Q4 2023 Taysha Gene Therapies Inc Earnings Call

Participants

Hayleigh Collins; Director, Head of Corporate Communications and Investor Relations; Taysha Gene Therapies Inc

Sean Nolan; Chief Executive Officer and Board Chairman; Taysha Gene Therapies Inc

Sukumar Nagendran; President and Head of Research and Development; Taysha Gene Therapies Inc

Kamran Alam; Chief Financial Officer; Taysha Gene Therapies Inc

Whitney Ijem; Analyst; Canaccord Genuity Securities LLC

Kristen Kluska; Analyst; Cantor Fitzgerald

Gil Blum; Analyst; Needham and Company, LLC

Yanan Zhu; Analyst; Wells Fargo Securities, LLC

Jack Allen; Analyst; Robert W. Baird & Co., Inc.

Silvan Tuerkcan; Analyst; JMP Securities

Presentation

Operator

Greetings, and welcome to Taysha Gene Therapies fourth quarter and full year 2023 earnings call. (Operator Instructions)
As a reminder, this conference is being recorded. It is now my pleasure to introduce Hayleigh Collins, Director, Head of Corporate Communications and Investor Relations. Thank you, you may begin.

Hayleigh Collins

Thank you. Good afternoon, and welcome to Taysha's full year 2023 financial results and corporate update conference call. Earlier today, we issued a press release announcing financial results for the full year ended December 31, 2023. 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 patient one or two, including the reproducibility and durability of any favorable safety results initially seen in our first and second patients dosed in the REVEAL trial to positively impact quality of life and also the course of disease in the patients we seek to treat our research development and regulatory plans for our product candidates, including timing 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 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, forecast of cash runway and future operating results. Discovery and development of product candidates, strategic alliances and intellectual property as well as matters that are not historical facts or information.
Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements. These risks include uncertainties related to the timing and results of clinical trials and regulatory actions 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 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 that we filed today.
This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, March 19, 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.

