Q4 2021 Taysha Gene Therapies Inc Earnings Call

Okay.

Operator: Welcome to Taysha Gene Therapy's fourth quarter and full year 2021 financial results and corporate update. At this time, all participants are in listen only mode.

Welcome to the tissue gene therapies fourth quarter, and full year 2021 financial results and corporate update.

At this time, all participants are in listen only mode.

Management's prepared remarks, we will hold a brief question and answer session.

As a reminder, this call is being recorded today March 31 2022.

Operator: Following management's prepared remarks, we'll hold a brief question and answer session. As a reminder, this call was recorded today, March 31, 2022. I'll now turn the call over to Dr. Kimberly Lee, Chief Corporate Affairs Officer. Please go ahead.

I'll now turn the call over to Dr. Kimberly Lee Chief Corporate Affairs Officer. Please go ahead.

Good morning, and welcome to patients fourth quarter and full year 2021 financial results and corporate update conference call. Joining me on today's call are already session. The second patient President founder and CEO . Dr. C. S Prasad Chief Medical Officer, and head of R&D, and Kamran Alam Chief Financial Officer. After their formal remarks, we will conduct a question and answer.

Dr. Kimberly Lee: Good morning and welcome to Taysha's fourth quarter and full year 2021 financial results and corporate update conference call. Joining me on today's call are Ari Session II, Taysha's President, Founder and CEO, 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 fourth quarter and full year ended December 31, 2021.

Dr. Kimberly Lee: A copy of this press release is available on the company's website and through our SEC filer. 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 product candidates. These statements include the effects of timing and results of clinical trials for our product candidates, or acceptances regarding the data necessary to support regulatory approval of Taysha 120, the regulatory status and market opportunity for our clinical programs, as well as Taysha's manufacturing plans.

Dr. Kimberly Lee: This call may also contain forward-looking statements relating to Taysha's growth and future operative results, discovering development of product candidates, strategic alliances, intellectual property, cash runway, and implementation and potential impacts of our strategic pipeline prioritization initiatives, as well as matters that are not of historical facts or, Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements. These risks include uncertainties related to the timing and results of clinical trials and preclinical studies of our product candidates, or dependence upon strategic alliances and other third-party relationships, our ability to obtain patent protection for our discoveries when mutations imposed by patents owned or controlled by third parties, and the requirement of substantial funding to conduct a research and development activity. For a list and description of the risks and uncertainties that we face, please see the reports we have filed with the Securities and Exchange Commission.

Dr. Kimberly Lee: This conference call contains time sensitive information that is accurate only as of the date of this live broadcast March 31st 2020, Taysha undertakes no obligation to revise or update any foreign looking statements to reflect events or circumstances after the date of this conference, except as may be required by applicable securities. With that, I'd now like to turn the call over to our President, Founder, and CEO, R.A. Seshan II. R.A.?

R.A. Seshan II: 2021 was a year of accomplishment that included positive data from three clinical programs, including GAN, GMQ Ganglios, and We are sharpening our strategic focus to prioritize key value-driving registration-directed programs, NGAN, which has an estimated addressable patient population of 5,000 worldwide, and Rett Syndrome, which affects over 350,000 patients worldwide. To increase operational efficiency, activities for other ongoing clinical programs will be minimized, and As a result, we have reduced our workforce by approximately 35%.

R.A. Seshan II: Our strategic pipeline prioritization, along with existing cash and financing under our current debt facility, is expected to extend cash runway into the fourth quarter of 2023. We look forward to our continued execution across our clinical and regulatory strategies, and we'll update you on progress throughout the remainder of the year. I will now turn the call over to Suyash to provide a more detailed update on our clinical program. So yes, please go ahead. Thanks, all right.

Session and instructions will follow at that time.

Although today tissue issued a press release announcing financial results for the fourth quarter and full year ended December 31st 2021.

A copy of this press release is available on the company's website and through our SEC filings.

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 product candidates.

