Q1 2021 Taysha Gene Therapies Inc Earnings Call

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Welcome to the T shirt gene therapies first quarter 2021 on natural result on corporate update conference call. At this time all participants are in listen only mode already managements prepared remarks, we will hold a brief question answer session. As a reminder, this call is being recorded.

Operator: Welcome to Taysha Gene Therapy's first quarter 2021 Financial Results and Corporate Update conference call. At this time, all participants are in listen-only mode. Following management's prepared remarks, we'll hold a brief question-answer session. As a reminder, this call is being recorded today, May 11, 2021. I will now turn the call over to Dr. Kimberlé Lee, Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.

They may 11th 2021 on Maui.

On the Colorado to Doctor, Kimberly Lee Senior Vice President of corporate Communications and Investor Relations.

She's go ahead.

Good morning, and welcome to the patient first quarter 2021 financial results and corporate average.

Joon So Lee: Good morning, and welcome to Taysha's first quarter 2021 Financial Results and Corporate Update Conference Call. Joining me on today's call are Ari Session II, Taysha's President, CEO, and Founder, Dr. Suyash Prasad, Chief Medical Officer and Head of R&D, and Kamran Alam, Chief Financial Officer. After our formal remarks, we will conduct a question and answer session, and instructions will follow at that time. Earlier today, Taysha issued a press release announcing financial results for the first quarter ending March 31, 2021.

Great.

Joining me on today's call are all right.

I think I E on founder Patrick He asked Prasad Chief Medical Officer.

And Kamran Alam Chief Financial Officer. After our formal remarks, we will conduct a question and answer session and instructions will follow at that time.

Alerts a day Acacia issued a press release announcing financial results from the first quarter ended March 31st line one.

What a copy of this press release is available on the company's website and through our E filing.

Joon So Lee: A copy of this press release is available on the company's website and through our SEC file. Please note that on today's call, we will be making forward-looking statements, including statements relating to the safety and efficacy and the therapeutic and commercial potential of our investigational drug candidates. These statements may include the expected timing and results of clinical trials for our drug candidates and the regulatory status and market opportunities for those programs, as well as patient manufacturing plans.

Please note that on today's call, we won't be making forward looking statements, including statements relating to the safety and efficacy and the therapeutic and commercial potential.

Kennedy D C.

Statements may include the expected timing of adult clinical trials, Parque, <unk>, Kennedy and the regulatory status and market opportunity for growth program as well on patient manufacturing plant.

This call May also contain forward looking statements relating to the tissue growth and future operating results discovery and development of drug candidates strategic alliances that intellectual property. It's all matters that are not historical background information.

Joon So Lee: This call may also contain forward-looking statements relating to patients' growth and future operating results, the discovery and development of drug candidates, strategic alliances, and intellectual properties, as well as matters that are not historical facts or information. Various risks may cause patients' actual results to differ materially from those stated or implied in such forward-looking statements. These risks include difficulties related to the timing and results of clinical trials and preclinical studies of our drug candidates.

Various risks may cause actual results to differ materially from Merck weighted on such forward looking statements.

Dressed included charges related to the timing and result of clinical trials and preclinical studies of our drug candidate our dependence upon strategic alliances and other third party relationships our ability to obtain patent protections for our discoveries limitations imposed by patents owned or controlled by third party requirements of substantial funding to kantar.

Joon So Lee: 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.

Research and development activity.

But lesson description of the risks and uncertainties that we face. Please see the reports we filed with the Securities and Exchange Commission.

Joon So Lee: For a list and description of the risks and uncertainties that we face, please see the reports we filed with the Securities and Exchange Commission. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, May 11. 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 said, I'd now like to turn the call over to our President, CEO, and Founder, R.A. Sessions II.

This conference call contains time sensitive information that is accurate only as the date of this live broadcast May 11 2021.

He shot undertakes no obligations to revise or update any forward looking statements to reflect circumstances. After the date of this conference call, except as maybe required by applicable securities.

With that I'd now like to turn the call over to our president CEO and founder or a cash in the second.

Thank you chip good morning, and welcome everyone to our first quarter corporate update and financial results Conference call as always we hope you and your families continue to remain safe and healthy.

Unknown Executive: Thank you, Kim. Good morning, everyone, and welcome to our first quarter Corporate Update and Financial Results conference call. As always, we hope you and your families continue to remain safe and healthy. Taysha has made great progress in the first quarter and continues to execute on its corporate initiatives. I will elaborate on some of the key achievements made thus far this year and highlight the expected milestones for the remainder of 2021.

Asia has made great progress in the first quarter and continues to execute on its corporate initiatives I will elaborate on some of the key achievements made thus far this year.

And highlight the expected milestones for the remainder of 2021.

Following that I will turn the call over day, so, yes, and Cameron or updates on our pipeline development and financial results respectively.

Unknown Executive: Following this, I will turn the call over to Suyash and Kamran for updates on our pipeline development and financial results respectively. Taysha has transformed into a pivotal stage gene therapy company with the recent acquisition of exclusive worldwide rights to a groundbreaking clinical program, Taysha 120, and AAD9 intramuscular dose gene therapy invented by our chief scientific advisor, Dr. Stephen Gray of UT Southwest. The NIH is conducting an ongoing clinical trial of KASIA-120 for the treatment of gynexonal neuropathy, or GAN.

Acacia has transformed into a pivotal stage gene therapy company with the recent acquisition of exclusive worldwide rights to a groundbreaking clinical program Asia, <unk> and a benign interest equal each dose gene therapy invented by our chief scientific adviser Dr. Steven Great.

Ut southwestern.

NIH is conducting an ongoing clinical trial Acacia 120 for the treatment of giant Exxon on the wapiti organic.

Notably the Gan program is the first interim equally dose AAV gene therapy study in history and as such has had significant impact on the field.

Unknown Executive: Notably, the GAN program is the first AAV gene therapy study in history and, as such, has had a significant impact on the. As the program has laid the foundation for our extensive pipeline, we believe this acquisition represents a clear, strategic, and value of creative opportunity that will provide read-through across our entire portfolio and inform the development of our gene therapy product. We are thrilled to carry on the work done by Dr. Gray's lab and the NIH.

As the program has laid the foundation for our extensive pipeline. We believe this acquisition represents a clear strategic and value accretive opportunities that will provide read through across our entire portfolio and inform the development of our gene therapy product candidates.

We are thrilled to carry on the work done by Dr Gray Black and the NIH.

Chris will discuss in more detail Acacia once when he has a comprehensive preclinical and clinical package that we believe may support an expedited approval pathway.

Unknown Executive: As Suyash will discuss in more detail, KASIA 120 has a comprehensive preclinical and clinical package that we believe may support an expedited approval path. The clinical data for Taysha 120 in patients with GAN are statistically significant, clinically relevant, dose-dependent, and durable, with a clear halt in disease progression at therapeutic doses. We are very encouraged that this represents significant value as the first potentially disease-modifying treatment for an estimated 2400 patients living with GAN in the U.S. and in Europe alone. As such, we intend to engage with major regulatory agencies as soon as possible, and in parallel, we'll be accelerating the build-out of our commercial infrastructure to support patient identification, payer engagement, and product distribution.

Clinical data expectation of 120 in patients with Gan are statistically significant and clinically relevant dose dependent and durable with a clear halt in disease progression at therapeutic doses.

We are very encouraged that this represent significant value as the first potentially disease modifying treatment.

An estimated 2400 patients living with Gan in the U S and in Europe alone.

As such we intend to engage with major regulatory agencies as soon as possible and in parallel we'll be accelerating the build out of our commercial infrastructure to support patient identification payor engagement and product distribution.

We believe the T shirt 120, if approved represents a near term commercial opportunity for acacia of more than $2 billion.

Unknown Executive: We believe that Taysha 120, if approved, represents a near-term commercial opportunity for Taysha of more than $2 billion. Beyond further advancing our new clinical stage programs, we continue to achieve significant progress with our preclinical programs that we expect will provide the next wave of novel. We are extremely excited to announce the recent publication of new preclinical data for Tayshia 102 in Rett Syndrome in the highly regarded scientific journal, Brain. For the first time, we have quantitative evidence of MIRARE's ability to demonstrate genotype-dependent regulation of MeGP2 gene expression across different brain regions, in both wild-type and knockout mouse models of red.

Beyond further advancing our new clinical stage programs, we continue to achieve significant progress with our preclinical programs that we expect will provide the next wave of novel gene therapies.

We are extremely excited to announce the recent publication of new preclinical data for <unk>, one O two and ret syndrome.

In a highly regarded scientific journal right.

The first time, we have quantitative evidence M I <unk> ability to demonstrate genotype dependent regulation.

Net peak two gene expression across different brain regions in both wild type and knockout mouse models of Ret syndrome.

Various challenges such as phenotypic variability.

Unknown Executive: Various challenges, such as phenotypic variability, osaicism, and targeting a dose-sensitive gene, like MeCP2, make the development of gene therapy difficult. MiRARE offers a solution by allowing for the regulation of MeCP2 gene expression on a cell-by-cell basis without causing overexpression-related toxicity. Importantly, treatment with Tayshia 102 and four to five week old knockout mice with Rett syndrome resulted in a statistically significant survival extension by 56 percent, which is a very impressive result as these mice had meaningful accumulated disease.

Susan and targeting a dose sensitive gene like Mcafee to make development of a gene therapy difficult.

Am I rare offer the solution by allowing for the regulation of net P. Two gene expression on a cell by cell basis without causing over expression related toxicity.

Importantly treatment with Tisha, one O two and four to five week old knockout mice with Ret syndrome resulted in a statistically significant survival extension by 56%.

Which is a very impressive result, as these mice had meaningful accumulated to date.

In our view the benefits in these adolescent knockout mice should be a more translatable model of the disorder in humans.

Unknown Executive: In our view, the benefits in these adolescent knockout mice should be a more translatable model of the disorder in humans. We believe these data validate our novel approach to treating REC, help de-risk the clinical program, and support the advancement of Taysha 102 into a Phase 1 slash 2 clinical trial by the end of the year. We remain on track to file an INB or CTA in the second half of this You will hear from Suya shortly, as he will review the robust data in greater detail.

