Taysha Gene Therapies Inc (TSHA) 2024 Q1 法說會逐字稿

Greetings and welcome to the Taysha Gene Therapies first-quarter 2024 earnings call. (Operator Instructions) As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Hayleigh Collins. Thank you. You may begin.

Thank you. Good afternoon, and welcome to Taysha's first-quarter 2024 financial results and corporate update conference call. Earlier today, Taysha issued a press release announcing financial results for the first quarter ended March 31, 2024. A copy of this press release is available on the company's website and through our SEC filings.

Joining me on today's call are Sean Nolan, Taysha's CEO; Sukumar Nagendran, President and Head of R&D; and Kamran Alam, Chief Financial Officer. We will hold a question and answer session following our prepared remarks.

Please note that on today's call, we will be making forward-looking statements, including statements relating to the therapeutic and commercial potential of TSHA-102, including the reproducibility and durability of any favorable results initially seen in our first and second patients dosed in the reveal trial to positively impact quality of life in force of disease and the patients we seek to treat our research, development and regulatory plans for our product candidates, including the timelines for clinical trials and reporting results there from 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 in the market opportunity for those programs. This call may also contain forward-looking statements relating to Taysha's growth, forecasted cash runway and future operating results, discovery and development of product candidates, strategic alliances and intellectual property, as well as matters that are not historical facts or information.

Various risks may cause those 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 are dependent 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 Securities 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 31, 2024, that we filed today.

This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, May 14, 2024. Taysha undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities laws.

With that, I would now like to turn the call over to our CEO, Sean Nolan.

Thank you, Hayleigh, 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. Suku Nagendran, President and Head of R&D of Taysha will provide an update on our lead TASH-102 programs in clinical evaluation for the treatment of Rett syndrome. Kamran Alam, our Chief Financial Officer will follow up with the 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 TSHA-102, our lead gene therapy program in 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 TSHA-102 . We believe this progress reinforces the therapeutic potential of patient one or two across a broad population of patients with Rett syndrome and supports the continued clinical value evaluation of our gene therapy program.

We believe that we are well positioned for continued execution across our key upcoming value-creating milestones for TSHA-102 program with the goal of generating critical longer-term clinical data across broad range of ages and stages of patients with Rett syndrome and 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, the cheat the genetic root cause of this disease and there is a significant unmet medical need. The random X inactivation and subsequent Mosaic pattern of MECP2 expression results in a mixture of cells that are either deficient in MECP2 protein or expression MECP2 protein normally, which makes Rett syndrome challenging to treat with traditional small molecule and gene therapy approaches.

We believe our TSHA-102 gene therapy candidate equipped with the novel MIRNA responsive auto regulatory element or MI rare technology has the potential to appropriately address this challenge by mediating MECP2 expression in the central nervous system on a cell by cell basis to overcome the risks associated with, both under and over expression of MECP2 protein.

We are evaluating TSHA-102 in two ongoing Phase 1/2 REVEAL trials. An adolescent and adult trials taking place in Canada and the US. And a pediatric trial taking place in the US with clearance in the UK. As a reminder, our REVEAL Phase 1/2 adolescent and adult trial is the first in human study, assessing the safety and preliminary efficacy of TSHA-102 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 TSHA-102 sequentially. Two patients have been dosed to date in cohort one with the low-dose of TSHA-102 of 5.7e 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 the TSHA-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, 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 TSHA-102 of one (inaudible)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 4 Rett syndrome and different genetic mutations and severity of disease.

Recall when we initiated REVEAL, 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 TSHA-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 was sustained a new improvements in the absence or reduction of steroid levels.

As of the six month assessment, TSHA-102 showed sustained improvement across key efficacy measures at decreased steroid levels with new improvements observed in the Rett syndrome behavioral questionnaire or RSDQ.

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 for our NDA as of the 12 week assessment and significantly reduce seizures as of the 19 week assessment following treatment.

Moreover, 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 a week 19 had decreased steroid levels for the second patient. Suku will discuss these observations in more detail.

The longer-term safety profile is also encouraging. Data from the first two adult patients showed the TSHA-102 was well tolerated with no treatment emergent serious adverse events as of week 35 assessment for patient one and as of the 19 week assessment for patient two.