These statements May include the effect of the timing and results of clinical trials for our product candidates our expectations regarding the data necessary to support regulatory approval Acacia one 'twenty, the regulatory status and market opportunity for our clinical programs as well as tissue manufacturing plants. This call may also contain forward looking statements relating to tatius growth in future.

With me adults discovery and development of product candidates strategic alliances intellectual property cash runway and Brooklyn reputation and potential impacts of our strategic pipeline prioritization initiative as well as matters that are not of 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 uncertainties related to the timing and results of clinical trials and preclinical studies of our product candidates.

Dependence upon strategic alliances and other third party relationships.

Ability to obtain patent protection for our discoveries limitations imposed by patents owned or controlled by third parties and the requirement of substantial funding to conduct our research and development activities.

Boy list and description of the risks and uncertainties that we face. Please see the reports we have 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 March 31, 2022, Acacia 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 law.

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

Thank you Kim good morning, and welcome everyone to our call.

2021 was a year of accomplishment that included positive data from three clinical program, including Gan G M <unk>, gangliosidosis and steel and seven to be.

We are sharpening our strategic focus to prioritize key value driving registration directed program, India, which had been estimated addressable patient population of 5000 worldwide and ret syndrome, which affects over 350000 patients worldwide.

To increase operational efficiency.

Activity score other ongoing clinical programs will be minimized.

All other research and development will be Paul.

As a result, we have reduced our workforce by approximately 35%.

Our strategic pipeline prioritization, along with existing cash and financing under our current debt facility is expected to extend cash runway into the fourth quarter of 2023.

We look forward to our continued execution across our clinical and regulatory strategy and we'll update you on progress throughout the remainder of the year.

I will now turn the call over to see us to provide a more detailed update on our clinical program.

Yes. Please go ahead.

Thanks, Alright recently, we reported positive initial clinical data for Gan G M. Two gangliosidosis ceiling seven disease.

Further validation of the therapeutic potential of our platform in multiple diseases of the central nervous system.

Let's begin with Taishan 120 for the treatment of gout.

Dr. Suyash Prasad: Recently, we reported positive initial clinical data for GAM, GM2, ganglicidosis, and further validating the therapeutic potential of our platform in multiple diseases of the central nervous system. Let's begin with Taysha 120 for the treatment of gout. Taysha 120 is the first gene therapy to be intrathecally dosed and is currently being evaluated as part of a groundbreaking historic dose escalation clinical trial at the NIH under the leadership of the principal investigator Carsten Bonner.

Actually 120th of course gene therapy to be interestingly dosed and is currently being evaluated as part of a groundbreaking historic dose escalation clinical trial.

H under the lead ship of the principle investigator cost in Baltimore.

We recently reported positive clinical efficacy and safety data for the high dose cohort of 3.5 E 14, total D G as well as long term safety and durability across all therapeutic.

Dr. Suyash Prasad: We recently reported positive clinical efficacy and safety data for the high dose cohort of 3.5 E14 total VG, as well as long-term safety and durability data across all their pucyc. Treatment with Taysha 120 achieved a clinically meaningful and statistically significant slowing or halting of disease progression seen in the highest dose cohort of 3.5 E14 total VG and cross all therapeutic best cohorts. At the highest dose, Taysha 120 demonstrated clinically meaningful and statistically significant improvements in the MFM32 score by year one compared to natural history, Additionally, long-term durability data across all therapeutic doses demonstrated a 10-point improvement in the mean change from baseline in MFM32 score by year three compared to the estimated natural history decline of 24 points.

Yes.

Treatment with Taishan, one 'twenty achieved a clinically meaningful and statistically significant slowing or halting of disease progression seen in the highest dose cohort of 358 14 total BG on across all therapeutic dose cohorts.

At the highest dose takes you one 'twenty demonstrated clinically meaningful and statistically significant improvements in the M. S. M 72 school by year, one compared to natural history.

Additionally, long term durability data across all therapeutic doses demonstrated a 10 point improvement in the main change from baseline and I'm a fan of 32 school by year three compared to the estimated natural history, a decline of 24 points.