We believe these data validate our novel approach to treating rare help derisk the clinical program and support the advancement of Tisha, one O two into phase one slash two clinical trial by end of year.

We remain on track to file an IND or Cta in the second half of this year.

You will hear from Sirius shortly as he will review the robust data in greater detail.

Our chief scientific adviser Dr. Steven Great initiated his work on M I rare and queso one O two.

Unknown Executive: Our Chief Scientific Advisor, Dr. Steven Gray, initiated his work on MI RARE and Taysha 102 in 2007. We are very pleased that his team's efforts are being realized and recognized, amongst other compelling preclinical data packages. We are particularly excited about Taysha113, which has demonstrated successful AAV-mediated gene therapy resulting in reduced tau expression in mouse models of human tau optics.

2000 and stack.

We are very pleased that his team's efforts are being realized and recognize.

Amongst other compelling preclinical data packages, we are particularly excited about Asia 113, which has demonstrated successful AAV mediated gene knockdown rizza.

Resulting in reduced Tau expression in mouse models of human talent bodies.

These data may have significant implications for certain neurodegenerative disease include.

Unknown Executive: These data may have significant implications for certain neurodegenerative diseases, including all timers. We are also pleased with preclinical results for Taysha 105 and SLC13A5 deficiency that demonstrate a reduction in plasma citrate. Normalize EEG activity, and reduced the number of seizures and seizure susceptibility in SLC 13A5 knockout and SLC 681, haploinsufficiency. Taysha 103 improves nesting and EEG activity in the SLC-681 knockout mouse model and reduces spike train activity in both the SLC-681 knockout and heterozygous. In leuphora disease, Taysha 1.11 leup In APBD, KSHO112 generated a significant reduction in GYS1 protein, abnormal glycogen accumulation, and polyglucosin body formation. In the APBD knockout, and Angel Mendez.

Including all time this disease.

We're also pleased with preclinical results for tissue, one O five and S. OSB 13, eight five deficiency that demonstrate a reduction in plasma Detroit levels normalized E G activity.

And reduced number of seizures and easier susceptibility and SLC 30 day five knockout mice.

And S O C. Six day, one half low insufficiency Asia, one O three improved nasty and EEG activity in the S. L. B day, one knockout mouse model and reduce spike trading activity in both the S. L. P 60 day, one knockout and heterozygous mouse models.

We look forward to be patient 111, the foreign assets.

Asia 111, Mallet have achieved effective knocked out of G y S. One expression in insoluble glycogen and decrease labore bodies formation in the appropriate laborde disease mouse model and.

In a P. P. D. K show 112 has generated significant reduction in G y S. One protein abnormal glycogen accumulation and poly Glucosan body formation in the a P. B D knockout mouse model.

And Angelman disease, it's a one O six increased U b E. Three a expression through S. H RNA mediated knockdown of UV E. Three E. A T S. In in vitro cell lines. We believe that this promising results demonstrated by our preclinical candidates validates our scientific approach and underscore.

Unknown Executive: Taysha 106 increased UBE3A expression through shrna-mediated knockdown of UBE3A-ATF, an in vitro cell line. We believe that this promising result, demonstrated by our preclinical candidates, validates our scientific approach and underscores our ability to drive a sustainable development engine for innovative gene therapies with the potential to impact meaningful patients. We are working diligently to advance our other preclinical programs in IND slash CTA enabling studies and, to date, have already advanced six programs into IND slash CTA enabling studies with an IND or CTA plan for at least one of these programs by the end of 2021.

Our ability to drive a sustainable development engine for innovative gene therapies with the potential to impact meaningful patient population.

We are working diligently to advance our other preclinical programs and I M. D Flash D. T E, enabling study and to date have already at bear fixed programs into I N D. Slash D. T E, enabling studies with an IND or Cta plan or at least one of these programs by the end of 2021.

We look forward to providing further updates on our key programs at our R&D, which.

Unknown Executive: We look forward to providing further updates on our key programs at our R&D event, which will take place over two days on June 28th and 29th. To support our programs, we have developed several key partners. Notably, we have established collaborations with Yale University, Cleveland Clinic, and the UT Southwestern Gene Therapy Program to support the creation of a novel next-generation mini gene platform that is designed to overcome key challenges in gene theory. These mini-gene payloads for AAV gene therapy will be targeted for the treatment of genetic epilepsy, neurodevelopmental disorders, and other CNS diseases.

Which will take place over two days on June 28, and 29.

To support our programs we have developed several key partnerships, notably we have established collaborations with Yale University, Cleveland clinic, and the UT southwestern gene therapy program to support the creation of a novel next generation. Many gene platform that is designed to overcome key challenges in gene therapy.

These many gene payloads for AAV gene therapies will be targeted for the treatment of genetic epilepsy, neurodevelopmental disorders, and other CNS diseases.

We are excited to leverage each partners unique capabilities to expand the boundaries of AAV vector engineering and potentially open the door to treating genetic CNS disease that had been traditionally precluded from treatment with gene therapies.

Unknown Executive: We are excited to leverage each partner's unique capabilities to expand the boundaries of AAV vector engineering and potentially open the door to treating genetic CNS diseases that have been traditionally precluded from treatment with gene therapy. Foundational to our success is our research and development team, which remains focused on advancing the development of our portfolio of innovative gene therapy. We intend to continue this momentum by further growing our experience. Since becoming a public company, we have expanded our team more than 10 times and have now surpassed 120 employees.

Foundational to our success is our team which remains focused on advancing the development of our portfolio of innovative gene therapy candidates.

We intend to continue this momentum by further growing our experienced team.

Becoming a public company, we have expanded our team more than tenfold and have now surpassed the 120 employees.

We expect to grow the team to approximately 150 employees by year end.

Unknown Executive: We expect to grow the team to approximately 150 employees by year. As noted, we are complementing the efforts of our internal team with our collaborators at UT Southwestern. With the collective expertise and dedication of these teams, our seasoned Board of Directors and independent, internationally renowned scientific advisory, we believe we are uniquely positioned to expedite the development of our gene therapy candidates and our technology. I will now turn the call over to Suyash to provide a more detailed update on our R&D initiatives. Suyash, please go ahead. Thanks, R.A.

As noted we are complementing the efforts of our internal team with our collaborators at Ut southwestern with.

With the collective expertise and dedication of the teams are seasoned board of directors and independent internationally. We're now scientific Advisory Board. We believe we are uniquely positioned to expedite the development of our gene therapy candidate and our technology platforms.

I will now turn the call over to <unk> to provide a more detailed update on our R&D initiatives. So yes. Please go ahead.

Alright, I've already mentioned <unk> has a robust portfolio of 26 gene therapy product counted this from monogenic diseases of the CNS.

Mahdi Goudarzi: Thanks R.A. As R.A. mentioned, Taysha has a robust portfolio of 26 gene therapy product candidates for monogenic diseases of the CNA. Our candidates target broad therapeutic categories of immense unmet medical need, including neurodegenerative diseases, neurodevelopmental disorders, and genetic ethics.

Candidates target growth therapeutic categories with immense unmet medical needs, including neuro degenerative diseases, neurodevelopmental disorders and genetic epilepsies.

We have recently added tissue on 'twenty for the treatments of Jive that sell on neuropathy or GAAP to our pipeline, making it our most advanced program. We believe the preclinical and clinical data generated to date holds significant promise again patients.

Mahdi Goudarzi: We have recently added Taysha 120 for the treatment of giant epithelial neuropathy, or GAN, to our pipeline, making it our most advanced program. We believe the preclinical and clinical data generated to date holds significant promise for GAN patients. Preclinical studies have demonstrated strong proof-of-concept data for both the construct and the delivery modality.

Preclinical studies have demonstrated a strong proof of concept data from both the construct on the delivery modality.

Peso on 'twenty performed well in preclinical studies, demonstrating improved motor function on the apology on.

Mahdi Goudarzi: Taysha 120 performed well in well-agreed clinical studies demonstrating improved motor function and nerve pathology and long-term safety across several animal models. Preclinical data also demonstrated that Taysha 120 showed a significant improvement in the pathological appearance of the dorsal root ganglia, a key component of disease progression. GRT information is a topic that has been the focus of much discussion within gene therapy circles in recent years. This is because it has been observed as a histopathological finding in some non-human primate gene therapy studies, although the NHPs exhibited no functional comparison. Interestingly, in GAM and in the majority of diseases in our neurodegenerative franchise, the DRG has a significantly abnormal histological appearance and function as a consequence of the underlying disease pathophysiology.

Long term safety across several animal models.

Preclinical data also demonstrated the tissue on 'twenty showed a significant improvement net ecological appearance of the dorsal root ganglia, a key component of disease progression.

Dr. Chi inflammation is a topic that has been the focus of much discussion within gene therapy circles in recent months.

This is because it has been observed as a histopathology findings and some non human primates gene therapy studies, although the anti itch creams exhibited nice functional compromise.

Interestingly in Gan and then the majority of diseases and on neuro degenerative franchise. The DLT has significantly abnormal histological appearance on function as a consequence of underlying disease pathophysiology.

Thus it was not surprised on the one treats with tissue on 'twenty, we saw considerable improvements in the pathological appears from the D. L G and the gallons knockout mice.

Mahdi Goudarzi: Thus, it was not surprising that when treated with Taysha 120, we saw considerable improvements in the pathological appearance of the DRG in the GAM knockout. We are fortunate that, in addition to robust preclinical results, there is considerable natural history that provides us with patient data to identify optimal markers and endpoints for a clinical trial. To date, there are data in 45 GAM patients that demonstrate an average 8-point decline per year in the MFM32 scores that is consistent across patients of all ages.

We are fortunate that in addition to robust preclinical results. There was considerable natural history that provides us with patient data to identify up from Marcus on endpoints for a clinical trial.

To date, though on data and 45 patients to demonstrate on average eight point decline per year and the NFL.

On the 32 schools, that's all consistent across patients of all ages recorded a four point decline until you have 32 is considered clinically meaningful.