We believe the safety profile and continued improvement across multiple clinical domains even at reduced steroid levels in both adult patients, in both adult patients with advanced stage 4 Rett syndrome treated with the low dose of Tier one and two supports the durability and transformational potential of TSHA-102 across multiple genotypes of Rett syndrome and further validates our construct.

We are also focused on evaluating the therapeutic potential of TSHA-102 in the pediatric population, where we hope to see similar, say, 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 TSHA-102 . Our ongoing review of Phase one two pediatric trial is evaluating the safety and preliminary efficacy of TSHA-102 in 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 TSHA-102 sequentially. We have dosed the second pediatric patient in cohort one, the low-dose cohort of 5.7e 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 adult adolescent and adult trial, it is important to understand that most patients with stage three, Rett syndrome have already developed the hallmark symptoms of the disease and therefore, present with many advanced disease manifestations.

Patients typically approach Stage three disease, known as the (inaudible) 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 stereotypical movements, which results in the loss of independence. And in most cases, leads to lifelong care different dependents. 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 Medicine 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 TSHA-102. A regenerative medicine therapies eligible for [ILAP] 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 [RMET] designation can benefit from increased interactions with FDA involving senior managers to help expedite drug development.

We believe receiving [RMET] designation is important recognition from the FDA that reinforces the high unmet need in Rett syndrome and the therapeutic potential of TSHA-102 to bring meaningful change to patients and families for Rett syndrome. We will work closely with the FDA and other regulatory agencies as we continue to advance our TSHA-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, an 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 from both of our REVEAL trials in the second half of 2024.

I will now turn the call over to Suku to provide a more in-depth discussion of TSHA-102. Suku?

Thank you, Sean, and good afternoon, everyone. I'm pleased to provide an update on a TSHA-102 gene therapy program in clinical evaluation for the treatment of Rett syndrome. 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 lots of communication and hand function growing and or regression of development, motor and respiratory impairment, seizures, intellectual disabilities and shorten 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 quarter deterioration.

As a reminder, TSHA-102 is a self-complementary intrathecally delivered AAV9 gene transfer therapy designed as a onetime treatment. Because of the risks associated with both [under an old expression] of MECP2, we have combined high throughput micro-RNA profiling and expression to create miRARE.

Our novel miRNA target panel design to mediate MECP2 expression in the central nervous system on a cell by cell basis, controls the therapeutic levels of MECP2. With miRARE endogenous miRNA for activated in the presence of MECP2 protein and are thought to best spend targets in the viral genome and coded micro-RNA to ultimately decrease protein expression levels through RNA interference.

Thus TSHA-102 is expected to provide the necessary function of the MECP2 protein in cells lacking MECP2, while protecting against toxic or expression of MECP2 in healthy cells. Clinical and preclinical data continue to support the ability of TSHA-102 to produce and maintain safe trans gene 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 one, two, adolescent and adult trial.

These patients have very different genetic mutations and associated disease severity. The first patient is a 20 year old female with a large deletion with MECP2 gene that manifests in a more severe disease phenotype and was completed and ambulatory at baseline. For the second patient is a 21 year old female with a missense mutation in her MECP2 gene that manifest as a milder phenotype and could walk with pumping at baseline.

Further protocol, prophylactic immunosuppressant therapy begin, TSHA-102administrations, but denied paper was initiated at week 17 and completed by week 33 for the first patient at (inaudible) post-treatment assessment for principal investigators observed that some initial improvements across multiple clinical domains had been maintained following completion of the steroid 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 restore like movement and the ability to sit unassisted for the first time in over a decade. And in hand function, including the gain ability to grasp objects, with a non dominant hands 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 its 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 TSHA-102, to bring meaningful change to patients and caregivers.

Sustained improvement in autonomic function were also observed in the first patient, including improved breathing pattern circulation and sleep quality. By the gained ability to sleep through the night for the first time in 20 years, resulting in the patient being more alert than interactive during the day.