Sean Nolan

Thank you, Hayleigh, and welcome, everyone to our 2023 full year financial results and corporate update conference call. Today, I will begin with a brief update on our corporate and clinical activities. Then Dr. Sukumar Nagendran, President and Head of R&D of Taysha will provide an update on our lead Taysha-102 program in clinical evaluation for the treatment of Rett syndrome. Kamran Alam, our Chief Financial Officer will follow up with a financial update. I will provide closing remarks and open the call up for questions.
In 2023, we made tremendous progress on the development of Taysha-102, our lead gene therapy program and clinical evaluation for the treatment of Rett syndrome, which is a rare neurodevelopmental disorder, was significant unmet medical need.
This included generating initial clinical data in adult patients and expanding the trial into the adolescent population, obtaining regulatory clearance to initiate the clinical evaluation of Taysha-102 into additional geographies and dosing the first patient in our pediatric trial.
Importantly, we believe these accomplishments enable us to focus our efforts this year on generating critical long term clinical data in a broad range of ages and stages of Rett syndrome patients across multiple geographies.
We now have two ongoing first-in-human trials evaluating the safety and preliminary efficacy of Taysha-102. The REVEAL Phase 1/2 adolescent and adult trial in Canada and the US and the Reveal Phase 1/2 pediatric trial in the United States with clearance in the UK.
Today, we are excited to report longer-term clinical data from our first two adult patients treated with the low dose of Taysha-102 and our adolescent and adult trial. As a reminder, our ongoing review of Phase 1/2 adolescent and adult trial is a first-in-human open-label, randomized dose escalation and dose expansion trial evaluating the safety and preliminary efficacy of Taysha-102 in females aged 12 years and older with Stage 4 Rett syndrome.
We are currently enrolling patients in Part A, the dose escalation portion of the trial, which is evaluating two dose levels of tissue one or two sequentially. Two patients have been dosed to date in cohort 1, evaluating the low dose of patient one or two of 5.7 e to the 14 and dosing in cohort 1 is now considered complete.
Today, we're pleased to provide an update on the encouraging follow-up data from the first two adult patients treated in the low-dose cohort. Recall, when we initiated the REVEAL trial, there were low expectations of efficacy for the Stage 4 adult population among KOLs in the RET syndrome community due to the advanced and relentless progression of disease focus was placed primarily on safety.
Therefore, it was very exciting when we announced the encouraging initial impact that tissue one or two appeared to have across multiple clinical domains in the first two adult patients treated as early as four weeks following the treatment that we reported in November 2023.
The data presented today for patient one is from her six months post treatment, six months post treatment assessment with clinical observations from week 35 post treatment. Importantly, we continue to see a durable response, and we are seeing sustained improvement in the absence or reduction of steroid levels.
We have received many questions since initiating since initially announcing patient one data about the possible impact of steroids on the disease itself, we were not surprised, but nonetheless, pleased to highlight today that patient improvements were maintained or further improved in the absence of steroids.
As of the six month assessment, Patient one has showed sustained improvement across key efficacy measures at decreased steroid levels, with new improvement observed in the Rett syndrome behavioral questionnaire or RSBQ.
Additionally, the second adult patient also sustained improvements across key efficacy measures with new improvement observed in certain measures, including the revised motor behavior assessment or M. our MBA and significantly reduce seizures at 12 weeks post treatment.
Longer-term clinical observations reported by the principal investigator showed that both patients had sustained and new improvements across multiple clinical domains, including autonomic function, social communication, motor skills and seizures compared to earlier treatment assessments.
Importantly, these continued improvements were reported at week 35 following completion of the steroid taper for the first patient at week 19, it decreased steroid levels for the second patient. As a reminder, these two patients have quite different genetic mutations. The first patient's MECP. two mutation manifests in a more severe disease phenotype than the second patient's mutation.
For example, Patient one was completely non-ambulatory at baseline for U.S. patients who could walk with prompting despite the different clinical baseline characteristics. Both patients showed improvements across multiple clinical domains as early as four weeks following treatment. And importantly, both patients showed sustained and new improvements across those clinical domains at the longer-term assessments.
In addition to the positive safety data. We are encouraged by the longer-term safety profile observed data from the first two adult patients showed that Taser one or two was well tolerated with no treatment emergent serious adverse events as of the 35 week assessment for patient one and as of the 19 week assessment for patient two.
We believe the safety profile and these continued improvements across multiple clinical domains, even at reduced steroid levels in both adult patients with advanced stage 4 Rett syndrome, support the durability and transformative potential of patient one or two across multiple genotypes of RET syndrome and further validate our construct. Suku will discuss the clinical observations and efficacy data in more detail shortly.
Now like to turn to our pediatric trial, our ongoing reveal Phase 1/2 pediatric trial is a first-in-human open-label, randomized dose escalation and dose expansion trial evaluating the safety and preliminary efficacy of patient one or two in females, aged five to eight years old with Stage 3 RET syndrome. We are currently enrolling patients in Part A, the dose escalation portion of the trial, which is evaluating two dose levels of tissue, one or two.
Sequentially, we've dosed the first pediatric patient in cohort 1, evaluating the low-dose of patient one or two of 5.7 e of the 14 here in the US the Independent Data Monitoring Committee or IDMC recently convened to review these longer-term clinical data from the first two adult patients and the initial six week data from the first pediatric patient treated with the low dose of Taser one or two following review.
The IDMC approved our request to proceed to dose escalation in the adolescent and adult trial, which enables us to initiate dosing with the high dose of patient one or two earlier than planned. This is a critical step in our development plan as advancing to the high dose accelerates our ability to further inform our clinical development and regulatory strategy for Part B of the study by at least a quarter.
With Cohort 1 now completed in our adolescent and adult trial, we plan to dose the first patient in cohort 2 evaluating the high-dose of Tesha-102 of 1 e to the 15 in the second quarter of 2024. Initial data from Cohort 2 of the adolescent and adult trial is expected in the second half of 2024.
The IDMC also approved dosing of the second pediatric patient in cohort 1 in the REVEAL Phase 1/2 pediatric trial. The patient has been identified and dosing is scheduled to take place this quarter. We plan to complete enrollment in the low and high dose cohorts of the pediatric trial this year with initial available data from the low-dose cohort expected in mid-2024, as we disclosed previously in early January.
Additionally, initial data from the high-dose cohort of pediatric trials expected in the second half of 2024. Overall, we're focused on completing dosing in Part A. of both studies this year. Importantly, data from Part A will be assessed by regulatory agencies and the IDMC to provide guidance to determining final key elements of Part B, the dose expansion portion of the study, including the hierarchy of efficacy endpoints, study design and the maximum tolerated dose for maximum administered fillers.
Another key focus in 2023 was broadening the clinical evaluation of patient one or two across geographies in our REVEAL adolescent and adult trial. We recently announced the expansion of the ongoing trial in Canada into the U.S. following our submission of the protocol to the U.S. Food and Drug Administration or FDA. We're now focused on site initiation activities in the U.S. for the adolescent and adult trial.
In addition to our ongoing U.S. site initiation activities in our pediatric trial in our REVEAL pediatric trial. We announced earlier this year that the UK Medicines and Healthcare products, regulatory agency, or MHRA. authorized a clinical trial application for patient one or two in pediatric patients with RET syndrome, enabling expansion of our ongoing pediatric trial in the US into the UK.
And we're currently focused on site initiation site initiation activities. Additionally, we are pleased to share that patient one or two received innovative licensing and access pathway designation, or I lap from the MHRA, which is a program that's designed to accelerate the review path of novel treatments. We believe this further reinforces the high unmet medical need for patients with RET syndrome.
As a reminder, Taser one oh two has already received fast track designation and orphan drug and rare pediatric disease designations from the FDA and has been granted orphan drug designation from the European Commission for the treatment of breast centers.
Lastly, we are pleased to share that we have strengthened our clinical and regulatory leadership with the promotion of Dr. Meredith Schultz, the Chief Medical Officer and Rumana Haque-Ahmed to Chief Regulatory Officer. Dr. Schultz and Ms. Haque-Ahmed will continue to report to Suku.
Dr. Schulz as a board certified licensed pediatric neurologists who is experienced in treating patients with RET Central. Dr. Schulz brings more than 17 years of clinical experience and has led numerous gene therapy clinical trials for rare diseases in her career.
As Chief Medical Officer, Dr. Schulz will lead the company's clinical development, clinical operations, medical affairs and safety activities. Rumana Haque-Ahmed brings nearly 30 years of experience in global regulatory strategy and product development in multiple therapeutic areas.
She has been instrumental in the development and execution of our regulatory strategies for Taser one or two, including obtaining IND. and CTA. clearances across three countries, and she's led the regulatory interactions across patients.
Gene therapy portfolio fueled continued to lead the company's regulatory affairs department and regulatory interactions, Dr. Schulz and Misaka, Omid, I've been instrumental to the clinical development of our tissue one or two program.
And we look forward to continuing to partner with them in their new leadership positions with a significant focus on execution in the year ahead. We believe our team is well positioned to continue to accelerate the development of tissue one or two. As you can see, we have made exciting progress across rotation one or two program over the past year.
The sustained and new improvements in both adult patients with advanced stage 4 syndrome, coupled with the initial six week clinical data from the first pediatric patient that was reviewed by the IDMC supports the therapeutic potential of taking a while to for a broad population of patients with RET Central.
Looking ahead, we are focused on generating clinical data across a broad range of ages and stages of patients with RET syndrome in multiple geographies with multiple value inflection catalysts anticipated in 2024.
We look forward to further evaluating the therapeutic potential of tissue, one or two for patients and families living with Rett syndrome element, I'll turn the call over to Suku to provide more in-depth discussion on our clinical program in Rett syndrome. Suku?