Mahdi Goudarzi: Recall that the 4-point decline per year in the MFM32 is considered clinically meaningful, notably and in line with recently published FDA guidance. Regulatory agencies appreciate the availability of a well-controlled and high-quality prospective natural history study as a comparator in clinical trials for rare diseases. In addition, we believe this natural history study provides us with a head start in identifying patients. Based on the positive preclinical results, an ID was opened, and Taysha 120 is being further evaluated in an ongoing clinical trial. The primary endpoint is to assess safety.

Notably and in line with recently published FDA guidance regulatory agencies appreciate the availability of a well controlled on high quality prospective natural history study.

Comparison in clinical trials for rare diseases.

Addition, we believe this natural history study provides us with a head start and identifying patients.

Based on the positive preclinical results on 19 was opened on tissue on 'twenty is being further evaluated and on ongoing clinical trial.

The primary endpoint is to assess safety with secondary endpoints measuring efficacy using Apple watch it, especially on logic functional on clinical markers.

Mahdi Goudarzi: The secondary endpoints measure efficacy using pathologic, physiologic, functional, and clinical marks. To date, 14 patients have been administered intrathecal Taysha 120, and six patients have at least three years' worth of long-term follow-up data. [inaudible] These results are very promising as a four-point change in the MFM32 score is considered clinically meaningful. Six of these patients treated at therapeutic dose levels have shown sustained dose-dependent improvements in MFM32 scores for more than three years.

So I think it's 14 patients have been administered interest equal tissue on 26 patients have at least three years' worth of long term follow up data.

Disease progression on the second highest dose level, one play type time sensitive 14 total specie, that's one year post treatment affecting a statistically significant eight point improvement on the MSM 32 school in comparison to the predicted natural history trajectory.

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These results are very promising as a full point changing them have 32 scores considered clinically meaningful.

So these patients treated at therapeutic dose levels have shown sustained and improvements and I'm not having 32 schools for more than three years.

Long term results demonstrated that treatment with peso on 'twenty at multiple dose levels was well tolerated with no severe drug related adverse events.

Mahdi Goudarzi: Long-term results demonstrated that treatment with Taysha 1 and 20 at multiple dose levels was well tolerated with no severe drug-related adverse events. We look forward to reporting additional data later this year, including results from the highest dose cohort, 3.5 times 10 to the 14 total VG.

We look forward to reporting additional data later this year, including results from the highest dose cohort 3.57 tenths on the 14th total D G.

The FDA has already granted tissue on 'twenty orphan drug and rare pediatric disease designations, we will continue to work closely with the regulator on coaches in the U S.

Mahdi Goudarzi: The FDA has already granted Taysha 120 orphan drug and rare pediatric disease designations, and we will continue to work closely with the regulatory authorities in the U.S. In the near term, we expect to have discussions with the FDA and engage with other major regulatory agencies by year-end to discuss the pathway to approval for Taysha 120. I would also like to highlight some of the promising preclinical data coming from our earliest phase candidates that demonstrate the incredible breadth, depth, and velocity of our development engine. However, it is important to note that there are no approved disease-modifying therapies for any of the programs in our portfolio.

And then that said, we expect to have discussions with the FDA and engaged with other major regulatory agencies by year end to discuss the pathway to approval potential in 'twenty.

I would also like to highlight some of the promising preclinical data coming from our earliest stage count it does demonstrate the incredible breadth depth and velocity of our development engine.

It is important to note that there are no approved disease modifying therapies or any of the programs in our portfolio.

With such compelling data to date from pipeline. We are very encouraged that's on gene therapy candidates could offer significant value to meaningful patient populations.

Mahdi Goudarzi: With such compelling data to date for our pipeline, we are very encouraged that our gene therapy candidates could offer significant value to meaningful patient populations. We are very excited to share new preclinical data for Tayshia 102 in Rett syndrome that was recently published in Brain. As discussed earlier, historically, it has been a challenge to find the right approach to safely regulate MeCP2 expression in this disease. The complexities are highlighted by phenotyping variability, mosaicism, and the need to regulate MeCP2 such that it does not cause overexpression-related toxicity.

We are very excited to show new preclinical data that takes you want us to invest and drive that was recently published in brain. That's alright discussed earlier historically it has been a challenge to find the right approach to safety regulators might be two expression on this disease. The complexities are highlighted by phenotypic variability mosaicism on that.

Need to regulate met pizza such that it does not cause overexpression related toxicity.

Today's day to give us confidence that we can achieve appropriate make me two expression no sales in a genotype dependent manner with no signs of toxicity.

Mahdi Goudarzi: Today's data give us confidence that we can achieve appropriate MeCP2 expression in all cells in a genotype-dependent manner with no signs of toxicity. For example, with the built-in regulatory element, MI-RARE, Taysha-102 provided a statistically significant survival extension in knockout RET mice by 56%, while the unregulated Mini-MECP2 gene transfer failed to significantly extend knockout survival in either of those tests. Additionally, the unregulated full-length MeCP2 construct did not demonstrate a significant extension in survival and was associated with an unacceptable toxicity profile in wild-type mice.

With the built in your regulatory elements MRI patient why don't you provided a statistically significant survival extension and low cats rats mice by 56%, while the unregulated Mini-vac P to gene transfer.

L to significantly extend knockout survival I thought the dose tested.

Additionally, the unregulated full length messy to construct did not demonstrate a significant extension of survival and was associated with unacceptable toxicity profile with wild type mice.

We believe that the 56 from improvement in survival mutation on one or two treated knockout mice is extremely impressive I say adolescent must have accumulated significant disease oftentimes sits right patients did not demonstrate symptoms until about one year of age and therefore will not be treated until after this point. We believe these data are likely to be highly translatable.

Mahdi Goudarzi: We believe that the 56% improvement in survival in Taysha 102-treated knockout mice is extremely impressive as these adolescent mice have accumulated significant disease. Of note, since RET patients do not demonstrate symptoms until about one year of age and therefore will not be treated until after this point, we believe these data are likely to be highly translatable for the clinical setting. In addition to survival, behavioral side effects were explored.

So the clinical sites it.

In addition to survival behavioral side effects were explored.

One or two treated wild type mice had a significantly lower meaning better main aggregate behavioral school than those treated with other regulated full length back pizza.

Mahdi Goudarzi: Taysha 102-treated wild-type mice had a significantly lower, meaning better, mean aggregate behavioral score than those treated with unregulated full-length MeCP2 and unregulated mini MeCP2. Importantly, miRARE-mediated genotype-dependent gene regulation was shown by analyzing tissue sections from wild-type and knockout mice treated with AAV9 vectors given interest economies. Taysha102 demonstrated reduced levels of MeCP2 in different regions of the brain, suggesting that miRARE inhibited mean expression in the genotype-dependent mouse. This demonstrates that Taysha 102 achieved MEC-P2 expression levels within normal physiological parameters. In summary, these quantitative data demonstrated MIRAS' ability to exhibit genotype-dependent regulation of MeCP2 gene expression across different brain regions in both wild-type and knockout mouse models of Rett syndrome without overexpression of toxin.

On the unregulated many make pizza.

Importantly M. I ran mediated gene has tightened dependent gene regulation well shown by analyzing tissue section is from wildfire.

And I was treated with AAV non Texas given interest equally.

Thank you on the two demonstrated reduced levels of might be two different regions of the brain suggestion that M. Iraq inhibited mean expression in the gene that's not dependent on my left this.

This demonstrates that patients went on to achieve <unk> two expression levels within normal physiological parameters.

In summary, these positive data demonstrated <unk> ability to exhibit genotype dependent regulation automatically to gene expression across different brain regions about walled hot knockout mouse models of rush syndrome without overexpression toxicities.

We are very encouraged by these results and look forward to filing an IV or Cta in the second half of this year follow up on initiation of phase one two trial by year end.

Mahdi Goudarzi: We are very encouraged by these results and look forward to filing an INV or CTA in the second half of this year, followed by initiation of a Phase 1-2 trial by year end. Taysha 102 has the potential to address a significant unmet need for an estimated 25,000 patients with Rett syndrome across the United States and in Europe. Now, I'd like to highlight some of our other preclinical programs that we've recently released.

It takes you one or two has the potential to address a significant unmet need for an estimated 25000 patients with ret syndrome across the United States and in Europe.

Now I'd like to highlight some of our other preclinical programs that were recently released tightrope.

Price, you're one like pool, which is currently in I N D. C. C line Amazing studies for the treatment of surf one associated lease syndrome has demonstrated the increased Cox one activity in brain and muscle on restored elevation of blood lactate on the go.

Mahdi Goudarzi: Taysha104, which is currently in IND's GCNA enabling studies for the treatment of SIRF1-associated Lee syndrome, has demonstrated increased COX-1 activity in brain and muscle and restored elevation of blood lactate on exhaustive exercise in a dose-dependent manner in SIRF1 knockout mice. Dr. Ching-Lan Ling of UT Southwestern will be presenting these compelling data this Thursday at ASGCT, and will remain on track to file 90 or CTA in the second half of this year.

Cost of exercise in a dose dependent manner and surf one knockout mice.

Dr. Cheng long leg of UC southwest they will be presenting these compelling data. This Thursday I S. T. C. T. We remain on track to file a nine day, you'll CCA in the second half of this year.

Thanks, you would've had five on gene therapy candidate, which is currently the O N D. C. T. I know there's been studies for the treatment of SLC Thursday may five deficiency caused a significant sustained decrease of plasma citrate levels up to three months post injection compared to age matched whilst tight controls.

Mahdi Goudarzi: Taysha 105, our gene therapy candidate that is currently in IND CTA and ASN studies for the treatment of SLC 1385 deficiency, causes a significant sustained decrease of plasma citrate levels up to three months post-injection compared to age-matched wild-type control. Taysha 105 also normalized EEG brain activity, reduced the number of seizures, and reduced seizure susceptibility compared to vehicle-treated Dr. Rachel Bailey will be presenting these positive data this Thursday at ASGCT.

When I finally normalized E G brain activity reduced the number of seizures from reduced seizure susceptibility compared to vehicle treated controls.

So it's a ratio Bailey, who will be presenting these positive data this thursday.

S G C T.

Takes you want a series on gene therapy candidate Int CCA, enabling studies for the treatment of SLC since day one.