At week 35 post treatment, the principal investigator of new improvements in the first patient in socialization and communication, including increased vocalization and the enhanced ability to use an idea one communication device. Difficulty in communication, including loss of speech is also prominent symptom of Rett syndrome on a key area of concern for caregivers as it directly interferes with the patient's ability to communicate their need to express their interest.

Based on caregiver input, we believe the ability to communicate to give patients a sense of control and greater independence. The suspension seizure for overall well control with a share of seizure events through week 35 at lower levels of anti-seizure medications relative to baseline and the patient now no longer experience on provoke seizures.

Now let's turn to the second patient, second adult patient. At the 19 week post treatment assessment, while the patient was on decrease derived levels, the patients showed sustained improvement in motor skills with improvement in hand (inaudible) for the first time, since regression at age three and in socialization and communication with the increased interest in social, communication and activities, including increased response to spoken words and eye contact.

The patient also saw improvement in autonomic function with sustained improvements in breathing patterns and circulation. The principal investigator also observed new improvements in the second patient seizure frequency at week 19. With a significant reduction in seizure and a 25% lower level of antiseizure medicine relative to baseline.

The patients pre-treatment seizure frequence of approximately two to four 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 the six-month assessment, a decreased (inaudible) levels for the first patient and 12-week assessment for the second patient. This includes sustained improvement in clinical global impression, improvement of CGII fair and Global Impression Improvement of PGII [device] motor behavior assessment or RMBA. Rett syndrome behavior questionnaire on RSBQ and in seizure.

The first patient also demonstrated a sustained improvement in CGIS and Rett syndrome Hand Function scale at six months post treatment relative to earlier for (inaudible) assessment. These similar assessments across key efficacy measures observed at both adult patients reinforces the clinical observations from their principal investigators.

Overall, we are a 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 severity.

We believe these improvements, even at reduced steroid levels completed with a well-tolerated safety profile, supports the durability and transformative potential of TSHA-102 across multiple genotypes for Rett syndrome.

With the low-dose cohort complete in the adolescent and adult trial, we are currently focused on collecting data with the high-dose to further explore the clinical impact of TSHA-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 one two pediatric trials similar to the REVEAL Phase one two adolescent and adult trial was designed primarily as a safety study. The 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 TSHA-102 across broad range for 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 17 patients with Rett syndrome.

Phenotypic variation commonly occurs between an individuals with the same MECP2 mutation and is attributed to different in the random X chromosome inactivation that results in a miniature mixture of cells, the 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 that data, regardless of age or stage of disease. Our hope is that the pediatric patients with different genotypes, who are treated with low-dose of TSHA-102 will show consistent safety profile and recapitalize 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 TSHA-102. Now expect to report the initial available safety and efficacy data from cohort one in mid 2024.

We remain focused on completing dosing in Part A of both REVEAL trials and anticipate significant data collection in 2024. Our efforts to expand our clinical trial remain underway, and we have to focus on additional site activation in the US.

But I'll reveal adolescent and adult trial with the goal of expanding ongoing trial in Canada into the US. Now reveal pediatric trial, as we have focused on site activation in the UK for the goal of expanding of ongoing pediatric trial in the US into the UK as well.

I will now turn the call over to Kamran to discuss our financial results. Kamran?

Thank you, Suku. 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 TSHA-102.

Additionally, clinical trial expenses increased primarily due to ongoing activities in the REVEAL adolescent adult and pediatric trials. General and administrative expenses were $7.1 million for the three months ended March 31, 2024 compared to $8.8 million for the three months ended March 31, 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 31, 2024 was $24.1 million or $0.10 per share as compared to a net loss of $17.6 million or $0.28 per share for the three months ended March 31, 2023. As of March 31, 2024, Taysha 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?

Thank you, Kamran. Throughout the first quarter of 2024, we have made important progress on the clinical development of TSHA-102 to sustained and new improvements in both adult patients with advanced stage for Rett syndrome are very encouraging. And we look forward to moving to the high dose and further evaluate TSHA-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. Operator?

(Operator Instructions) Kristen Kluska, Cantor Fitzgerald.