Sukumar Nagendran

Thank you, Sean, and good afternoon, everyone. I'm pleased to provide an update on our cash, our No. two gene therapy program in clinical evaluation for the treatment of Rett syndrome. Threat syndrome is a rare neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene encoding material CPG. binding protein two or MECP2 protein, which is essential for regulating neuronal and synaptic function in the brain.
This disorder is characterized by a loss of communication and Hand Function slowing and regression of development more than respiratory impairment, seizures, intellectual disabilities and shortened life expectancy.
Project syndrome progression is divided into four key stages beginning with early onset stagnation at 6 to 18 months of age, followed by rapid regression battle and lead motor deterioration. It's chromosomal inactivation and silencing of MECP2 expression and then occur randomly with such syndrome results in a mixture of cells that are deficient in or express MECP2.
Normally, this heterogeneity in MECP2 expression is what makes Rett syndrome challenging with traditional small molecule and simple gene therapy approaches. But we believe our construct equipped with the novel MIR and a responsive auto regulatory element of a mine rare can appropriately address this challenge and provide therapeutic benefit.
As a reminder, additional one or two is that self-complementary intrathecally delivered AAV9 gene transfer therapy designed as a onetime treatment. Because of the risk associated with both and then over expression of MECP2, we have combined high throughput micro-RNA profiling and genome mining to create a myopia on novel micro RNA target panel designed to mediate MECP2 expression in the central nervous system on a cell by cell basis.
With Amira endogenous microRNA, which activated in the presence of MECP2 or thought to base pair with targets in the viral genome encoding mRNA and ultimately decrease protein expression levels through RNA interference.
At that stage 1 or 2 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. By increasing MECP2 levels of MECP2 deficient cells and maintaining healthy levels of MECP2 output in normal cells, tissues one or two has demonstrated the ability to produce and maintain same transgene expression in the CNS in preclinical models.
As Sean mentioned, taking one or two is currently being investigated in the ongoing review phase one two adolescent and adult trial, the trial, which was designed primarily as a safety study is also measuring pre-specified efficacy measures.
All efficacy data being collected in this Phase 1 Phase 2 trial is hypothesis-generating as we continue to generate long-term data across more patients and cohort this year. These data cost measures will further inform our thinking relative to optimize primary endpoint selection for registrational study purposes.
Today, we are pleased to share for long-term data from the two adult patients treated with stage 1 or 2 . I will be discussing data from two different time points for each patient. Efficacy assessments are captured at month 6 for patient one and week 12 for patient two.
Safety data and clinical observations from the principal investigator for capture at week 35 for patient one following completion of a steroid taper and week 19 for patient two a decreased steroid levels compared to earlier post treatment assessments. All these data have been reviewed by the independent data monitoring committee.
We will begin with an overview of the baseline status of the two patients prior to treatment with stage 1 or 2. As a reminder, the two adult patients who have been treated with a low dose of tissue, one or two differ in the severity of their disease.
What patients had been diagnosed with stage 4 and some of the lead motor deterioration stage, which is the most advanced stage of the disease. However, the patients possess different genetic backgrounds and mutation types in the MECP2 gene, which manifests in dramatically different phenotypes and clinical severity.
Studies have confirmed that MECP2 mutation types can be relapse can be reliable, predictable syndrome disease severity with more severe mutations correlating to greater motor dysfunction, loss of ambulation and higher prevalence of scoliosis creation.
Patient one, a 20 year old female has a large population with the MECP2 gene that manifests as a highly severe phenotype. This patient severities in evidenced by his clinical presentation at baseline prior to treatment.
She was in a constant state of high petroleum with complete loss of ambulation and was wheelchair-bound. She had lost the ability to sit or stand by eight years of age as documented in the patient's medical history. She also became non-viable at this time, additional in the patient had limited body movement requiring constant back support has had lost fine and Gross Motor Function early in childhood.
We had a very good hand function with essentially no function of non-dominant hand. She experienced frequent apnea and hypoventilation episodes and had a history of seizures.
Patients' level of severity is reflected in our baseline scores across efficacy measures, including clinical global impression, severity of CGIS, which is a seven point scale and kept the signs and symptoms of brick syndrome, but read the severity of the patient's illness relative to the clinician's experience with participants who have the same diagnosis. At baseline, the patients he just called was six indicating CBOE deal.
In contrast, the second patient, a 21 year old female has a missense mutation in the MECP2 gene function that manifest in a milder phenotype patient presented with a milder form of disease, which is reflected in how clinical presentation at baseline prior to treatment.
She had only partial loss of ambulation and could walk with prompted, but she experienced progressive type forces and very tiny here that developing her late teens impacting her gait and balance as documented in the patient's medical history hand, stereotypical appeared at three years of age following regression and she mostly held our hands firmly together.
We also became nonverbal at this time for our ability to reach and gas objects was weak at issue with the patient experienced frequent hypoventilation episodes and had a history of frequent procedure for level of severity in the baseline scores across efficacy measures as reflected in our business goes across efficacy measures for baseline CGIS. score was four, indicating moderately deal.
The key takeaway is that there are phenotypic differences between the two stage 4 patients which are correlated to their genetic status. We saw a consistent pattern of improvement across key clinical domains and efficacy measures as early as four weeks post treatment with low-dose uptake of one or two in both adult patients despite the differences in the genetic centers of severity.
As Sean mentioned, we are pleased to share long-term data showing that both patients are having a durable response, specifically, both patient sustained improvements and demonstrate a new improvements compared to the initial post treatment assessments based on the efficacy assessments and observations from the principal investigator based on clinical observations from the principal investigator.
Both patients showed sustained and new improvements across multiple clinical domains, impacting activities of daily living, including autonomic function, seizure, socialization and communication and motor skills following treatment with the low-dose of stage 1 or 2.
Let's begin with an overview of the long-term clinical observations for patient one. Further protocol prophylactic immunosuppressant therapy begin or began prior to taking one or two administration. The first patients derive tape-out was initiated at week 17 and completed at week 33.
35 week post treatment assessment, the principal investigator observe that the patients improvements across multiple clinical domains had been maintained following completion of the steroid taper as well as the new improvements that were observed compared to earlier post treatment assessments.
Basically 35 weeks following treatment, the first patient demonstrated sustained improvements from the initial four and six week assessment in multiple clinical domain.
After the completion of the steroid taper, including motor improvement at the patient's initial six week assessment, she had gained the ability to sit unassisted for the first time in over a decade and have restored more months in length at week 35 following the completion of the patient steroid taper.