Mahdi Goudarzi: Taysha103 is our gene therapy candidate that is in IND-CPA enabling studies for the treatment of SLC6A1 haploinsufficient. In the FLC 6A1 knockout mouse model, Taysha103 improved nesting and EEG activity. In addition, an SLC6A1 knockout of heterozygous mouse models takes your 103 reduced spike train activity, which is a recording of abnormal neuronal activity associated with seizures. We believe the estimated prevalence is 17,000 patients in the US and in the EU. Taysha-111-Liforin and Taysha-111-Malin are gene therapy candidates in IMD-CTA-enabling studies for the treatment of both subtypes of Lifora disease achieved effective knockdown of GYS1 expression in the Lifora disease Liforin and Malin mouse models respectively. Both product candidates decreased leuphora body formation within the brain and their respective mouse models.

Flow and sufficiency in.

And the SLC six day, well knockout mouse model. So you should want us to really improve next day on EEG activity.

In addition, and that's I'll say, you shouldn't say well knockouts on heterozygous mass models types, you wanted through reduced spot trading activity, which is a recording of abnormal from your own longevity associated with seizures.

We believe the estimated prevalence is 17000 patients in the U S and EU.

Thanks, you won 11 foreign tissue on 11 Mellon on gene therapy candidates in on the Cta, enabling studies for the treatment of both subtypes of lung disease achieved effective knockdown of G Y S. One expression and look for disease, the foreign on Mellon mouse models, respectively.

Both product candidates decreased look for body formation within the brain and their respected mouse models.

It takes it wouldn't want too is being tested 90, Cta, enabling studies for the treatment of adults publicly because on body disease or a P. P. D. In preclinical studies <unk> RNA knockdown of G Y S wasn't induced significant reductions in G. I S. One mrna G wise from protein abnormal glycogen accumulation.

Mahdi Goudarzi: Taysha112 has been tested in IND and CTA-enabling studies for the treatment of adult polyglutazone body disease, or APBD. In preclinical studies, miRNA knockdown of GYS1 induced significant reductions in GYS1 mRNA, GYS1 protein, abnormal glycogen accumulation, and polyglutazone bodies throughout the brain in an APBD knockout mouse model. For GM2AB variants in preclinical studies, Tessia 119 caused a significant dose-dependent reduction of GM2 accumulation at 20 weeks in mice that were dosed intrathecally at postnatal day one or at six weeks of age. Long-term follow-up studies, including bioanalytic behavioral, as well as biochemical and histological analyses, are currently ongoing.

On police loses on bodies throughout the bright and on a P. P D knockout mouse model.

For Jim to I'd be variance in preclinical studies tells you 119 cause a significant dose dependent reduction of GM true accumulation at 20 weeks in mice. So does interest equally Oh Staples day, one or six weeks of age.

Long term follow ups from new which include bi monthly behavioral as well as biochemical histological analyses are currently ongoing.

Thanks, you when they're six is being developed for the treatment of Angelman syndrome.

Mahdi Goudarzi: Taysha-106 is being developed for the treatment of Asian Lung Syndrome. In vitro testing and a neuroblast cell line demonstrated consistent knockdown of UBE3A-ATS and a subsequent increase in UBE3A expression across 26 distinct shRNA candidates. Selection of a development candidate is expected by mid-year, followed by interim expression and safety data from confirmatory non-human primate studies by year end. Taysha 113, an AAV mediated gene lockdown construct, has shown particular promise. Taysha 113's AZ-9 capsid package's microRNA shuttles are designed to target tau mRNA for all six isoforms found in the human and or mouse brain.

True testing in Europe on seller demonstrated consistent knockdown of you'd be three I E. T. S. On the subsequent increase in U B E. Three I expression across 26 States I'd say charter and they come to this.

Selection of a development candidate is expected by mid year, followed by interim expression on safety data from come from Atria non human Primate studies by the year end.

Patient 113, an AAV mediated gene construct shown particular promise.

Thanks, you want on trees, AAV non captive packages micro RNA shuffles Dizzy.

Designed to target Tau mrna Porosis ice forms filed with the human and the mouse brain treatment with takes you want on three has shown a significant reduction in tau mrna and protein levels, while demonstrating widespread expression in neurons on glia. This is potentially significant implications for patients with near.

Mahdi Goudarzi: Treatment with Taysha 113 has shown a significant reduction in tau mRNA and protein levels while demonstrating widespread expression in neurons and glia. This has potentially significant implications for patients with neurodegenerative disorders characterized by deposition of abnormal tau protein in the brain, including Alzheimer's disease, MACD-associated frontotemporal dementia, and progressive supranuclear pulse.

Right, Jonathan So there's characterized by deposition of abnormal tau protein from the brain, including Alzheimer's disease might see associates, the frontal temporal dementia and progressive Supranuclear palsy.

As you can see collectively these preclinical data highlights on the next wave of novel Gene therapies, that's on the potential to impact patient populations affected by significant diseases in a meaningful way.

Mahdi Goudarzi: As you can see, collectively, these preclinical data highlight our next wave of novel gene therapies that have the potential to impact patient populations affected by significant diseases in a meaningful way. With that, we intend to file a 9D CTA for one of the following programs by the end of 2021: SLC13A5 Deficiency, Lepora Disease, APBD, or GM2A-BVAC.

With that we intend to file 90, CPA, but one of the following programs by the end of 2021.

I'll see Thursday night, five deficiency look forward disease, a P. P. D O G M. Two I'd be barriers. We also remain on track to fall line D. C tape. It takes you're willing to invest on drug and tissue on that for and surf one associates at least syndrome. The 90, if it takes you one on one and GM to getting this two doses in the U S. During the second half of this year.

Mahdi Goudarzi: We also remain on track to file 9D-CTA for Tayshia 102 in Rett syndrome and Tayshia 104 in SIRF1-associated Lee syndrome and a 9D for Tayshia 101 in GM2 ganglia pseudosis in the U.S. during the second half of this year. Additionally, we expect to initiate a Phase 1-2 trial for Tayshia 1-1-8, which is under an We are excited to have six near-term Phase 1-2 trial initiations planned throughout our portfolio. We are making incredible progress advancing our product candidates into clinical development, and we look forward to providing additional updates at our R&D day that will span two days in June.

We expect to initiate the phase two trial for tissue on one night when she's on the on the already opened on M D.

We're excited to have six near term phase one two trial initiations planned throughout our portfolio.

We are making incredible progress advancing our product candidates into clinical development and we look forward to providing additional updates at the R&D day that will span two days in June.

We will continue to advance our pipeline by leveraging on next generation platform technologies.

Mahdi Goudarzi: We will continue to advance our pipeline by leveraging our next-generation platform technology. As part of this initiative, we have recently established collaborations with Dr. Dennis Lal at the Genomics Institute, Cleveland Clinic, and Dr. Yong Hui Jiang at Yale University to further push the boundaries of AAV vector engineering by developing next-generation mini gene payloads that have the potential to overcome current limitations of packaging capacity, which is a critical barrier to treating genetic diseases not addressable by conventional AAV gene therapy techniques.

Part of this initiative, we have recently established collaborations with also Dennis law on the Genomics Institute, Cleveland Clinic, and thus a young Queen Qiang Yale University.

Further push the boundaries of AAV vector engineering, but developing next generation. Many gene payloads. This has the potential to overcome current limitations of packing capacity, which is a critical pirates treating genetic diseases not addressable by <unk>.

Angel AAV gene therapy technologies this free.

That enable us to effectively treat a wider range of devastating CNS diseases.

Mahdi Goudarzi: This may enable us to effectively treat a wider range of devastating CNS diseases. UT Southwestern will produce viral vector constructs that incorporate the mini gene payloads and evaluate the constructs in both in vitro and in vivo studies. Through the collective efforts of Taysha and our partners, we will continue to strive for innovations in our platform technologies that will enable us to treat a broad range of CNS diseases with novel gene therapy. With that, I'll turn the call over to Kamran to review our financial results.

Do you see southwestern what could evolve it to concho since incorporate diminishing pay letters on Italian.

Construction, both in vitro and in vivo studies through the collective assets of patients. All partners. We will continue to strive for innovations and our platform technologies that will enable us to treat a broad range of CNS diseases with novel gene therapies.

With that I'll turn the call over to Cameron to review our financial results. Thank.

Thank you Sue.

This morning, I will discuss key aspects of our first quarter 2020 one financial results more details can be found in our form 10-Q, which will be filed with that shortly.

Kamran Alam: Thank you, Suryash. This morning, I will discuss key aspects of our first quarter 2021 financial results. More details can be found in our Form 10-Q, which will be filed with the SEC shortly. As indicated in our press release today, R&D expenses were $23.9 million for the first quarter ended March 31, 2021, compared to $5.5 million for the first quarter ended March 31, 2020. The increase was primarily related to the company's development programs as a result of increased manufacturing-related spend, clinical and preclinical activities, and headcount.

As indicated in our press release today R&D expenses were $23 $9 million for the first quarter ended March 31, 2021, compared to $5 $5 million for the first quarter ended March 31 2020.

The increase was primarily related to the company's development program as a result of increased manufacturing related spend clinical and preclinical activity and head count.

G&A expenses were $8 $2 million for the first quarter ended March 31, 2021, compared to a 0.0 to $7 million for the first quarter ended March 31 2020.

The increase was primarily due to an increase in personnel costs, resulting from increased headcount professional services fees and other corporate related expenses.

Net loss for the first quarter ended March 31, 2021 was $32 million or <unk> 87 per share as compared to a net loss of $5 $4 million or <unk> 50 per share for the first quarter ended March 31 2020.

Kamran Alam: G&A expenses were $8.2 million for the first quarter ended March 31, 2021, compared to $0.07 million for the first quarter ended March 31, 2020. The increase was primarily due to an increase in personnel costs resulting from increased headcount, professional services fees, and other corporate-related expenses.

As of March 31, 2021 pace, you had $228 $7 million from cash and cash equivalents.

We continue to expect that our working capital will be sufficient to fund our operations into 2023 inclusive of the development regulatory and operational milestones are a until you actually have outlined today.