Hi, everyone. Congrats on the RMAT designation. So, you've been very transparent providing all the data you've collected, 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 heterogeneity with different genetic backgrounds, but for younger patients, are there any domains in particular that stand out? Thank you.

Thanks for the question, Kristen. I will take (inaudible) and ask you to do 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 age is 5-8 has very advanced disease and they have generally all the hallmark symptoms that people who are adults have. They may not have had a very long, but again, they may have had it for 6 or 7 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, you know, 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 a ultimately a better outcome than, let's say, in adults. But just remember, it takes time for people to make such dramatic improvements. I mean, if you put it in the terms of probably most on the call can appreciate it, if you have children, the first words maybe coming at 8 to 10 to 12 months post birth.

So, there 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 going to 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 functions improving, fine motor functions improving, the hands are becoming more efficient what they can do.

But the socialization and the attentive communication improves seizure improvement. Those are the things that I think are going to tell us that 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 Suku is there anything you would add to that for perspective?

So, Sean, I mean you have, 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 gene replacement therapy. The duration of the disease that younger patients 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 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 patient across the age ranges fairly efficaciously. But we have to see, as we recruit the patients in the pediatric trial and gather that data to confirm this as well.

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 patient the third patient yet. But can you comment to us the lanes or the amount of data that the FDA had from this patient when they gave you that designation? Thanks so much again.

Yes. Thank you, Kristen. And Suku, do you want to take that question?

Yes, sure, absolutely, Sean. So, when we file for the RMAT designation system, we filed with the data from the two adult patients, who are both in Canada and one pediatric patient was dosed in the US and the FDA reviewed that data set and found that our product has, but they'll continue to have significant clinical impact to qualify to receive the RMAT designation, and then as you know, once you get the RMAT designation, the FDA obviously then commit 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 need and justifies a very close collaboration between the sponsor and the FDA. So, overall, we are very excited that we received it and it's a good thing for patients.

Salveen Richter, Goldman Sachs.

Good afternoon, thanks for taking my questions. With regard to the major uptake 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 and or basically maintain 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.

Sure, thanks Salveen. So, in terms of what to expect. So, we're going to give an update midyear 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, this session at this time, both four patients would be off of steroids as an example.

So, you know, we'll make sure we highlight the endpoints that we've shared today. The clinical observations that we've shared today and tried to give a very full some update on and how they are tracking over the course of time.

And with the pediatrics, think of it in the same terms relative to the endpoints. It's possible we could show some additional data that wasn't collected in the adult study on as part of this on midyear update as well. And we'll provide the most recent available information we have for both of these patients. And so what we wanted to do is really give all of you a good Lance, a landscape shot over the course of time in adults what have we seen.

And again, to date, we've been able to outline as 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 the genotype.

We want to provide that same type of an overview for the first two pediatric patients. And in our view, a win at the low dose would be seen consistent type of effect across these domains for the pediatric patients. As it relates 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 in a potentially registrational trial.

So, we are very thankful to the agency for granting that particular designation to us. What you do is within about 60 days is your initial meeting with them. So, again, as we're generating this data, it will very early on, we'll be able to have nice pulse checks with the FDA relative to our thinking and their thinking. And 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 one of the most critical aspects of garnering the RMAT designation or living as Suku, you know, if there's additional considerations that I didn't outline that you think are important.

So, I mean, based on what you've already discussed with Salveen, and as I said earlier, the RMAT obviously gives you a 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 has to 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 our 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, 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.

Yes. The only other thing I would add is that we highlighted it in our remarks, but the other thing I think that's important about RMAT has been granted based on the preliminary clinical data that you're sharing. And so we shared the two adult patients with the data, and I think Kristen asked the question about the the pediatric patient, I believe was a four week data from the pediatric population.

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 to have it and look forward to the first interaction under RMAT with the agency.

Next question, please.

Whitney Ijem, Canaccord Genuity.

Hey, guys. I'll add my congrats on RMAT. And I guess my question is around the sellers. 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?

Sure, Whitney. I mean, there's formal structure around quarterly updates, you know, to the SLS team. But I would also just remind everybody that we do have Richard Wilson as an observer on our Board. So, he obviously is 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, members from the SLS team are participating in that. So, I would say there's very clear transparency with SLS about the data that's being generated and key strategic aspects of the program in communications with regulatory authorities that are being shared. Hopefully, that helps you out Whitney.

