondering in that context, for the two patients you have dosed so far, what are the baseline disease severity levels? Are they you know, reasonably high so that it's reasonable to expect to see some benefit if there could be any? Or could there be, for example, one of the patients may have a very mild disease and therefore difficult to demonstrate benefit?
spk09: So I think the heterogeneity, to my understanding, is across the board. when it comes to Rett syndrome, regardless of age. But having said that, I think if you take a patient by patient with Rett syndrome, regardless of age, and look at the complexities of the syndromic presentation, at the present time, what we would anticipate is a consistent response clinically, given that the gene therapy has shown rapid response and more sustained response in the two adult patients, where one never expected a response, right? So pediatric patients, obviously, we haven't disclosed baseline characteristics or any of the data yet. So all I can say is stay tuned. And my hope is when you go to the higher dose, the effect that we have, regardless of the clinical features of the syndrome, should be consistent and across the board. Now, the only other thing I think to, again, address is the autonomic dysfunction seen in young pediatric patients. where I guess the concept is if your network is young, the odds are you should respond even quicker. I mean, so obviously I don't think anyone has done gene therapy to assess that, and hopefully as we gather more data in the pediatric population, we can help answer that question.
spk10: Yeah, the only other thing I would say to that, Yanan, is that for the protocol, basically you're going to see similar severities in that The CGIS, you know, range is between four to six. Okay, so it's very similar to the adult trial in severity.
spk02: Got it. That's super helpful. And then maybe the follow-up is about the next patient. Or perhaps if I may ask, for patient number two, has the IDMC safety evaluation been done yet, or is that still upcoming? And for the third patient, I was wondering, is this plan still to do that patient with the low dose, or could you do something similar to what you did for the adult cohort and reassign that patient to a higher dose based on the data you have accumulated? Thank you.
spk10: Yeah, that's a good question, Jan. And so, basically, the IDMC has not yet met for patients who is coming in the next, you know, couple weeks. And, you know, I think the answer to your question on would you go to the high dose, you know, after only two patients, I think it's going to depend on a combination of things. It'll certainly start with the safety and any observed efficacy. you know, to evaluate. And also, again, we haven't talked to the IDMC, so don't read into what I'm saying. I'm just giving you an example. They could say, well, it's pediatrics, and, you know, we would like to see, you know, a third patient's dose just simply because they're pediatrics. So, you know, I think your logic makes a lot of sense. We'll just have to see how things play out, and it'll start with the data presentation to the IDMC.
spk03: Understood. Thank you for taking all the questions. Sure. Thank you.
spk04: The next question we have is from Jack Allen of Baird. Please go ahead.
spk14: All right. Thanks for taking the questions and congratulations on all the progress. Just one quick one from me and similar question of mine as the last couple of questions I've asked you here. But I know it was asked about the phenotypes of these patients, the pediatric patients that we're going to get data from in the next couple of weeks here. How about the genotypes? Anything you can say as it relates to what kind of genotypes these two patients have?
spk10: Yeah, I mean, we haven't disclosed that, but Sukru, you want to comment on that?
spk09: So, I just want to ask you, Sean, I got the question. So, this is in the two pediatric patients, right? Right. Yeah. Okay.
spk10: like seeing a significant deletion? Are we seeing, you know, missense mutations, you know?
spk09: Yeah. So, Sean, I mean, can I, I guess, we haven't disclosed the genotypes at this point in time, so I assume without going into too much detail, what I can tell you is one patient is, as I recall, very mild, or mild, and the other patient is more towards the severe side. And now keep in mind that they do evaluate CG, IS, and so forth to see how sick the patients are. And so that also gives you a feel for what one would anticipate as a response to the therapy. But that's a caveat, though. What we're observing is even if someone as a patient with retinopathy has a milder phenotype due to a myosin mutation, some of their symptomology actually gets treated remarkably well. And the reason I say that is, if you think of a second adult patient who was dosed in Canada, this was a patient who had multiple seizures and was on two antiepileptics. And if I recall, had four seizures a week. Now this patient appears to be seizure-free, and the antiseizure medicine doses have been decreased by 25%. So I guess I hope that draws a parallel because sometimes these patients have 10 different clinical features. The question on the table then becomes, which of these can you hopefully address, control, or eliminate such that the patient gets much stronger and can have a productive life?
spk03: Got it. Great. That's great, Kyler. Thanks so much. I'm looking forward to the data. Thanks, Jack.
spk04: The last question we have is from Sylvain Turcan of Citizens JMP. Please go ahead.
spk12: Thank you for taking my question and congrats on the RMAT designation. I also have a question on the pediatric patients, given that they may be more heterogeneous. Is there anything on the safety side that will be important to consider here? Do they have comorbidities? Anything in that vein, please? Thank you.
spk10: Sure, I would just clarify, too, and Sukhu, correct me if I'm wrong, the pediatric patient isn't any more heterogeneous than the adult. That's correct.
spk09: It's the same distribution, to my knowledge, Sean.
spk03: Right. And Sukhu, any comments on Yannan's question? So, Yannan, your question, I mean, do you mind repeating it? I'm sorry, still then.
spk12: Yeah, sure. Um, I was just wondering in, in pediatrics in general, um, if, if there's anything on, on the safety profile side, uh, that, you know, we, we may have to be aware of, you know, there's, there's smaller livers, they, um, you know, anything with toxicities, but also, uh, maybe comorbidities that, that smaller patients have that adolescents don't have. Thank you.
spk09: No, no, that's, that's a good question because, uh, we did discuss that in great detail, you know, before we launched this program. And, um, given that the intrathecal dose, about 15% to 20% does get into systemic circulation. And, you know, as you know, AV9 is tropic to the liver. That's where it goes. But elevation in liver enzymes with an intrathecal dose, which is pretty low compared to systemic dose, is highly unusual. Any change in blood count, highly unusual. Complement activation and, you know, the thrombotic events that have been seen in DMT, highly unusual, if ever, with interstitial therapies, purely because you're giving such a low dose. The antibodies and T cells being made to the transient, highly unusual. So I guess my point is, from a gene therapy standpoint, I guess there's also ganglion changes. But again, it's not common. So my point is, if you do the risk-benefit analysis, for direct syndrome program, the benefit, I think, far outweighs the risk. And we haven't had any concern up to now.
spk03: Great. Thanks for the call. Thanks, Sultan.
spk04: We have reached the end of the question and answer session, and I would like to turn the floor back over to Sean Nolan for closing comments.
spk10: Just thank everybody for your time this evening, and we look forward to providing further updates here in the next coming weeks on both the Cohort 1 adults as well as the available data for the two pediatric patients.
spk03: Thank you all. Have a good night. This concludes today's conference. Thank you for joining us. You may now disconnect your lines.
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