Kamran Alam: The net loss for the first quarter ended March 31, 2021 was $32 million, or $0.87 per share, as compared to a net loss of $5.4 million, or $0.50 per share, for the first quarter ended March 31, 2021. As of March 31, 2021, Taysha had $228.7 million in cash and cash equivalents. We continue to expect that our working capital will be sufficient to fund our operations into 2023, inclusive of the development, regulatory, and operational milestones RA and Suyash have outlined today. And with that, I will hand the call back to RA. Thanks, Kamran.

And with that I will hand, the call back to Ari.

Thanks, Tamra, we're pleased to have shared with you our success over the first quarter. Looking ahead, we will continue to focus on rapidly advancing our pipeline with many key milestones anticipated over the next 18 months, we have made a significant transition into a pivotal stage gene therapy company with our acquisition of <unk>.

120, and we expect to provide both clinical and regulatory updates by year end.

Further we remain on track to report first in human clinical data for <unk> 101, and G. M. Two gangliosidosis as well as initiate a phase one slash two trial.

Our tastes on 118 and seal in one day that currently has an open R&D.

As you've heard today.

We have an extensive pipeline of preclinical programs that are advancing quickly.

Unknown Executive: We are pleased to have shared with you our success in the first quarter. Looking ahead, we will continue to focus on rapidly advancing our pipeline, with many key milestones anticipated over the next 18 months. We have made a significant transition into a pivotal stage gene therapy company with our acquisition of Apatia 120, and we expect to provide both clinical and regulatory updates by year end. Further, we remain on track to report first-in-human clinical data for Keisha-101 and GM-2 ganglioside doses, as well as initiate a phase one flash two trial for Taysha 118 and CLN1 disease, which currently has an open eye.

We expect to open or I N E. R. C T A's and have a total of five programs in clinical development, including for Ret syndrome, and surf one associated lease syndrome by year end and have an additional six programs currently in IND or Cta, enabling studies.

In parallel we will continue to support our R&D initiatives by expanding our team to approximately 150 employees by year end.

Leading the build out of our Dallas corporate headquarters by mid year as.

As well as continued with the construction on our internal GMP manufacturing facility in Durham, North Carolina with.

With numerous potentially value, creating near term milestones. We expect this year to continue to be a transformational period and we look forward to providing further updates on our progress at our upcoming R&D day event next month.

Unknown Executive: As you've heard today, we have an extensive pipeline of free clinical programs that are advancing quickly. We expect to open four INDs, four CTAs, and have a total of five programs in clinical development, including for Rett syndrome and SIRF1-associated Lee syndrome, by year-end, and have an additional six programs currently in IND or CTA-enabling studies. In parallel, we will continue to support our R&D initiative by expanding our team to approximately 150 employees by year end, completing the build out of our Dallas corporate headquarters by mid year, as well as continuing the construction of our internal GMP manufacturing facility in Durham, North Carolina, with numerous potentially value-creating near-term milestones.

Lastly, I would like to give special thanks to the continued support and dedication of our case employee.

Board of directors.

Terrific Advisory board collaborators and the patients and advocates who remain our motivation every day.

Can you on our mission to develop curative gene therapy to eradicate devastating monogenic CNS disease.

I'll now ask the operator to begin our Q&A session operator.

We will now begin the question and answer session.

So during the question queue you May Press Star then one on your telephone keypad.

Total acknowledging your request.

[laughter] Speakerphone, please pick up your handset before pressing any gene.

So as Cory Your question. Please press Star then two.

Unknown Executive: We expect this year to continue to be a transformational period, and we look forward to providing further updates on our progress at our upcoming R&D Day event next. Lastly, I would like to give special thanks to the continued support and dedication of our Taysha employees, Board of Directors, Scientific Advisory Board, collaborators, and the patients and advocates who remain our motivation every day to continue on our mission to develop curative gene therapies to eradicate devastating monogenic CNS. I will now ask the operator to begin our Q&A. Operator.

We will pause for a moment lets call is going to queue.

The first question comes from Celgene Richter from Goldman Sachs. Please go ahead.

Good morning, Thanks for taking my questions. So one quick one in here about good morning, one question here about capital and resource allocation as your you know.

Running multiple trials building out of a GMP facility and hiring employees. So how should we think about that over time and secondly on with regard to the Ret program, maybe if you could touch on the registration path here and what you'd like to see from that first clinical data set to inform the pivotal program.

No I appreciate the question on solving and good morning, So I'll take the first one and so yes. If you could if you could address the question on rats as far as capital allocation goes we reaffirmed our guidance. This morning that we still have the capital resources to take us into.

Operator: We will now begin the question and answer session. To join the question queue, you may press star then 1 on your telephone keypad. You are here totally acknowledging your request. If you're using a speakerphone, please pick up your handset before pressing any key. To withdraw your question, please press star, then two. We will pause for a moment as other callers join the queue. The first question comes from Salveen Richter from Goldman Sachs. Please go ahead.

'twenty 'twenty three I you know is.

As it pertains to gene therapy drug development, it's it's much different than kind of classic drug development from a time and cost of tests, because you're not doing kind of high throughput screening you know I'm trying to identify a target you already know the targets and so it's actually much more capital efficient to go after gene therapy versus versus other forms or other modalities.

Salveen Jaswal Richter: Good morning. Thanks for taking my questions. So one question here about, good morning.

Salveen Jaswal Richter: One question here about capital and resource allocation as you're, you know, running multiple trials, building out a GMP facility, and hiring employees. So how should we think about that over time? And secondly, with regard to the RET program, maybe you could touch on the registration path here and what you'd like to see from that first clinical data set to inform, you know, the pivotal program.

And so the way that we're thinking about this is again.

Because our portfolio is appropriately stage, we have some programs that are moving into the clinic. Some programs that have Jessica animal proof of concept on some early discovery programs most of our translational and discovery work is being done by our collaborators at Ut southwestern and having that academic partner isn't really capital efficient way to do kind of your early.

Unknown Executive: No, I appreciate the question, Salveen. Good morning. So I'll take the first one.

Mahdi Goudarzi: And so, yes, if you could, if you could address the question on RET. As far as capital allocation goes, we reaffirmed our guidance this morning that we still have the capital resources to take us into 2023. You know, as it pertains to gene therapy, drug development, it's much different than kind of classic drug development from a time and cost perspective because you're not doing kind of high throughput screening, you know, trying to identify a target; you already know the target.

Translational discovery work is it.

Pertains to the clinical development again, this is a pretty capital efficient modality, because the number of patients you need to actually get a signal and to achieve human proof of concept is quite small compared to some other modalities. So again, you know I think we.

And we feel very strongly about this moving five programs into clinical development. This year already having a few programs in the clinic, we still feel strongly that our capital takes us into 2023.

Mahdi Goudarzi: And so it's actually much more capital efficient to go after gene therapy versus other forms or other modalities. And so the way that we're thinking about this is, again, because our portfolio is appropriately staged, we have some programs that are moving into the clinic, some programs that have just hit animal proof of concept, and some early discovery programs. Most of our translational and discovery work is being done by our collaborators at UT Southwestern, and having that academic partner is a really capital efficient way to do kind of your early translational discovery work.

I'll stop there and see yes, do you want to address the question around Red syndrome, and kind of what our thoughts are on the path in the clinic and a path to.

To approval.

Yes, absolutely.

Alright, Thanks for the question solvent, Yes, I said for Ret syndrome.

You know I think we've been spending a lot of time thinking about the clinical development program on the pathway to approval.

Mahdi Goudarzi: As it pertains to clinical development, again, this is a pretty capital efficient modality because the number of patients you need to actually get a signal and achieve human proof of concept is quite small compared to some other modalities. So again, you know, I think, and we feel very strongly about this, moving five programs into clinical development this year, already having a few programs in the clinic, we still feel strongly that our capital takes us into 2023. I'll stop there. And C.S., do you want to address the question around Rett syndrome and kind of what our thoughts are on the path in the clinic and our path to improve? Absolutely not. Thanks to all.

What does it take a slightly more cautious approach so for some of our other conditions such as Jim to sit on one gan, whether diseases or a little less Coleman and Wow there is a.

Ongoing relatively high risk of mortality quite early on.

So that's the way we're thinking about Iraq is the first study of a group with two will be more of a phase one two.

Primarily safety study with some exploration on preliminary efficacy following on from that fuel line.

Perform a phase two three study which focuses it takes learnings from initial phase one two study tastes of learnings from that from the plaza into way more expensive.

Phase two three pivotal.

Efficacy study now.

Now with regard to the first study the phase one two study likely will between hitting on older patients as you know yesterday tends to push you away from children towards analyst first and in this particular situation with right. We actually tend to agree with that approach you know they're all these risks.

Mahdi Goudarzi: Absolutely. Thanks for the questions, Salveen. Yes, so for Rett Syndrome... You know, I think we've been spending a lot of time thinking about the clinical development program and the pathway to approval, and we're going to take a slightly more cautious approach than for some of our other conditions, such as GM2, CLN1, GAN, where the diseases are a little less common and where there is an ongoing relatively high risk of mortality quite early on.

Toxicity with overexpression of might be too. So we'll just have to be quite mindful because on this initial study. So the first study will be phase one two.

Mahdi Goudarzi: So the way we think about RET is that the first study of the group of two will be more of a phase one, two, primarily safety study with some exploration of preliminary efficacy. Following on from that, we will then perform a phase two, three study, which focuses on taking the learnings from the initial phase one, two study, takes the learnings from that, and applies them to a more extensive phase two, three pivotal efficacy study.

Proof of concept safety and preliminary efficacy in the Arab population in terms of endpoints will be looked on the safety aspects of.

Safety initially and then we'll be looking at efficacy really in three different buckets, the efficacy will be looked at.

Firstly with a number of the different ret specific clinical clinically rated scales. For example to the rest of the time much behavior assessment the restaurant behaviour questionnaire, so the ret scales well.

Mahdi Goudarzi: Now, with regard to the first study, the Phase 1-2 study, likely, we'll be doing it in older patients. As you know, the FDA tends to push you away from children towards adults first. And in this particular situation with Rett, we actually tend to agree with that approach.

Seizures in some detail because children with Tourette syndrome have significant seizure activity. So open line.