Very helpful. Thank you.

Sure.

Chris Raymond, Piper Sandler. Chris, your line is live, you may ask your question.

Joon Lee, Truist Securities.

Congrats on the data and the progress, and thanks for taking our questions. You are scheduled to present data on June 19, at Rett's conference. Is that when we can expect initial pediatric data in the low dose? And do you have any plans to host a webcast around the events could be investors. Thank you.

Yes, that that would be the platform of we'd like to give the update on the pediatric data and the update on the adult cohort one. And we haven't decided the specifics around further investor communication, but there will be some, Joon.

Looking forward. Thank you.

Thank you.

Maury Raycroft, Jefferies.

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 midyear update from pediatric patients?

I don't believe we gave specific dosing date for the second pediatric patient. But what I would think about is that, we would have four to eight weeks of data, most likely for that second patient.

Got it. And also clarifying for the pediatric data. Are there specific measures or any unique efficacy measures they are going to show for the pediatrics like the MSLA measure in the midyear update?

We're still working through the presentation. It's like I can tell you the things that you're seeing up on the results, you know, we'll do our best to share that information. I would say that we are 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 stay tuned on that. Again, simply because we're working through it on and collecting the data at this point, but stay tuned for more on that, Maury.

Okay. Thanks for taking my questions. I'll hop back in queue.

Sure.

Chris Raymond, Piper Sandler.

Sorry about the technical issues earlier. Just to, if this got asked already, I apologize, I got disconnected, but we've heard some market chatter around the relative advantages of interest equal administration versus competitor program, which uses ICV.

And we've heard some folks maybe positing that they're there might be a disadvantage for one or two in terms of impacting brain function. I guess, I'm kind of curious about this because, you guys have seen pretty clear early improvement in autonomic functions and communication proven even seizures.

So, that maybe just in broad strokes, remind us of the data that you have this shows the vector gets into the brain has broad distribution, and then I have a follow-up.

Yes, I'll ask Suku to take this question. I would just say that the what I would point to and then Suku can fill in any gaps or take it down a different path. But I think the most important thing is that, your it's a combination of biodistribution and likely total MECP2 produce. There are some threshold you have to get over where you right, you really start to see the impact on the disease.

And when you point to all of the preclinical work, that's been done, right. I mean, I think other gene therapies here have done one clinical trial in or one pre-clinical trial and P0, P2 mice in ICV. We've done that and I think the results are very striking for [flotation] one or two at a lesser dose given interest equally. And then importantly, we also did work in different ages of mice, right, P7, P14, P28 looking, you're trying to (inaudible)harder mice to affect the phenotype.

And again, we saw very good 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 reported like we have thus far is we wanted to share with everybody the different clinical domains that are being effected, right? So, if you're looking at gross and fine motor function, you're looking at speech and socialization, seizure impact can coordination those are all different areas of the brain, right?

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 unmet need. So, you know, 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 one or two has a significant effect on the disease, and we're seeing that in real time. But Suku, you may have more more to add. Please go ahead.

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 (inaudible) function.

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 thinner in the nucleus of every neuron for extra side, it activates, it appears thousands of genes. Some of these genes are silenced or transcription is prevented, while other genes actually activated.

So, I guess what I'm getting at is just think of this construct conductor like picture, where MECP2 is the SIC (inaudible) conductor and wants to wake him up and we show him the entire cost of starts playing and then your brain function starts getting restored, and that's kind of what you're seeing with the adult patients that we have dosed up to now.

Thanks. Maybe and just to follow up. I think when you guys gave your last update, there was some discussion around the presence, the fact that you had some tapering steroids and the impact of steroid tapering on the RSBQ improvement in patient one. Any progress here maybe or update on teasing that out as you continue it's dosing patients?

Well, I would say Suku feel free to jump in here. But you know that end of one patient I think, is interesting. We'll have to see as more time elapses with other patients if we see the same thing. But initially, there was a thesis that the benefit that we were seeing efficacy wise was because of the steroids. And what we've demonstrated is that number one.