These improvements are sitting unassisted and restored movement in their legs had been maintained as documented by video evidence. Further a patient sustained improvement in hand function at week 35, including the gain the ability to gas objects with a non-dominant hand and transfer them to a dominant hand for the first time since infancy as documented by video evidence.
At week 35, she also showed a sustained improvement in hybrid to graft with a dominant hand. Additional patient demonstrated the ability to open a hand dissociated fingers, Catcher North and touch screen following treatment.
Progressive loss of hand function is a hallmark characteristic of Rett syndrome and a key concern for caregivers that impacts a patient's ability to communicate and impedes daily activities, but ultimately limits independence.
These sustained improvements in hand function 35 weeks following treatment, which are not observed in the natural history of breath syndrome are very encouraging and supports the potential of patient one or two to bring meaningful therapeutic benefit to patients and caregivers.
Patients also demonstrated sustained improvement in autonomic function at week 35 with improved operating performance, reduced industry demand, including less breath holding spells and in infrequent hypoventilation compared to before treatments.
As a result, we experienced a sustained improvement in sleep quality and duration through week 35 fairly well reported that following treatment. The player patients sleep through the night for the first time in 20 years. Therefore, she is much more alert during the day.
Additionally, 12 perfusion of the extremities is a characteristic sign in patients with Rett syndrome that is thought to result from this automobile, meaning it's controlled by the autonomic nervous system. Therefore, it's encouraging that the patient also showed a sustained improvement in circulation at week 35 post treatment with the patient's hands and feet restored to normal temperature and color, whereas before treatment, the hands and feet we used to call them blue based on the principal investigators clinical observations at week 35 post treatment.
The principal investigators observed new improvements in socialization and communication since the patient's initial six week assessment as of the week 35 assessment, the patient was more alert and socially interactive with the increased communication of our needs using localization.
Cadia was reported actually showed an enhanced ability to use an IT-driven communication device which caregiver said she hadn't express interest in before treatment.
Specifically following treatment, the patient was able to use the device much more efficiently with this gain, the ability to activate functions on the screen of the device. Difficulty in communication, including loss of speech is one of the most prominent symptoms of Rett syndrome and is an area of key area of concern for caregivers directly interfere with the patient's ability to communicate their needs and express their interest.
These new improvements observed at week 35 post treatment for highly encouraging as alternative and of Mandatum communication speech output technologies activated by ideas can be leveraged by patients and families with which track syndrome as a supplement to our replacement for natural speech. We believe that the ability to communicate could give patients a sense of control and greater independence.
Principal Investigator also observed that the patient seizures have overall been well controlled through week 35 following treatment at lower levels of antiseizure medicines relative to baseline and that the patient no longer experiences and provoke seizures. These observations are supported by data from the seizure diary.
Now let's turn to the second and outpatient at the 19 weeks post-treatment assessment, the principal investigator observe for the patient's improvement across multiple clinical demand had been maintained while the patient was on decreased steroid levels as well as new improvements that were observed compared to initial four and six week assessment statistical issue sustained improvement in motor skills, the reduction enhanced junior TP.s which are repetitive per-customer sand movements on the diagnostic hallmark of X syndrome before treatment, the patient mostly held our hands firmly together.
Perhaps your peer to peer had improved for the first time since regression at page 3 at the initial four six week assessment. Based on the principal investigators observations and supported by video evidence, the fashion displayed less forceful happening and that hands mobile often open and relaxed through week 19, sustained improvement.
Enhanced utility piece at week 19 post treatment is encouraging, and it provides new opportunities for fine motor skills, learning profession, also sustained improvements in socialization and communication through week 19 with an increased interest in social communication and activities, including increased response to spoken word and iContact.
She also sustained improvement in autonomic function at week 19, with improvements in breathing this repairs, including hypoventilation and reduced ethnic spells. The patient also showed sustained improvements in circulation at week 19 post treatment with the patient's hands and feet, restoring normal temperature and color.
Whereas before treatment, the patient's hands and feet, we usually call them rule based on the principal investigators observation, notably the second patient demonstrated a pronounced improvement in seizure frequency at week 19 post treatment, the significant reduction of seizures at lower levels of anti-seizure medicine related for baseline.
These observations are supported by data from the seizure diaries, which I will discuss in more detail later. Both patients also demonstrated sustained and new improvements across key efficacy measures following treatment mutation one or two, which reinforces the clinical observations from the principal investigator.
Let's begin with an update on the efficacy data reported at the six month post-treatment assessment from the first patient. The first patient sustained improvements across key efficiency, efficacy measure that decreased steroid levels and showed improvement at six months post treatment.
Specifically share sustained improvement from the initial four week assessment in Clinical Global Impression Improvement or CGI-I Clinical Global Impression severity or CGIS, Parental Global Impression Improvement or PGII., the Rett syndrome Hand Function scale all of us at FS the revised motor behavior assessment up our MBA and seizure that.
CGII. is a clinician reported seven point assessment of overall improvement following treatment adaptor Tourette's syndrome. It accounts for key aspects of the disease could determine global change score. The sustained score to indicating much improved was reported at the six month assessment, which is consistent with the score important at the four week assessment.
Additionally, the patient demonstrated a sustained one point improvement from the baseline score of six, indicating similar yield to a score of five indicating market.
Neal in CGIS. at month six, which is consistent with the score at week four PGII. is a caregiver reported assessment of overall improvement following treatment that uses a seven point scale, a sustained score to indicating much improved was reported at month six.
The RSHFS. is a clinician reported assessment of hand function in patients with Rett syndrome, which is evaluated by an experienced independent physical therapists with expertise in the hand, functional reputations for Cogent, but demonstrative hand function in each video at one oh four levels assessing the best score for large objects ranging from no active grafting of any object to independent prospects.
The highest score that can be achieved for this assessment is for the first patient demonstrated a sustained improvement in our SHFS. at six months following treatment. Although there are no changes from the baseline score, three indicated the ability to hold an object for at least two seconds in hand, dominant hand.