How frequently you saw how plenty of medications to Charles on what triggers the seizures, how durable the seizures all on another time high school belt to see a reduction in seizure activity on bring them on medications and Youll see an improvement in the E. G. And then the third bucket on the clinical assessments will incur.

Mahdi Goudarzi: You know, there are these risks of toxicity with overexpression of MeCP2, so we just have to be quite mindful when we design this initial study. So the first study will be Phase 1-2, clinical proof of concept, safety, and preliminary efficacy in the adult population. In terms of endpoints, we'll be looking at the safety aspects of safety initially, and then we'll be looking at efficacy really in three different buckets. Efficacy will be looked at firstly with a number of different Rett-specific clinically rated scales, for example, the Rett Syndrome Motor Behavior Assessment and the Rett Syndrome Behavior Questionnaire. So they're called the Rett scales.

<unk> Ah.

A general multi systemic multi organ type aspects of ret syndrome disease characteristics such as the.

Respiratory assessments, which as you know you have a special rhythm abnormalities in ret syndrome sleep apnea issues cardiac issues such as Qt prolongation.

Mahdi Goudarzi: We'll also be looking at seizures in some detail because children with Rett Syndrome have significant seizure activity. So we'll be looking at how frequent the seizures are, how many medications the child is on, what triggers the seizures, and how durable the seizures are. And over time, hopefully, we'll be able to see a reduction in seizure activity and we can take them off their medications and also see an improvement in the EEG. And then the third bucket of clinical assessments will include general multi-systemic, multi-organ type aspects of Rett Syndrome disease characteristics, such as respiratory assessments, which, as you know, you have respiratory rhythm abnormalities in Rett Syndrome, sleep apnea issues, and cardiac issues, such as QT prolongation.

So I think that the first study once again faced initially on some of these areas of preliminary efficacy, we will build on that on.

Just on the phase two three studies subsequent to that as we've already talked about we'll be engaging with our regulator agencies. During the course of this year to pressure test our thinking around these particular plans on will be stopped from the clinical study towards the end of free yeah.

Okay. Thank you.

Thanks for the question.

The next question comes from Matthew Harrison from Morgan Stanley. Please go ahead.

Good morning. This is Thomas on for Matthew.

Can you give an update on where you are with manufacturing. She began program in particular, what sort of assay work do you still need to complete thank you.

Okay.

Thanks, Thomas for the question I'll turn that question over to Fred <unk>, Our Chief Technical Officer on the line to talk about our manufacturing Bret.

Mahdi Goudarzi: So I think that the first study, once again, we'll look at safety initially, and some of these areas of preliminary efficacy, we will build on that and design the Phase 2-3 study subsequent to that. As we've already talked about, we'll be engaging with regulatory agencies during the course of this year to pressure test our thinking around these particular plans, and we'll start the clinical study toward that.

Yeah.

Thanks, Alright, thanks for the question Matthew Yeah, obviously, we're in the process of on boarding the Gan program and so we're really beginning is with the assays on reviewing the assets. They were conducted by the NIH for the phase one phase two clinical material and what our intention is to try to update those methods to qualify and then Val.

Get them to prepare for late stage pivotal work. So we're actively engaging on all the critical quality attributes assays.

Matthew Harrison: The next question comes from Matthew Harrison from Morgan Stanley. Please go ahead.

With our with our partners to move that forward with our CMO. In addition, we're looking very deeply into the potency assay development work and this is something that's happening.

Mahdi Goudarzi: Good morning, this is Thomas Tan from Matthew. Can you give an update on where you are with manufacturing for the GAN program? In particular, what sort of assay work do you still need to complete?

Jointly between C. Ushers group in my my own to move forward, a potency assay very quickly to kind of synchronize a fully developed and qualified potency assay with pivotal lot manufacturing.

Unknown Executive: Thank you. Thanks, Thomas, for the question. I'll turn this question over to Fred Porter, our Chief Technical Officer, on the line to talk about our manufacturing. Fred. Yeah, thanks, Ari. Thanks for the question, Matthew. You know, obviously, we're in the process of onboarding the GAN program. And so where we're really beginning is with the assays, reviewing the assays that

Happy to answer any questions about that.

Okay.

No I can ask one more comment Oh, it's about one more comment on top of I'll talk a friend.

Important question to ask about bad assets. The other I'd say that we're spending some time thinking about and really pulling the trigger on with some some considerable assets as the as more from the Q PCR assay to the DD PCR So I guess on a slightly more accurate.

Unknown Executive: were conducted by the NIH for the Phase I and Phase II clinical trials.

Unknown Executive: Nathaniel. And what our intention is to try to update those methods to qualify and then validate them to prepare for late-stage pivotal work. So we're actively engaging in all the critical quality attribute assays with our partners to move that forward with our CMO. In addition, we're looking very deeply into it.

Numbers in terms of timeframe. So that's another almost what happened in parallel with the potency of the CMC characterization that Fred mentioned.

Unknown Executive: to the potency assay development work. And this is something that's happening jointly between

Thank you.

Thanks, Tom.

Once again, if you have a question. Please press Star then one.

The next question comes from Rajiv Prasad from William Blair. Please go ahead.

Unknown Executive: Jointly between Siyasha's group and my own to move forward a potency assay very quickly to kind of synchronize a fully developed and qualified potency assay with pivotal LOP manufacturing. I'm happy to answer any questions about that. You know, I can add one more comment.

Hey, guys. Thanks for taking my question and congrats on the progress.

You know.

I'm kind of looking down on your pipeline and I see a lot of low tech.

Allergies that you're derisking from a payload perspective, yeah, my rare platform to bias the stronach vector.

I can see you know follow on indications once those technologies are de risked well my question was more on the regulatory side.

Unknown Executive: I can add one more comment. I can add one more comment on top of Fred.

You know as you're kind of dealing with regulators on these different indications.

Unknown Executive: And it's an important question to ask about an assay. The other assay that we're spending some time thinking about and really pulling the trigger on with some considerable effort is morphing the qPCR assay into the vdPCR, so we get some slightly more accurate numbers in terms of

What types of aspects of the programs you think will be derisked by.

Clinical data there yet on endpoints and dealing with endpoints with the FDA.

Is it on the I T administration, and maybe some color there would be great. Thanks.

No. It's a great question and it's kind of central to our scientific thesis and really our focus on the use of validated gene therapy technology, coupled with very targeted novel payload design and really trying to achieve and economies of scale to really allow us to go after.

Operator: Once again, if you have a question, please press star then 1. The next question comes from Raju Prasad from William Blair. Please go ahead.

Mahdi Goudarzi: Hey guys, thanks again for the question and congrats on the progress.

Is this kind of large portfolio of product candidates and we were able to do that because we hold a couple of quick things constant that the first thing is all of our programs are benign.

Mahdi Goudarzi: You know, I'm kind of looking down your pipeline, and I see a lot of technologies that you're de-risking from a payload perspective, the MIR platform, the Bifrostronic vector. I can see, you know, follow-on indications once those technologies are de-risked, but my question was more on the regulatory side, as you're dealing with regulators on these different indications. What types of aspects of the programs do you think will be de-risked by, you know, clinical data there? Is it on endpoints and dealing with endpoints with the FDA? Is it on the IT administration? Maybe some color there would be great. Thanks. No, it's a great question.

Good thing they all use had 293 suspension manufacturing as a platform and and the third is really around.

This notion of Interstate delivery, and then and this really allows us to take learnings and achieve economies of scale from one program to the next I'll pause there and so you. So I'll allow you to kind of talk about maybe some of the things that we plan to discuss with regulators on how we plan to apply those learnings from one program to the next day.

Ah. Thanks, Thanks, Sara and thanks, Roger for the question Yeah, there's lots, there's lots and lots of commonalities I think between on programs over and above the simple the tri factor of common suite, but anything on unless you pay 293 in I T administration, there's many many other coming out because on.

Unknown Executive: And it's kind of central to our scientific thesis and really our focus on the use of validated gene therapy technology, kind of coupled with very targeted novel payload design, and really trying to achieve an economy of scale that really allows us to go after, you know, this kind of large portfolio of product candidates. And we were able to do that because we hold a couple of things constant. The first thing is that all of our programs are AV9.

We shot.

Right.

For more money thing.

Let me touch on a couple of things so Seamus.

I think moving to learn huge amount from just one program to a full on the next.

You know we are there's a lot of debate in the field about you know I T. This is on ICM vs. I C V on the subtlety.

Unknown Executive: The second thing is that they all use Head 293 suspension manufacturing as a platform. And the third is really around this notion of interfaith delivery. And this really allows us to take learnings and achieve economies of scale from one program to the next. I'll pause there. And Suyash, I'll allow you to kind of talk about maybe some of the things that we plan to discuss with regulators and how we plan to, you know, apply those learnings from one program to the next.

It should be from between the mall I keep coming back from that.

With respect to that.

Administration works has worked for decades, I've, given it myself and the world of oncology and honesty geology, and it's worked for decades.

Look at the clinical data from.

Again from ceiling three ceiling, six and indulge asthma, you see it it works and it works beautifully and I think as we continue to build our portfolio of programs.

Mahdi Goudarzi: Thanks Saree and thanks Raju for the question. Yeah, there's lots and lots of commonalities I think between our programs over and above the simple trifecta of comments we all think about AP9, HGK 293 and IT administration. There's many, many other commonalities I think we share and we're really... Let me touch on a couple of things. So you may...

We can really I think the S. T I a on other regulators will just become increasingly comfortable with interest equal administration on its main nuances around that.

Many details for example, with.

Mahdi Goudarzi: I think we're going to learn a huge amount from just one program to inform the next. You know, there's a lot of debate in the field about, you know, IT versus ICM versus ICV and the subtle differences. But I keep coming back to the perspective that, you know, IT administration works, has worked for decades.

We spent some time yesterday talking about a different touch on infusion kits you might use to get interest equaled drug on the comparability compatibility testing them on it needs to for some of these different.

Methods of administration, so I think there's lots and lots of learning in particular from GAAP.

Moving forward the rest of our portfolio. Another piece of learning I think what's important from Gan as our programs progress. It's just from the immunosuppression regime, we like to use so.