We tried to highlight to everybody that no one uses steroids to treat this disease, not number one. And I think we've just missed that, but we wanted to show that half of the steroids were gone, feel there was no loss or dimunition of effects. But the flip side to it is, I think that we may see that there's a case to be made that steroids are as actually masking some of the benefits of the therapy.

And I think patient one is showing that she had reduced anxiety inherent ability as a result of going off the steroids. And I can tell you, you know, 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 dirt or reflux, will the steroids make that worse and then steroids can make you irritable, right? And they 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 back down and eventually are removed. There may be positive outcomes that we see that were being masked, particularly when you think about in RSPQ or the carrier give us 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, I think that's the distinction that we are trying to make. We'll have to see as more patients come off steroids, if that's totally accurate. But that seems to be the case and certainly I think patient one would help support that thesis. But Suku, is there anything else you'd add to that one?

Not much Sean. I mean, as you pointed out, I think steroids and other immunosuppressants, what we're learning is the short end, either the use of them, the more effective it's going to be here.

Yeah.

Thanks guys.

Gil Blum, Needham & Co.

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 you guys mean by similar pattern of activity, means 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.

Yes, sure. I mean, I would say very simplistically, if you think about the endpoints like CGII, CGIS, RSPQ and within that, those measure, yes, 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 this seizure aspect of things. So we've always tried to paint a snapshot of the fact that disease just hits so many different on areas for each patient and each patient can have more or less severity in one area versus another.

I mean, it's very, you know, header of the genius, 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 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 foreseeing in the adults at the low dose.

But Suku, again, if there's something there you want to highlight further, please do.

I mean, look, I don't really have too much to add other than remind everyone, this is a very complex syndromic disease. There are multiple aspects of, I guess the human biology is made abnormal and I think as Gil pointed out, and as you know, the phenotypic presentation does vary quite a lot.

So, when it comes to the impact of a therapeutic intervention, I mean, look, our hope, my hope is that once 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.

It is very helpful. Now is there any reason to believe that potential improvements in pediatrics will be larger than what we've seen in adults, but maybe not and kind of the learning functions that you guys discussed before (inaudible) functions. I mean, they are younger patients. Thank you.

Suku, you want to take that question.

Yes, so was that Gil's, Sean?

Gil was asking my autonomic function, you have a faster improvement or a greater improvement in a pediatric patient versus an adult.

That is a tough question. I mean, I would assume at this point in time, it's probably safer to say, given that the two adult patients, we were rapidly collecting autonomic dysfunction within 10 days. If we are 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 has seague, is can you do it in half the time? I 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 occurs the features they are aware of in Rett syndrome, rapidity of response like say you won't get it addressed in 2 days versus 8 or 10 days. I don't think in the bigger picture clinically, we made that much of a difference.

Hope that helps Gil.

Yanan Zhu, Wells Fargo.

Great. Thanks for taking our questions. Since you mentioned the heterogeneity, 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. And then I have a follow-up. Thanks.

Do you take that one Suku, please?

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 that scenario, is that what you said?

Right? I'm just saying I thought I heard in the prepared remarks, you highlighted variability of disease for the pediatric patient population?

Yes.

So, I was wondering in that context, for the two patients, you have dosed so far. Is there, what are the baseline disease severity levels? Are they a reasonably high, so that it's reasonable to expect to see some benefit if there could be any or could there be could, for example, one of patient may have a very mild disease and therefore, difficult to demonstrate benefit?

So, I think the heterogeneity, my understanding is across the board. When it comes to Rett syndrome, regardless of age. So, 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, we would anticipate is a consistent response clinically, given that the gene therapy has shown rapid response and not sustained response in the two adult patients, where one never expected 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 that 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 addresses is the autonomic dysfunction seen in our young pediatric patient, where I guess the concept is if your network is young, the odd value for this one 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.

The only thing I would say that Yanan is that per the protocol. Basically you're going to see similar severities in that the CGIS range is between four to six. Okay. So, it's very similar to the adult trial in severity.