She was able to increase the number of objects sale from one to two additional share gains, some basic grasping ability in a non dominant end and sustain this improvement at six months post treatment. At baseline, she could not hold any objects in a non-dominant pan out at six months a score of two was demonstrated indicating the ability to hold an object, but with two seconds when assisted progress.
Again, it is very important to note that hand function improvements are rarely observed in the natural history of retina. The RMB, which is the 24 question clinician reported scale measuring disease behaviors of Rett syndrome showed a total score improvement of one point from the baseline score of 43 to a score for two at month six, improvements observed in motor dysfunction and respiratory behaviors.
Seizure diaries showed that the patient had stable sea shipments at lower level of anti-seizure medication relative to baseline through week 35 post treatment based on caregiver reported medical history before treatment, the patient had two to four seizures per year.
As of the Stratify, the patients seizures are confined to periods where anti-seizure medication levels declined to below 50 micromoles per liter, whereas before treatment plantation of one or two to required levels of 100 micromoles per liter or greater to control seizures.
Importantly, the first patient also showed new improvement in the six month assessment in the Rett syndrome behavior questionnaire RSBQ. not as big here, which is a 45 item caregiver administered question. You that assesses risk syndrome characteristics.
The patient demonstrated a 30 point total score improvement from the baseline score of 52 to a score of 22 at month six. For score was driven by improvements in hand behavior and many breathing problems. General mode repetition you face more months, nighttime behavior, fear and anxiety, body dropping and facial expressions.
Now let us discuss the efficacy data reported at the week 12 post treatment assessment from the second-generation recall that the second patient had a CGIS. severity score or indicating moderately ill wasn't a baseline CPS score of six indicating severely ill patient one at week 12 post treatment.
The second patient demonstrated sustained and new improvements across key efficacy missions from the initial four week assessment assistance score of three indicating minimally improved was reported at week 12 in both CGII. and PGIA., which is consistent with the scope of the product at the four-week assessment for patient two patients showed a two point improvement in the RSBQ. total score from the baseline score of 37 to a score of 35 at week 12.
Improvements observed in breathing body knocking facial expression, general ward and repetitive fast movements. Importantly, the second patient also demonstrated new improvements at the 12-week assessment in our MBA.
She demonstrated a 17 point improvement in the RMB total score from the baseline score of 38 to a score of 21 at week 12, which was driven by improvements in social skills, respiratory behavior, including less frequent hypoventilation and but holding seizures, truncal rocking stereotypical movements and our mounting an aberrant behavior.
The patient also showed new improvements at week 19. In seizures, the seizure diaries showed a significant reduction in seizure event that 25% lower levels of anti-seizure medicines relative to baseline to week 19 or post treatment based on caregiver reported medical history relative to the baseline seizure frequency of two to four seizures per week.
There has been a significant reduction in seizures post treatment with stage 1 or 2 since straight, but retention one or two patient two had a single seizure event with 17 weeks reported seizure-free as of week 19 Boston. So there were no changes reported in CGISRRSATEFRS. at week 12 hour at week 12. The principal investigator reported a sustained improvement. In the patient's hand.
Stereotype is not measured in our SHFRS. for the first time since regression at age three, depression displayed less forceful handling and more open and relaxed hands. More data details on this available data can be found in our press release issued today and our Form 10 K for the year ending December 31st, 2020, and three, filed with the SEC.
Overall, we are highly encouraged by the safety profile and the durable response reported in these long-term data in both adult patients treated with the low dose of 1001 oh two critical takeaway is that following treatment with 1001 oh two, there were early improvements observed across multiple clinical domains in the two stage 4 adult patients with different genetic mutation severity and phenotypic expression.
And importantly, both patients showed sustained new improvements across those clinical domains at week 35 post treatment for patient one and week 19 post treatment for patient two. We believe the safety profile and continued improvements observed even at reduced levels in both adult patients with advanced stage 4 Rett syndrome, support the durability and transformative potential of cash of one or two across multiple genotypes of Rett syndrome.
With a low low-dose cohort completed in the adolescent and adult trial, we'll focus on collecting data with the high-dose patients on or to further explore the clinical impact of patient one or two in patients with stage 4 at syndrome.
Based on the IDMC review of the clinical data from both adult and the initial clinical data from the first pediatric patient treated with low-dose Acacia one or two, the IDMC approved our request to proceed to a earlier dose escalation in the adolescent and adult trial.
The IDMC also approved dosing in the second pediatric patient in cohort 1, the low-dose cohort now reveal Phase 1/2 pediatric trial. Both REVEAL trials have two-part trial design. Dose escalation from Part A. will be assessed by the regulatory agencies and IDMC to provide guidance on key financials.
Key elements of Part B are the dose expansion portion of the study, including hierarchy of efficacy endpoints, study duration and the maximum tolerated dose or maximum administered dose. Therefore, advancing to cohort 2 in the adolescent and adult trial will expedite our ability to inform our clinical development and regulatory plan for Part B of the study.
This year, we are focusing on completing dosing in Part A. of both trials. We anticipate significant data collection in 2024 with many clinical catalysts expected in the year ahead. As we discussed in early January, we expect to report initial safety and efficacy data from cohort 1 evaluated a low dose of patient one or two in the pediatric trial, mid 2024. We also expect to report initial data from Cohort 2 evaluating the high dose occasional one or two in the second half of 2024 in both the adolescent and adult and pediatric trial.
As Sean noted earlier, our efforts to expand our clinical trials remain underway, and we are currently focused on additional site activation in the US for our adolescent and adult trial with the goal of expanding our adolescent and adult trial in Canada into the US.
We are also focused on site activation in the UK for our pediatric trial with the goal of expanding our ongoing pediatric trial in the US into the UK. As a reminder, there are no approved disease-modifying therapies currently available that treatment group, the genetic root cause of Rett syndrome.
There is a significant unmet medical need syndrome caused by a pathogenic likely pathogenic MECP2 mutation afflicting between 15,000 to 20,000 patients in the U.S., EU and U.K., and a high burden of care associated. We are pleased that tissue one or two recently received a lump designation from the U.K. MHRA.
Fisher one or two has also received fast track designation and orphan drug designation and rare pediatric disease designation from the FDA and has been granted orphan drug designation from the European Commission for the treatment of Rett syndrome.
Overall, we are highly encouraged by the safety profile and long-term efficacy reported in the first two adult patients as well as IDMs is approval for both the second pediatric patient following review of the initial six week clinical data from the first pediatric patient dose limitation of one or two.
This year, we are focused on collecting data across multiple ages of patients, the low and high dose of patient one or two, to further inform our clinical and regulatory strategy for the next phase of the study. We look forward to sharing additional progress this year.
I will now turn the call over to Kamran to discuss our financial results. Kamran?