Mahdi Goudarzi: I've given it myself in the world of oncology and anesthesiology, and it's worked for decades there. And when you look at the clinical data from GAN, from CLN3, CLN6, and others, and Zolgasma, you see it works, and it works beautifully. And I think as we continue to build our portfolio of programs, the FDA and other regulators will just become increasingly comfortable with intrathecal administration. And there are many nuances around that, but, you know, many details.

The whole world the immunology of gene therapies involved on the both rapidly over the past few years initially people didnt give any immunological therapy.

Just treated liver inflammation or reactively with all the Prednisolone then it was decided that hey, let's get the prednisolone first has shrunk prevents it from an additional medications have been traveling on it and we've subtle very not on this very nice regime of six months of old Prednisolone, plus 12 months of of Rapamycin are specific doses.

Mahdi Goudarzi: For example, we spent some time yesterday talking about the different types of fusion kits you might use to give intrathecal drugs and the compatibility testing you might need to do for some of these different methods of administration. So I think there's lots and lots of learning, in particular from GAN, that will inform the rest of our portfolio. Another piece of learning I think that's important from GAN, and as our programs progress, is just the immunosuppression regime we like to use.

We have a lot of experience with now on learnings from the gown program, where a number of patients have been managed through this regime and this precious therapy very very successfully to the point, where actually we're not seeing any evidence of any T cell mediated inflammation in any of the patients who've received the spreadsheet from the Gamma study.

We use on that approach and Jim to see them on one and stuff on that and I think once again were going to build up this body of evidence for that particular rating.

Mahdi Goudarzi: So the whole world of the immunology of gene therapy has evolved, and evolved rapidly over the past few years. Initially, people didn't give any immunological therapy, and just treated liver inflammation reactively with oral prednisolone. Then it was decided, okay, let's give the prednisolone first to try and prevent it, and then additional medications have been trialed and added. And we've settled on this very nice regime of six months of oral prednisolone, plus 12 months of rapamycin, at specific doses that we have a lot of experience with now, and learnings from the GAN program, where a number of patients have been managed with this regime in this aggressive therapy very, very successfully, to the point where actually we're not seeing any evidence of any T-cell-mediated hepatic inflammation in any of the patients who've received this regime from the GAN study.

I think the third thing I'll mention and you touched on it just as endpoints in the clinical trial on what we can learn from from one to the Alco.

Think.

For a lot of heart diseases.

There are all these neurological features there's a developmental regression on the lack of failure to gain most times and we've said from the very nice group of developmental assessments, the bayley scales with volume on the chop intend on there's one or two other system more disease specific.

We now have to train the rates as they do these particular assessments, we know to video the assessments in a particular way when it's upload the biggest with server whether it can then be reviewed externally by a second right or a second group a rights issue of blinded towards the patients have been treated almost all these things out of low the robustness.

Mahdi Goudarzi: We're using that approach in GM2, in CLM1, in CIRF1, and I think, once again, we're going to build up this body of evidence for that particular regime. I think the third thing I'll mention, and you touched on it, is endpoints in the clinical trial and what we can learn from one to the other. You know, I think... For a lot of our diseases where there are these neurological features, there's developmental regression and a failure to gain milestones.

To the Hum to the clinical development program on the learnings from one to the other the only thing I mentioned when we were talking about rest a few minutes ago. It was just seizures, how we collect seizure inflammation seizure activity E. G. The medications to patients are on etcetera, So I think that.

In our discussions with the regulators there are many many come on line with novelties in particular on the clinical development side, though I think there's going to be applicable to all programs on world.

Constitute additional learnings from one one to the other.

I hope that answers your question Roger.

Mahdi Goudarzi: And we've stepped on a very nice group of developmental assessments, the Bayley scale, the Vineland, the CHOP intent, and there are one or two others that are more disease-specific. And we know how to train the raters that do these particular assessments. We know to video these specimens in a particular way. We know to upload the videos to a server where they can then be reviewed externally by a second rater or a second group of raters who are blinded to whether the patient has been treated or not.

Yeah, No. That's extremely helpful. Maybe just a quick follow up on that last point.

As it relates to the upcoming FDA discussions on the Gan program.

How should we be looking at the results of those discussions as it relates to.

Potential request from the FDA.

I'm thinking, particularly about natural history comparator versus having to you know.

Run a yeah placebo arm or a sham control treated arm I mean, you know.

Is that something that you're looking to see kind of agony to extrapolate to the rest of the pipeline like it if they do give you a natural history comparator.

Mahdi Goudarzi: All these things add a lot of robustness to the clinical development program and the learnings from one to the other. The other thing I mentioned when we were talking about rats a few minutes ago was just seizures, how we collect seizure information, seizure activity, EEG, the medications the patients are on, etc. So I think that, in our discussions with regulators, there are many, many commonalities, in particular on the clinical development side, that I think are going to be applicable to all programs and will constitute additional learnings from one to the other. I hope that answers your question, Raju.

Four pivotal that's something that you might try it for Jim to income diseases, where do you think that the discussions on Gan are only going be related gain in each individual indication will probably be a different.

You know kind of a different kind of discussions with the agency.

So it's a really important point you know the how much data already existing from particular disease and it's there are certainly commonality saved from program to program, but there are also some subtle differences on but doing things a little bit differently from program to program.

Mahdi Goudarzi: Yeah, no, that's extremely helpful. Maybe just a quick follow-up on that last point, as it relates to, you know, the upcoming FDA discussions on the GAN program. You know, how should we be looking at the results of those discussions as it relates to, you know, potential requests from the FDA? I'm thinking particularly about the natural history comparator versus having to, you know, run a placebo arm or a sham control treated arm.

What I will say at a high level is there's some very nice guidance that was published by the FDA on gene therapy development. The neuro degenerative disease on how the specific section on I'm not sure. It's true suddenly historical controls on that as I said, probably clearly this may be appropriate for a gene therapy product.

Treat a rare and serious near just finished disease, if there's a clear unmet medical need which is absolutely. The case from a small programs while the inclusion of income couldn't control theres not practical or ethical which is also true certainly for programs like G. M. Two will ceiling on where this is ongoing high risk of mortality.

Mahdi Goudarzi: I mean, you know, Is that something that you're looking to see, kind of, extrapolate to the rest of the pipeline? Like, if they do give you a natural history comparator for pivotal, that's something that you might try for, you know, GM2 and some of these other diseases? Or do you think that the discussions on GANs are only going to be related to GANs, and each individual indication will probably be different... You know, kind of a different set of discussions at the agency? Thanks.

They also talk about the disease course is well documented and.

Mahdi Goudarzi: So it's a really important point, you know, the amount of data that already exists for a particular disease. And it's like that.

Spectra treating effect as large it may be very very suitable to use a natural history comparator control massive gamma specifically, we have 45 patients in fact, we presented data from 45 patients.

Mahdi Goudarzi: There are certainly commonalities here from program to program, but there are also some subtle differences, and we do things a little bit differently from program to program. What I will say at a higher level is that there's some very nice guidance published by the FDA on gene therapy development for neurodegenerative diseases and has a specific section on natural history studies and historical controls, and they said very clearly that these may be appropriate for a gene therapy product. Unknown Executive, Eun Yang, Joon Lee, Mahdi Goudarzi, Yevgeniya Livshits, Salman Bhai, It's also predictable.

And the natural history study.

With data that no patient was enrolled in that study in 2013 stores seven.

Seven day as a data on some of these patients and will go very very clear indication that there was a consistent draw from the primary efficacy endpoints.

From 32 eight points per year, I think because of that it's also predictable the disease course is predictable and sorry for Gan.

Mahdi Goudarzi: The disease course is predictable. And so for GAN, a very rare disease. We're seeing a very nice treatment effect in interventional studies, so all those things really contribute to the fact that for GAN in particular, I think it checks all their boxes for the Natural History Study being an appropriate comparator. So my guess is it's unlikely they will ask us to do any kind of more formal concurrent control.

Very rare disease.

With were seeing a primary loss treatment effect hold on special study. So all of those things really contribute to.

The fact that for gallon in particular I think it's.

He doesn't know what they have taken to say, but I think it checks all the boxes for us.

In natural history study had been on the appropriate comparator. So my guess is it's unlikely they will ask us to do any kind of more formal concurrent control.

Mahdi Goudarzi: Once again, you don't know what the FDA is going to say, but it checks all their boxes from that perspective. GMT, there's a lot of good natural history data already out there in publications, and so we're making use of that. CLN1, there is a prospective natural history study ongoing currently with about 40 to 50 patients in it. This is international, so we'll be using that. So it's a little bit different from program to program. For Rett syndrome, there are huge natural history databases that are available.

Once again, you said it all yesterday on the site, but it checks all the boxes from that perspective G. M. Two there's a lot of them already good enough trade Street day traveler and publications.

And so we're making use of that ceiling. One there was a prospective natural history study ongoing currently with about 40 to 50 patients in it and this is international so we'll be using that so it's a little bit different from from program to program. The Ret syndrome. There is huge natural history databases that are available although for ret, we will likely build enough.

Mahdi Goudarzi: Although for Rett, we will likely build in a concurrent control for a randomized but non-blinded concurrent control to add a little more robustness to that clinical development. So, let me stop there. I hope I've answered your question and given you some context, but I can stop. I think we can go into more detail if you like, Rajiv, but let me stop.

A concurrent control on a randomized, but non blinded concurrent control that a little more robustness, but clinical development plan. So.

So let me start with our type of assets Youre question give us some context, but I can stop I think we can get into more detail. If you like Roger you, but from store now.

No. That's extremely helpful. Thank you. Thank you for the question.

Eun Kyung Yang: No, that was extremely helpful. Thank you. Thank you for the question. Thanks for watching. The next question comes from Eun Yang from Jeffreys, please go ahead.

Thanks Raj.

The next question comes from June Young from Jefferies. Please go ahead.

Thank you so.

Eun Kyung Yang: Thank you. So, you know, today, when we talk about addressing the patient population for your gene therapy programs, it's been kind of a focus on the U.S. and Europe. But now you look to potential approval of 120 in 2023. What are you thinking about market opportunities outside the U.S. and Europe?

So today when we talk about interest the patient population for your gene therapy programs.

It's been kind of a focus on the U S on year round.