Dr. Suyash Prasad: These long-term data confirm the disease-modifying effect and sustained durability of Taysha 120. Notably, nerve biopsy data pre-unpost treatment with TAYCHA 120 provided evidence, active regeneration of nerve fibres, thereby demonstrating pathological improvement to complement the clinical benefits, In addition, preservation of visual acuity, as measured by the log mask was observed, and this was in conjunction with improvements in retinal nerve fiber layer thickness as a fast biopticle coherence to mocks.

These long term data confirm the disease modifying effect.

Sustained durability of takes your 120.

Notably the biopsy data pre and post treatment with Taishan, one 'twenty provided evidence active regeneration nerve fibers.

Thereby demonstrating technological improvements to complement the clinical benefits thing.

In addition preservation of visual acuity as measured by the lock Moscow was observed and this was in conjunction with improvements in rental.

Fitness has assessed by optical coherence tomography.

There were no significant safety issues and no increase in adverse events at higher doses.

Dr. Suyash Prasad: There were no significant safety issues and no increase in adverse events at high doses. All adverse events related to immunosuppression or study procedures were comparable to other gene therapies and transient in nature. There were no dose-limiting toxicities reported following treatment with Taysha 120, no evidence of dorsal root ganglion inflammation, and no evidence of thrombocytopenia. Overall, this dataset is the most comprehensive gene therapy dataset in GAN, offering Taysha120 a potentially de-risk regulatory path.

All adverse events relates to immunosuppression or study procedures were comparable to other gene therapies and transient in nature.

There were no dose limiting toxicities reported following treatment with tissue on 'twenty.

No evidence of dorsal root ganglion inflammation and no evidence of thrombocytopenia.

Overall, the states such as the most comprehensive gene therapy data set and again offering tissue in 'twenty I potentially derisk regulatory path.

Dr. Suyash Prasad: We believe this program currently meets most registration requirements based on FDA and EMA guidance for gene therapy for neurodegenerative diseases. We look forward to our continued discussions with major regulatory agencies on potential registration pathways for Taysha 120 and anticipate a regulatory update by mid-2022. As a reminder, Taysha 120 has already received orphan drug and rare pediatric disease designations from the FDA. We also have partnerships in place to help raise awareness and facilitate early diagnosis of Goudarzi.

We believe this program currently meets most registration requirements based on F. D. A M.

His guidance for gene therapy for neuro degenerative diseases.

We look forward to our continued discussions with major regulatory agencies on potential registration pathways for tissue on 'twenty and anticipate a regulatory update Bob.

2022 .

As a reminder, it takes you 120th already received orphan drug unwrap pediatric disease designation from the FDA.

We also have partnerships in place to help raise awareness and facilitate early diagnosis of gas.

This includes a partnership with gene Dx the global leader in genetic testing to include the genetic marker to test again in the gene Dx routine hereditary neuropathy screening panel, which is free of charge to individuals' patent risk called or suspected of having gap.

Dr. Suyash Prasad: This includes a partnership with GeneDx, a global leader in genetic testing, to include a genetic marker to test for GAN in the GeneDx routine hereditary neuropathy screening panel, which is free of charge for individuals at risk of or suspected of having GAN.

It also includes collaborations with hereditary neuropathy foundation on the shell Camry Tooth Association centers of excellence as well as health care professionals and patient advocacy groups.

Dr. Suyash Prasad: It also includes collaborations with the Hereditary Neuropathy Foundation and the Schalke-Marie II Association Centers of Excellence as well as healthcare professionals and patient advocacy groups to increase access to genetics. Turning to Rett syndrome, Taysha 102 is the first and only gene therapy in clinical development for Rett syndrome and is designed to deliver a MeCP2 transgene using a novel miRARE platform or micro RNA responsive auto-re This technology is exclusively licensed to Taysha and developed by Dr. Sarah Sinnott. Steven Gray, Beauty Southwest. MIRA is designed to provide sophisticated regulation of transgene expression genotypically on a cell-by-cell basis, delivering controlled expression that prevents toxicity associated with excessive levels of MEK-P2.