Kamran Alam

Thank you, Suku, and good afternoon. Revenue for the full year ended December 31, 2023, was $15.5 million compared to $2.5 million for the full year ended December 31, 2022, as revenue was derived entirely from our option agreement with Astellas gene therapy. The increase in revenue was primarily a result of red syndrome research and development activities performed in 2023.
Research and development expenses were $56.8 million for the full year ended December 31, 2023, compared to $91.2 million for the full year ended December 31, 2022. The decrease was due to reduced research and development headcount, lower research and development manufacturing expenses and a reduction in third party research and development consulting fees, mainly related to preclinical studies and IND-enabling toxicology studies.
General and administrative expenses were $30 million for the full year ended December 31, 2023, compared to $37.4 million for the full year ended December 31, 2022. The decrease was primarily attributed to a reduction in compensation expenses as a result of lower headcount and reduced corporate insurance and consulting expenses.
Net loss for the full year ended December 31, 2023 was $111.6 million or $0.96 per share as compared to a net loss of $166 million or $3.78 per share for the full year ended December 31, 2022 net loss includes the nonrecurring and noncash expense of $34.5 million relates to the change in fair value from the prefunded warrants as a result of the August 2023 private placement financing.
As of December 31, 2023, Taysha had $143.9 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?

Sean Nolan

Thank you, Kamran. As you heard today, we've made significant progress in the clinical development of our Tier 1 or 2 program. We are highly encouraged by the safety profile and durable response reported that reduce steroid levels and the longer-term data from both patients in the low-dose of our REVEAL adolescent and adult trial.
These continued improvements in both adult patients with advanced stage 4 Rett syndrome, coupled with the IDMC has approval to dose the second pediatric patient following review of the initial clinical data from the first pediatric patient dose flotation wanted to reinforce the transformative potential of patient one or two across a broad population of patients with RET syndrome.
Building on the momentum from 2023, we believe 2024 is poised to be a transformational year for the company. This year, we're focused on data generation across a broad range of ages and stages of patients with RET syndrome in multiple geographies with the goal of completing dosing in Part A of full trials with the low and high dose of tissue one oh two to inform the next phase of the studies. With many clinical catalysts expected in the year ahead, we look forward to providing additional updates on our progress.
With that, I will now ask the operator to begin our Q&A session. Operator?

Question and Answer Session

Operator

Thank you. (Operator Instructions)
Whitney Ijem, Canaccord.

Whitney Ijem

Hey, guys, thanks for things for all the updates. I guess Please limit myself to one. I just can you help set expectations into the pediatric data midyear and in particular, our understanding of Stage 3, and I think we've talked about this a little bit before.
But is that the disease is kind of stable, more variable and potentially some improvements in terms of the natural history. So how should we be thinking about kind of what you could show at the initial update versus maybe over the longer term in the pediatric updates as we progress through the year?
Thanks.

Sean Nolan

Thanks Whitney. I guess I would say that number one. Keep in mind that the pediatric patients will likely be in a severity range of CGIS. of between four and six, which is which is similar to what's happening in the adolescent and adult trial.
And I think if you talk to the KOLs out there, you'd get very consistent feedback that that's the most appropriate severity range to study in a first-in-human trial for gene therapy with this particular disease. So I think we'd need it to answer your question.
You know, you're going to see them a bit of a spectrum of patients, right? You know, someone who's a four is going to be different than someone who's a six. We've seen that with our first two adult patients here of the time to impact, you know, it's a new population.
You would you'd like to think that you should see a relatively similar time to effect and hopefully in our initial magnitude of effect is relatively similar. And depending upon the severity of the disease, it's also possible that it could take longer to see change in someone that's less severe versus more severe so if you think about a midyear readout, I would say that we dosed our first patient at the end of 2023.
And so we'd likely have between four to six months of data at that particular time, we've guided to dosing the second patient this quarter. So you're probably talking between two to three months of data for that patient essentially early data for the third patient, depending upon the timing of that particular dosing. So hopefully that gives you a little bit of flavor of what to expect.

Whitney Ijem

Yeah it does. Thanks.

Sean Nolan

Thank you.

Operator

Salveen Richter, Goldman Sachs.

Hey, guys, good evening. This is Elizabeth on for Salveen. Thank you for taking our question and congrats on the data. Mechanistically, what is your hypothesis around what is driving the RSPQ. improvement for patient one at week 25, noting that that score was relatively flat from week 4 to 12? And then how should we think about expectations for that in particular score metric on the forward? Thank you.

Sean Nolan

I think first and Suku can jump in, but I would say with patient number one, the changes that you saw on our SPQ. were primarily driven by anxiety going down, general mood, improving and hand function improvement.
Those are the those are the three main drivers in the latest increase in that particular scale. Um, you know, I would just say one potential hypothesis right now on some of the mood aspects is that these patients are on very high levels of steroids for a long period of time, and we'll have to see how other patients do that as well.
But one potential is that if you're reducing the steroids, you know, the level of durability, the impact on sleep, just the overall mood could be improving as a result of that. And put another way, it is possible that the steroid Keno somewhat masks benefits until they're either reduced significantly or further withdrawn. So we're quite encouraged by what we see in that aspect of things. And hopefully that gives you a bit of perspective and how we're thinking of it and looks at this juncture.

Well, thank you.

Sean Nolan

Thank you.

Operator

Kristen Kluska, Cantor Fitzgerald.

Kristen Kluska

Hi, everyone. Thanks for taking my question and congrats on the data update. I wanted to ask about the Leap anecdote, you shared for patient one. So we understand that sleep issues are very common in RET mutations, but they can present pretty differently depending on the type of mutation.
So can you speak more to the background expected for the patient based on their mutation? And, you know, essentially what difficulties they were having sleeping through the SI? So was there any fleet screaming or laughing or other notable effects? And essentially what you believe it's happening that you are able to see the drastic change there. Thank you.