Now you look to a potential approval of a 120 interest that's I'm 23 on what are you thinking about the market opportunity outside the U S from Europe.

Thank you for the question. It's a great question, you know in and what's interesting about rare disease commercialization is the fact that you're able to leverage a major market approval pretty much all over all over the world and what I mean by that and approval in the U S or in the EU.

Unknown Executive: Thank you for the question. That's a great question.

Unknown Executive: You know, and what's interesting about rare disease commercialization is the fact that you're able to leverage a major market approval pretty much everywhere in the world. And what I mean by that, an approval in the U.S. or in the EU, you're able to initiate almost immediately reimbursed named patient or early access programs in some of the more highly reimbursable markets where you also have an overexpression of genetic diseases.

Were able to initiate almost immediately reimbursed named patient or early access programs and some of the more highly reimbursable markets, where you also have an over expression of genetic diseases and so in some countries like the GCC region of the middle the Middle East, Saudi Arabia, Israel, Turkey.

Unknown Executive: And so, in some countries like the GCC region of the Middle East, Saudi Arabia, Israel, Turkey, some of the Latin American countries where reimbursement is actually quite good, Brazil, Colombia, these are areas that we would actually look to commercialize post a major market approval either under a reimbursed named patient program or early access program, would eventually you would seek marketing approval over time. So, that's really the way that we're thinking about commercialization.

Are some of the Latin American companies countries, where reimbursement is actually quite good Brazil, Colombia. These are areas that we would actually look to commercialize post a a a major market approval either under a reimbursed named patient program or early access program would eventually.

You would you would seek a marketing approval on over time. So that's really the way that we're thinking about commercialization. We are looking globally. We would most likely do this to some of your more established a distribution partners. There's a number of partners, particularly and Israel and the Middle East Turkey.

Unknown Executive: We are looking globally, and we would most likely do this through some of your more established distribution partners. There are a number of partners, particularly in Israel, the Middle East, Turkey, Brazil, that are highly skilled at achieving reimbursement for specialized products, gene therapies, high-priced products. And so, we would probably most likely go this route. We most likely would not look to out-license our product from a commercialization perspective early on but really do our commercialization through distribution collaboration in some of these countries that I mentioned.

Brazil that are highly skilled in achieving reimbursement for four specialized products gene therapies high price products and so we would probably most likely go. This route we went.

We most likely would not look to out license our product from a commercialization perspective early on but but really do our commercialization through distribution.

Distribution collaborations and some of these areas and some of these countries that I that I mentioned, so that's that's the way that we're thinking about things today, obviously as time goes on you you you gain more information and an you alter your thinking that way, but at least for now that's the way that we're approaching our commercialization our pre commercialization plans.

Unknown Executive: So, that's the way that we're thinking about things today. Obviously, as time goes on, you gain more information, and you alter your thinking that way, but at least for now, that's the way that we're approaching our commercialization, our pre-commercialization plan.

Thank you and also one more question on <unk> syndrome program. So I'm sure day, you're familiar with Novartis a program and I don't know how much you can speak about it but aside from are.

Eun Kyung Yang: Thank you. And I have one more question about your Rett syndrome program. So I'm sure that you're familiar with Novartis' program, and I don't know how much you can speak about it, but aside from your program, you know, potentially has a better regulation of the transgenic expression. Can you talk about any kind of differentiation compared to Novartis? And is Novartis actively pursuing their RETT program?

Your program.

You know what.

I actually have a better.

Regulation of the transit gene expression can you talk about kind of a differentiation continues to novartis and novartis actively pursuing their rep program.

Yeah.

Unknown Executive: Thank you for the question. So, what I'll just do is highlight the difference, kind of the main difference between the two approaches, and then I'll turn it over to Suyash to kind of talk about the differences in more depth.

Thank you for the question so what I'll just do with highlight the different.

The main difference in the two approaches and then I'll turn it over to Sue you guys to kind of talk about the differences in more depth. So really the main difference in the two programs is our program tasteful one O. Two is a is a.

Unknown Executive: So, really, the main difference between the two programs is that our program, Taysha 102, is a gene therapy product, AAV9, with a self-regulatory feedback loop built into the transgene that caps gene expression on a cell-by-cell basis, or as described in the paper that was recently published, that has a genotypic regulation of gene expression. That's the term that we're using. Essentially, what we're doing is having a safety valve to guard against overexpression-associated toxicity.

Gene therapy product AAV nine with a self regulatory feedback loop built in to the Trans gene that caps gene expression on a cell by cell basis or as we describe or what was described in the paper that was recently published that has a genotypic regulation of gene expression.

That's the term that that we're using essentially what we're doing is is having a safety valve to guard against over expression associated toxicity.

On a novartis abaxis construct is essentially self complementary AAV nine with falling to make P. Two with no regulatory component that that at least is the last construct that was published that that we are all publicly aware on I'll stop there. So yes, maybe you want to go through in a little bit more.

Unknown Executive: The Novartis-Avexis construct is essentially self-complementary AAV9 with full-length MeCP2 with no regulatory component. That, at least, is the last construct that was published that we are all publicly aware of. I'll stop there. Suyash, maybe you want to go through in a little bit more detail some of the nuances.

Some of the nuances.

Yeah. Thanks, Alright. Thanks for the question I think it's an important question and it's already mentioned.

Mahdi Goudarzi: Yeah, thanks, Arie, and thanks for the question. I think it's an important question.

Mahdi Goudarzi: As Arie mentioned, the only major difference really is the fact that, you know, we include, we have the Minimek P2 gene, which was developed by Professor Sir Adrian Bird, a very esteemed and knowledgeable Rett expert from Edinburgh, who was actually the first person to demonstrate unequivocally that Rett syndrome is a highly reversible disease. So we use his design for the Minimek P2 gene, and then we attach this strip of microRNA binding sites, the MIRF platform, which stands for microRNA responsive auto-regulatory element.

On the only major difference really is the fact that.

You know we include we have the mini Mac P. Two gene, which was developed by professor Adrian but.

And a very sustained and eligible grants expense from Edinburgh, who was actually the first person to demonstrate unequivocally that a rash syndrome.

Hardly reversible disease. So we use his designed for the many let Pete to gene and then we attach the strip of my call when they binding sites D. M I wrap platform, which stems from my car and I.

Smith also regulatory elements, so when might be true levels go up within the cell as a consequence of the gene therapy.

Mahdi Goudarzi: So when Minimek P2 levels go up within the cell, as a consequence of gene therapy, the down-regulatory microRNA binding sites are triggered; they bind to this MIRF platform, which is in the untranslated region of the construct, and bring down levels of Minimek P2, as Arie suggested, acting as a safety valve. Now, we're very excited to be able to say to you that the first quantitative data demonstrating this reduction in Minimek P2 to the point where you have enough so it's efficacious but not too much that it's toxic were published in Brain, which is a very prestigious neuroscience journal. It went online on Friday, and we issued a press release yesterday.

The dam regulatory micro RNA binding sites on what triggered the bonds the same amount or a platform, which is me on transplanted reason that the construct and bring down levels. It might be too I've already suggested on it seems the safety valve now we're very excited.

To be.

On the up to say to you that the first quantitative data demonstrating this a reduction in net P too.

Expression to the point, where you have enough. So it's efficacious, but not too much to this toxic was published and Brian which is a very prestigious neuroscience true. It went online on Friday, and we issued a press release.

Yesterday.

And I would encourage you to look at the paper the lead author Cyrus day nuts.

Mahdi Goudarzi: And I would encourage you to look at the paper. The lead author is Sarah Spinnett, and the senior author is our good friend and colleague, and our chief scientific advisor, Stephen Gray. And there's a particular diagram in that paper that I suggest you look at, which looks specifically at different levels of expression of MeCP2 in different parts of the brain and different parts of the spinal cord. And you can see very nicely that the non-MIR construct overexpresses, whereas the MIR construct expresses enough so that it is efficacious but not toxic.

On the senior roles to resolve our good friend and colleague and our Chief scientific adviser Stephen Gray zone.

Diagram, and that and not paper, which I suggest you look at which looks specifically at different levels of expression of might be true in different parts of the brain in different parts of the spinal cord and you can see it very nicely.

Non M Iraq construct over expresses whereas the M. Iraq construct expresses enough so the fitness efficacious, but not toxic so.

We're very excited about that particular type of them.

Mahdi Goudarzi: We're very excited about that particular paper. So I think that's the main difference, the fact that we can demonstrate this, the ability to... express MeCP2 within these normal physiological parameters now we've shown in different parts of the brain, and we've shown it quantitatively as well. My understanding is that Novartis is still moving forward with their program. The last I heard was they were planning to move forward with an IND, but I don't know exactly where they are with that. But I think that's the main difference, really, between our products and theirs.

So I think that's the main difference is the fact that we can demonstrate this the ability to.

Express might be too within these normal physiological parameters now we've shown in different parts of the Brian and we're showing that quantitatively.

Wow.

My understanding is that Novartis is still moving forward with that program last I heard was the planning to move forward to the nine day, but I don't know exactly where they are with that but I think that's the main difference really between all our projects from last.

Thank you for the details.

Eun Kyung Yang: Thank you for the details.

Thank you.

There are no further questions I will now turn the call over to Mr sessions for his closing remarks.

Unknown Executive: There are no further questions. I will now turn the call over to Mr. Sessions for his closing remarks.

Unknown Executive: So again, we appreciate everyone joining us on the call this morning. As you can see, the company has made great strides during the first quarter, and we will continue to make progress throughout the rest of this year. And so we hope that you guys join us at our R&D Day, which will take place over two days in June, June 28th and June 29th. And we'll provide further updates as the year goes on. Thank you for joining us. Have a good day.

So again, we appreciate everyone joining us on the call. This morning is as you can see the company has made great strides during the first quarter and we continue to make progress throughout the rest of this year and so we hope that you guys join us at our R&D day, which will take place over a two.

Days in June June 28th on June 29th and we'll provide further updates as the year goes on thank you for joining have a gate they have a good day.

Operator: Ladies and gentlemen, this concludes today's presentation. Thank you once again for your participation. You may now disconnect.

Ladies and gentlemen, this concludes today's presentation.

Thank you once again for your participation.

You may now disconnect.

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