Kris access to genetic testing.

Turning to Ratzinger Taisha one O. Two is the first and only gene therapy clinical developments for West syndrome.

On to deliver a much pizza transgene usual novel M. I wrap platform all micro RNA responsive also regulatory element platform.

This technology is exclusively losses to teacher and developed by DOCSIS, Sarah Situps and Steven Great of Ut Southwestern Medical Center.

Am I right is designed to provide sophisticated regulation of transgene expression gene are typically.

On a cell by cell basis, delivering controlled expression that friends toxicity associated with excessive levels of Max Pizza.

We were very pleased to announce earlier this week to initiation of clinical development for <unk>, one or two with the acceptance of our Cta by health Canada in March.

Dr. Suyash Prasad: We were very pleased to announce earlier this week the initiation of clinical development for PACIA 102 with the acceptance of our CTA by Health Canada in mind. Feng-Justein, Mother and Child University Hospital Center in Montreal, Quebec, Canada, has been selected as the initial clinical site under the direction of Dr. Alsa Rossignol, Principal. We also announced positive preclinical data that supported the CTA acceptance, including a pharmacology study in Rett knockout mice assessing the efficacy of Taysha 102 and a six-month GLP toxicology study in non-human Taysha 1.2 has a robust preclinical beta package that supports and validates the ability of MIRR to safely regulate transdune expression.

So interesting mother and child University Hospital Center in Montreal, Quebec, Canada has been selected as the initial clinical sites under the direction of Doctor Elsa Raw single principal investigator.

We also announced positive preclinical data that supported the Cta acceptance, including the pharmacology study in rats knockout mice assessing the efficacy of tissue when I too.

Six months G. L. P. Toxicology study in nonhuman primates exploring the budge distribution on mechanism of action of takes you wanted to.

Chris you want that too has a robust preclinical data package that supports and validate the ability of M. IRA to safely regulate to transgene expression.

Data from the I M. D. C. T. I know you've been pharmacology study in mouse models of Rushydro demonstrates that the M. Iraq regulated transgene expression improved survival.

Dr. Suyash Prasad: Data from the IND CTA-enabled pharmacology study in mouse models of Rett syndrome demonstrated that miRARE-regulated transgene excretion improved survival, respiratory function, and motor function assessments across multiple dose levels. A one-time intrathecal injection of Taysha 102 significantly increased survival at all dose levels, with the mid to high doses improving survival across all age groups compared to vehicle-treated controls. Treatment with Taysha 102 significantly improved body weight, motor function, and respiratory assessments in MECP2 knockout mice. An additional study in neonatal mice is currently ongoing, with preliminary data suggesting normalization of survival.

Respiratory function and motor function assessments across multiple dose levels.

A one time in particular injection that takes you up one night to significantly increase survival at all dose levels with a mid to high doses improving survival across all age groups compared to vehicle treated controls.

Treatment with case, you wanted to significantly improved body white, multifunction respiratory assessments and M. A C P to knockout mice.

An additional study in D&A Komatsu is currently ongoing with preliminary data suggest the normalization of survival.

Positive on D C J neighboring states ones GOP toxicology data H p's.

Dr. Suyash Prasad: Positive IND-CTA-enabling 6.1 GLP toxicology data in NHPs reinforced Taysha 192's favorable safety profile across all dose levels tested, including doses up to four fold above the presumed clinical stop. These data are supported by distribution as reflected by DNA copy number in multiple areas of the brain as affections of spinal cord. Perhaps most importantly, we observed correspondingly low levels of MR, across multiple tissues. This indicates that the miRAR downregulation is appropriately minimizing the transgene expression from the construct in the presence of endogenous MeCP2 in these wild-type NHPs as expected.

Enforced tissue when they choose favorable safety profile across all dose levels tested including doses up to four fold above the Brazilians clinical starts with docs.

These data supported by distribution.

As reflected by DNA copy number in multiple areas of the brain sections of spinal cord.

Perhaps most importantly, we observed correspondingly low loves it tomorrow night across multiple tissues.