Sukumar Nagendran

Yes. So that's an important question because as you pointed out, many patients with Rett syndrome do have significant sleep abnormalities and sometimes they are also correlated with the respiratory abnormalities that can coexist.
And in this patient one, what was observed by the parents was that this patient never ever seem to have a reasonable night's sleep and always had a very disruptive night sleep, which included Restless Leg features, nine, Terra, et cetera, and post gene therapy.
The feedback from the cardio, especially the father was that this patient was not sleeping through the night, and that's the first time, he was getting a good night's sleep. So obviously, the gene therapy itself I think, was most speculating, but we think is restoring MECP2 function in the sleep centers and probably helping with many features of sleep that resulted in this patient are being restored to almost a normal state.
Your second question I think was on seizures. So patient one is thought to have about two to four seizures a year. I'm sorry, did you have

Kristen Kluska

And I forget, sorry, the question was just on of the differences about sleep disturbances relative to the mutations that they experience that they have to hold.

Sukumar Nagendran

So this first patient had a large deletion, which resulted in a severe phenotype. But to my knowledge, I don't think and the severity of the genotype is necessarily correlated with the severity of the sleep abnormalities. That correlation doesn't seem to be clear. So but this Spansion, any patient one had a severe sleep abnormalities. And if your question also, is that what is the actual type of physiology behind it?
I don't think anybody fully understands that, but all I can tell you is the clinical observation is that the gene therapy appears to have restore normal sleep patterns. So that help?

Kristen Kluska

Yes. Thank you so much. Appreciate it.

Sean Nolan

Thank you.

Operator

Gil Blum, Needham & Company.

Gil Blum

Good afternoon, and let me also add my congratulations to the progress. So just one from us. Can you maybe put into context, the burden experienced by adult patients from being on steroids on a daily basis and are steroids ever tapered during the standard of care for adult patients during the natural course of the disease. Thank you.

Sukumar Nagendran

Yes. So that's another good question. So immunosuppression or immunomodulation in general is not used to treat patients in a disease modifying fast fashion.
Yes, it has been tried in the past using a drug like sirolimus or prednisone hydrocortisone retreat that syndrome, but it hasn't had any positive impact on disease duration, severity of outcome. So what you're seeing in our trial, though, is because it's a gene therapy trial, steroids and sirolimus are being used as immunomodulatory agents to allow us to get over that initial period where there might be some theoretical risk of the treatment itself.

Operator

Joon Lee, Truist.

Hi, good afternoon. This is [Maggie] on for Joon. And congrats on the quarter and thanks for taking our questions. We have a couple, if I may. First, could you please elaborate on the safety and efficacy of using a fixed dose for patients as young as three years old to adults. And if you expect to achieve a comparable exposure level in the CNS of the siRNA patient.

Sean Nolan

The answer to that, I can start would be that the on the overall CNS fluid volume between a three-year-old and an adult actually is very there's very little difference, which is why we're comfortable the IDMC is comfortable. The regulators have all been comfortable based on the preclinical data using that fixed dose on the same across patient populations, essentially.

Thank you. And the other question is that how do you envision a registered registrational trial would look like if data supports and if you think MDRI. as a measure could be considered given the nature of the disease requiring multiple domain improvements analysis?

Sean Nolan

You know, I would say a couple of things as it relates to clinical trial design. I think the headline is we feel like there's multiple pathways that we can go down and multiple endpoints that are there for consideration, which is a good place to be at this particular juncture.
And we've always been very steadfast in our view that we were going to use Part A. to get to a better informed view and that we would have a discussion with the FDA prior to starting Part B of the study if we wanted to refine endpoints and refine our trial design.
So that was one of the reasons we put a press release out a few weeks ago when we announced that the IDMC had allowed us to go to the higher dose earlier because we think that step up will hopefully provide more clarity to us relative two endpoints and potentially trial design as well. So we can't say anything declarative with right now about what exactly we're going to do.
I would say we're we continue to be very encouraged of the pathway that we're on to be further informed in the coming quarters that can help us with the FDA. And I think in terms of the endpoints, again, we know that there's a pathway there with CGII. and RSBQ.
And there may be additional on endpoints for consideration that again, we think we'll be better informed on as we continue to step through dosing patients, particularly at the high dose. Hopefully, that makes.

Thank you. Yeah thanks for taking our question.

Operator

Yanan Zhu, Wells Fargo.

Yanan Zhu

Okay. Thank you for taking our questions and congrats on the progress. So I was wondering this, the first patient seen a pediatric trial has gone through the six week arm safety monitoring committee evaluation. I'm wondering if there's any color from that patient in terms of improvement that could be consistent with what you are seeing in the adult trial or in general a potential for such improvement in pediatric population? Thanks.

Sean Nolan

Really appreciate the question. I just would go back to we dosed the first patient in the pediatric patient at the very end of it of December and about a week later, we put out a press release saying that we wanted to begin to disclose data on a cohort basis and that we felt that was the most appropriate thing to do versus going patient by patient.
And so you know, all I can tell you at this point in time is that the IDMC saw the initial pediatric data as well as the data that we just reported on the two adults, and that was in their calculus as they decided that we could go to the high dose in the adolescent and adult study, and we can proceed to dosing the second adolescent patient. So beyond that, we'd really prefer not to comment and proceed with our path forward to disclosing that data in a more fulsome manner at midyear.

Yanan Zhu

Understood. Thank you for the answer, if I may, I do have a quick follow-up question on the patient went into in a adult data dataset and what we can see clearly, a patient one has continued improvement or new improvement in our SB. two patient to have new improvement in our MDA.
But interestingly, the other endpoint for those patients seems to be pretty flat. So how do you think about that? And is there a potential for the other endpoint to also improve in the future? Thank you.

Sean Nolan

If you're referring to CGII. I would say this is that what you're talking about?

Yanan Zhu

Sorry, it's CGII. I fully appreciate. And even maintenance of the prior and numbers according to our heart attack with doctors that and that's a very, very encouraging sign to have those minimum many improved ratings are maintained in a following in a follow-up and also to have them much improved for further the other patient maintain, those are great achievements.
And talking about our SB. two and our MDA, where both patient had one score improve and the other score relatively flat, yes, because that's what I'm talking.