Got it. That's super helpful. And then maybe is follow-up is about the next patient. And perhaps, if I may ask for patient number two, has the IDMC's safety evaluation been down yet or is that still upcoming? And for the third patient, I was wondering, is the plan still to build 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.

Yeah. It's a good question, Yanan. So, basically, the IDMC has not yet met for patients who is coming in the next couple of weeks. And, I think the answer to your question on would you go to the high dose after only two patients.

I think it's going to depend on a combination of things. It will certainly start with the safety and any observed efficacy to evaluate. And also, again, we haven't talked of the IDMC. So, like don't read into what I'm saying. I'm just giving an example. They could say, well, it's pediatrics and we would like to see, you know, a third patient's dose just simply because, they're pediatrics.

So, I think your logic makes a lot of sense. We'll just have to see how things play out and it will start with the data presentations of the IDMC.

Understood, thank you for taking all the questions.

Sure. Thank you.

Jack Allen, Baird.

Hey, thanks for taking the questions and congratulations on progress. Just one quick one from me, similar question, mine as the last couple of questions that were asked here. But I know it was asked other phenotypes of these patients in the pediatric patients that we're doing at data from in the next couple weeks here. About the genotypes, anything you can say as it relates to what kind of genotypes patients have?

Yes, we haven't disclose that, but, Suku, you want to comment on that?

So, I have some pictures on I got the question. So this is in the two pediatric patients, right?

(multiple speakers) We are seeing a significant dilution or are we seeing missense mutations would (inaudible)

So, Sean, I mean, I can I guess we haven't disclosed them 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 I recall, very mild, a mild and other patient is the more towards the severe side. And now keep in mind that they do evaluate CGIS and so forth to see how sick patients are.

And so that also gives you a feel for what one would anticipate as a response to the therapy. But there's a caveat of what we are observing is even, if someone has a patient retraction has a milder phenotype due to a missense mutation (inaudible) symptomology actually gets treated remarkably well.

And the reason I say that is, if we think of our second adult patient was dosed in Canada. This was a patient who had multiple seizures and wasn't too anti-epileptic(inaudible) four seizures a week.

Now this patient is appears to be seizure free and the anti-seizure 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 are these, can you hopefully address control or eliminate such that the patient gets much stronger and can have a productive life.

Got it. Great. That's great color. Thanks so much and looking forward to the data.

Thanks, Jack.

Silvan Tuerkcan, Citizens JMP.

Yes, thank you for taking my question and congrats on the RMAT designation. I also just have a question on the pediatric patient. Given that maybe more heterogeneous. Is there anything on the safety side that will be important to come to the year to the co-morbidities, anything that [time], please? Thank you.

Sure. I would just clarify too. And Suku, correct me if I'm wrong. The pediatric patients isn't any more heterogeneous than the adults (multiple speakers) Right. And Suku any comment on on governance question?

So Sean, your question, I mean, do you mind repeating it?(multiple speakers)

Yes, sure. I was just wondering in pediatrics in general, if there's anything on the safety profile side that we may have to be aware of because, they're small levers, they think the toxicities, but also maybe co-morbidities that smaller patients have that adolescent don't have? Thank you.

That's a good question. Because, we did discuss that in great detail before we launched this program and, given that the intrathecal dose about 15% to 20% does get into the systemic circulation and AAV9 is dropping to the liver that's right goes, but elevation in liver enzymes with an intrathecal dose, which is pretty low compared to systemic dose, it's highly unusual. Any change in blood count, highly unusual.

Complement activation and that (inaudible) events that have been seen at DMT highly unusual, if you ever. (inaudible)clinical therapies purely because you're giving such a low dose what we think. 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 the dorsal root ganglion changes, but again, it's not common. So, my point is, if you do the risk benefit analysis for Rett syndrome program, the benefit, I think far outweighs the risk and so and we haven't had any constraint after now.

Great. Thanks.

Thanks, Silvan.

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.

Just thank you, everybody, for your time this evening and we look forward to providing you further updates here in the next coming weeks on both the Cohort one adults, as well as the available data for the two pediatric patients. Thank you all. Have a good night.

This concludes today's conference. Thank you for joining us. You may now disconnect your lines.