This indicates that the M. Iraq downregulation is appropriately minimizing the transgene expression from the construct and the presence of endogenous pizza and these wildfire and hps as expected.

Let me repeat that high levels of DNI in target tissues means that theres good distribution of drug from an interest equal injection, but low levels of mrna mainland downregulation of by the M. Iraq platform is working well to minimize any toxicity.

Dr. Suyash Prasad: Let me repeat. High levels of DNA in target tissues mean that there is good distribution of the drug from an intravehicular injection but low levels of mRNA, meaning that the downregulation by the miRAR platform is working well to minimize any toxicity. Indeed, no toxicity for intransion expressionals was observed, which was confirmed by functional evaluations, demonstrating no detrimental change in neuro-behavioral assessments, and histopathologic evaluations, demonstrating no adverse tissue findings in Necroft.

Indeed, no toxicity from trenching expression was observed which was confirmed by functional evaluations demonstrating no detrimental change and your behavioral assessments in histopathologic evaluations, demonstrating no adverse tissue fundings on necropsy.

Collectively these data.

Dr. Suyash Prasad: Collectively, these data, further support the therapeutic potential, safety and tolerability of Taysha 102 to treat Rett syndrome across a broad dose range. These pre-clinical safety and advocacy data will be presented at the International Wretsendrome Foundation, Wretsendrome Scientific Meeting, taking place April 26th to 27th, 2022 in Nashville, Tennessee. Currently there are no disease modifying therapies to treat over 350,000 patients, estimated to suffer from rest and drone worldwide. We're excited to advance Taysha 102 as the first gene therapy in clinical development for the treatment of this devastating neurodevelopmental disorder, and look forward to reporting preliminary Phase 1-2 clinical data by the end of 2022.

Further support the therapeutic potential safety and tolerability of tissue when they choose to treat ret syndrome across a broad dose range.

These preclinical safety and efficacy data will be presented at the International Ret Syndrome Foundation Ret syndrome scientific meeting.

Taking place April 26 to 27 2022 in Nashville, Tennessee.

Currently there are no disease modifying therapies to treat over 350000 patients.

Estimated to suffer from Reston drug worldwide.

We're excited to advance tissue when I too as the first gene therapy in clinical development for the treatment of this devastating neurodevelopmental disorder.

I look forward to reporting preliminary phase one two clinical data by the end of 2022.

As a reminder.

Dr. Suyash Prasad: As a reminder, Taysha Winotu has been granted a rare pediatric disease designation, an orphan drug designation from the FDA, and more recently, an orphan drug designation from the European, For GM2 gangliosidosis, Taysha 101 is the first and only bisistronic vector in clinical development, representing an important first for the field of gene therapy. Driven by the same promoter, Taysha 101 Expresses both the hex-A gene, coding the alpha subunit, and the hex-B gene, coding for the beta subunit in a one-to-one ratio, enabling the production of functional hetero-dimeric beta hex-A subunit a-A, for providing the ability to restore and normalize enzyme activity in GM2 gangliosidosis using one vaccine.

So when they two has been granted rare pediatric disease designation and orphan drug designation from the FDA and more recently orphan drug designation from the European Commission.

Well Jim to ganglia Pseudocyst takes you will know when the first and only buys to strongly backed up some clinical development, representing unimportant first for the field of gene therapy.

Driven by the same promote itself takes you one O. One expresses both the hex aging coatings the alpha subunit in that speech, a coding for the beta subunits and I want to one ratio, enabling the production of functional heterodyne Merit beat the Heck says hey.

Providing the ability to restore a normalized enzyme activity in GM to kind of lift pseudocyst using one vector.

We reported initial positive biomarker data in January if it takes you a one on one demonstrating normalization to pretax estimate, but as I always say enzyme activity in patients with multiple forms of G. M. Two gangliosidosis.