Sean Nolan

I got you. So in patient number one, so first of all, the R & DA. is administered by the clinician in the hospital. The RSD. two is provided by the caregivers in the home setting and they asked different questions. Okay. So it's a little difficult to put apples to oranges, but I would I would say this, we actually asked the primary investigator of the same question and what she said was the patient number one, it has gotten very aware of what's going on in her surroundings.
If I showed you the video phone from pre treatment, she was very, very that almost like in a cationic state in a wheelchair really not interacting now. She's much more aware, she's trying to communicate and localize and basically what the PI. told us that she does not like going through the testing at the hospital, she gets irritated and she doesn't want to cooperate.
And at this point, she has the strength to not cooperate. So that is that has been driving some of the it's driving the score that you're saying should choose essentially not necessarily cooperating with some aspects of the disease of the testing where in the in the home setting.
She's getting very much a comfortable situation and on she's the parents are seeing as the other thing I would say is that some of the improvement that I mentioned earlier in the RSBQ., the patient one had was in the anxiety, the general mood aspect of things that is not captured in the RMB yet. So that's one aspect there.
On patient two, you know, her our MBA improves significantly. And it was driven essentially by her socialization or interest in communicating with people and also her seizures. Those were big drivers and the RSD. two neither of those is his address, neither one of those is quantified.
And in the RSB. two, again, she had an elevation in anxiety and some of the nighttime behaviors which again, if you think about what I said about patient one and steroids, that that could also be the case, she has had a bit of an issue with tolerating the steroids. So hopefully, again, that gives you some perspective on those two things and Suku heads on that as well.

Sukumar Nagendran

And also for patient two, I would highlight the seizures are decreased by 95% post gene therapy treatment. So this patient had, I think, 8 this could have made to 16 seizures a month and other than one seizure data in post treatment. The patient has had none, no sit new seizures and also the use of a combination antiepileptic, massive drop by 25%. That is a big deal from a clinical standpoint and for the parents and caregivers and from an activities of daily living standpoint.
Second thing, you should notice inpatient to some of the hand function of Cedar traffic movements have decreased, which also makes it a promising that this patient may eventually get independent functionality of the hand.
And there is something else that goes on in about 40% of these patients with Rett syndrome, which is the upper and lower extremities, have abnormal circulation, which means the hands and feet get quite cool and at times painful.
And you would note in patient two and patient one of that resolved post gene therapy treatment. So other than our RNBNRSBQ., which obviously we focus on for different reasons these major clinical observations, I think it could be life-changing in this patient population.

Operator

Jack Allen, Robert W. Baird.

Jack Allen

Thanks for taking the question and congratulations on the progress. I'm looking to zoom out a little bit and take attention to the Astellas collaboration that you have. It seems like you're really developing data quite quickly, especially with the pediatric low-dose data extract in the middle of this year and the potential initial high dose data later this year.
Can you remind us of the structure of the Astellas deal and how it relates to the RET program and what measures are in place to ensure you get a fair deal? I believe the option was fairly open-ended when that deal was struck?

Sean Nolan

Yes, I mean, essentially what Astellas has is a is a right to negotiate an option with us than exclusive rights that they have there's no predetermined terms to your to your particular point on the option period gets triggered after a number of about a handful of pediatric patients and don't have to call it, six months of data or so. So there's no time crunch at this particular point in time on, you know, we're Astellas has to come in and either request and opt in or not, that's likely a 2025 topic.
The other point that I want to I want to really stress is that Astellas certainly has line of sight to things, but it doesn't the agreement itself doesn't preclude from another party who might be interested in the program or in the company from making an unsolicited offer that that's fine.
We would just have to notify us tell us about that and they would have the ability to counter, if you will. But there's no there's no blocking right at it. Hopefully, Jack, that gives you some perspective on that, or did you have a follow-up?

Jack Allen

That's great color. Actually do have a brief follow-up around our enrollment. How are you thinking about enrollment in these studies and any interpatient staggers, I know your competitor has recently announced that they are extending a lower dose cohort and they're allowed to dose in concurrent. At what point do you think you could get to concurrent dosing? And what's the current stagger between patients or no.

Sean Nolan

The current staggers 42 days and an IDMC meeting before you can proceed to the next patient. I think that, you know, it's a bit of a of an art than a science. I think it's when you have enough data that you can make a request to remove the stagger.
I think for us, it's a good fit. As you know, we took the three patients' worth of data and said, We think based on this data, we've demonstrated safety, preliminary efficacy. And based on the preclinical data, there's a rationale to go to a higher dose and we're able to do that.
So instead of dosing three low dose of patients in the adult study, we were able to do two patients and then move to the higher dose, which we think is going to be more informative to the overall program and potentially better for patients.
And so if you apply that logic, you know, there would be a point in time where we would be comfortable potentially going to the IDMC at and talking about removing the staggered. And that's just something we'll have to do when we feel that we've got data that we feel sufficient to support that request credible manner.

Jack Allen

Got it. Very, thanks so much for the color, and congratulations again on the progress.

Sean Nolan

Thanks, Jack.

Operator

Silvan Tuerkcan, Citizens' JMP.

Silvan Tuerkcan

Yes. Thank you, and congrats on the great update and thank you for taking my questions. I just am I have a question about your dose. You're roughly going at your you can double the dose faster than you expected. Can you just talk about what that means in the terms of the efficacy results that you're hoping for, do you think that could be a greater increase? Or what is your hope for the higher dose?

Sean Nolan

Yes, I'll start and that Suku upon as well. But first of all, when you look at the preclinical data, there is a dose response. So you would expect there to be a greater response moving to the higher dose, what's driving that?
You do anticipate that by giving roughly at 75%, 80% more, dose that you'd be transducing more cells, you'd be generating more MECP2 in the cells that need more MECP2 and that overall news should have a more significant clinical effect. Then what was seen in the low-dose.

Silvan Tuerkcan

Very well, thank you. (multiple speakers)

Operator

That is all the time that you got for questions. I'd like to hand it back to management for closing remarks.

Sean Nolan

Okay. I just wanted to thank everyone for taking the time and appreciate you listening to the story and are eager to continue to progress in 2024 and generate additional data and hopefully, more value-creating milestones for the investors and care for the patient. So thank you and have a good night.

Operator

Ladies and gentlemen, this does conclude today's teleconference, and thank you for your participation. You may disconnect your lines and have a wonderful day.