Dr. Suyash Prasad: We reported initial positive biomarker data in January for Taysha at 1-I-1, demonstrating normalization of beta-hexazomabase A, or HexA, enzyme activity in patients with multiple forms of GM2 gangliosidase. We shared data for two patients, including month 1 and month 3 analyses for a patient with standoff disease, and month 1 analysis for a patient with Tay-Sachs. Following one intrathecal administration, Taysha 101 achieved hexaenzyme activity of 190% of normal at month one and 288% of normal at month three in patient one with Sandoz disease, representing 38-fold and 58-fold above the presumed asymptomatic level of 5% of normal identified by natural history at month one and month three respectively.

We shared data the two patients including month, one month three analyses for patient with standoff disease.

One month, one analysis for patients with Tay Sachs disease.

Following when that particular administration takes you one on one achieved pack sizes I'm activity of 190% of normal a month, one and 298% of normal at month, three and patient one with Sandoz disease, representing 38 fold on 58 fold above the presumed asymptomatic level.

A 5% of normal identified by natural history at month, one a month three respectively.

Patient two with Tay Sachs disease achieved xa enzyme activity of 25% of normal at month, one which represented five folds above the presumed asymptomatic level of 5% normal identified by natural history.

Dr. Suyash Prasad: Patient 2 with Tay-Sachs disease achieved hexaenzyme activity of 25% of normal a month, which represented fivefold above the presumed asymptomatic level of 5% of normal identified by natural. Preliminary data suggested that Taysha 101 was well-tolerated with no significant drug-related events in both patients. The unfortunate death of patient one was attributed to pneumonia and pleural effusion with a concomitant hospital-acquired MRSA infection.

Preliminary data suggest that that takes you when I, one was well tolerated with no significant drunk relates to events in both patients.

The unfortunate death of patient one was attributed to pneumonia pleural effusion that with a concomitant hospital acquired M RSA infection.

Dr. Suyash Prasad: The Independent Data Safety Monitoring Board agreed with the initial assessment from the principal investigator and confirmed that the patient's death was unrelated to study drugs. Patient 2 continues to progress well, and we are continuing to monitor patients 2 and 3. We do not intend to pursue further enrolment in the Phase 1-2 trial at this time, due to prioritization of programs to increase operational efficiency. But we will continue to follow the patients who were previously dead.

The independent data safety monitoring board agreed with the initial assessment from the principal investigator and confirmed that the patient that was unrelated to study drug.

Patient two continues to progress well and we are continuing to monitor patients two and three.

We do not intend to pursue further enrollment in the phase one two trial at this time due to prioritization of programs to increase operational efficiency.

But we will continue to follow the patients who were previously ducks.

Well ceiling seven we reported positive preliminary clinical safety data for the first generation construct and sealant and seven batten disease.

Dr. Suyash Prasad: For CLN7, we reported positive preliminary clinical safety data for the first-generation construct in CLN7 Batten disease from the ongoing clinical trial in collaboration with UT Southwestern Children's Health and Children's Medical Center Foundation. We recently dosed a fourth patient at 1E15 total VG, bringing the total to three out of the four patients dosed at 1E15 total VG, which is the highest dose ever safely administered intrathecally in humans for gene therapy. The escalation from 5E14 to 1E15 total VG was supported by the Data Safety Monitoring Board.

Ongoing clinical trial in collaboration with Ut southwestern children's health on.

Children's Medical Center Foundation.

We recently dosed the first patient.

One a 15 total BG, bringing the total to three after the full patients dosed at 115 total D. G, which is the highest ever safety administered interests equally in humans for gene therapy.

Dose escalation for $5 14 to 115 total Vijay was supported by the data safety monitoring board.

Initial data from three patients supported a favorable tolerability.

Dr. Suyash Prasad: Initial data from three patients supported a favorable tolerability and safety profile with no major adverse events across both. Further development of the CLM7 program will focus solely on the first generation construct in collaboration with our existing.

Your profile with no major adverse events across doses.

Well the development of a sale and seven program will focus solely on the first generation construct in collaboration with our existing partners.

And 2022 we expect several potential value, creating catalysts include the regulatory feedback the tissue when 20 and gab by mid 2022.

Dr. Suyash Prasad: In 2022, we expect several potential value creating, including regulatory feedback for Taysha 120 in GAM by mid-2022, and preliminary phase 1-2 data for Taysha 102 with Rett syndrome by year 8. Clinical development of the first-generation construct, the CLN7, remains ongoing with our existing partners. We will continue clinical development of Taysha 118 in CLN1 disease and expect to initiate clinical development of Taysha 105 in FLC13A5 deficiency this year. With that, I'll turn the call over to Kamran to review our financial results. Kamran?

Preliminary phase one two data to take out one or two in the ret syndrome by yearend.

Clinical development of the first generation construct the ceilings seven remains ongoing with our existing partners.

We will continue clinical development of <unk>, one one night and see them on one disease unexpectedness shape clinical developments of tissue when I five and that's healthy 39 deficiency this year.

With that I'll turn the call over to Cameron.

Are you all financial results.

Cameron.

Thank you C. S. This morning, I will discuss key aspects of our fourth quarter and full year ended December 31, 2021 financial results more details can be found in our Form 10-K , which will be filed with the STC shortly.

Kamran Alam: Thank you, Suyash. This morning, I will discuss key aspects of our fourth quarter and full year ended December 31, 2021 financial results. More details can be found in our form 10-K, which will be filed with the SEC shortly. As indicated in our press release today, research and development expenses were $37.9 million for the three months ended December 31, 2021, compared to $12.3 million for the same period in 2020. Research and development expenses were $131.9 million for the full year ended December 31, 2021, compared to $31.9 million for the full year ended December 31, 2020.

As indicated in our press release today research and development expenses were $37 $9 million for the three months ended December 31, 2021, compared to $12 $3 million for the same period in 2020.

Research and development expenses were $131 $9 million for the full year ended December 31, 2021, compared to $31 $9 million for the full year ended December 31, 2020. The 100 million dollar increase was primarily attributable to an increase of $38 $3 million of expenses.

Kamran Alam: The $100 million increase was primarily attributable to an increase of $38.3 million of expenses incurred in research and development, manufacturing, and other raw material purchases, which included CGMP batches produced by Catalan and UT Southwestern. We also incurred an increase in employee compensation expenses of $32.7 million, which included $7.1 million of non-cash stock-based compensation, due to an increase in the employee headcount and the research and development function. We also incurred an increase of $29 million in third-party research and development consulting fees primarily related to GOP toxicology studies, clinical trial CRO activities, and consulting for regulatory and clinical studies.

You heard in research and development manufacturing other raw material purchases, which included E. G. M. P batches proved by Cadillac <unk> and Ut southwestern.

We also incurred an increase in employee compensation expenses of $32 $7 million, which includes $7 $1 million of noncash stock based compensation due to the increase in the employee head count and the research and development functions. We also incurred an increase of $29 million of third party research and development consulting fees primarily.

Related to GOP toxicology studies.

Clinical studies zero activity and consulting for regulatory and clinical studies general and administrative expenses were $11 $8 million for the three months ended December 31, 2021, compared to $6 1 million for the three months ended December 31 2020.

Kamran Alam: General and administrative expenses were $11.8 million for the three-month end of December 31, 2021, compared to $6.1 million for the three-month end of December 31, 2020. General and administrative expenses were $41.3 million for the full year ended December 31st, 2021, compared to $11.1 million for the full year ended December 31st, 2020. The full year increase of approximately $30.2 million was primarily attributable to $16.3 million of incremental compensation expense, which included $7.7 million of non-cash stock-based compensation due to increases in employee headcount.

General and administrative expenses were $41 $3 million for the full year ended December 31, 2021, compared to $11 $1 million for the full year ended December 31, 2020, the full year increase of approximately $32 million was primarily attributable to $16 $3 million of incremental compensation expense, which included $7 $7 million or not.

Noncash stock based compensation due to increases in employee head count. We also incurred an increase of $13 $9 million in professional fees related to legal insurance Investor Relations Communications accounting personnel recruiting market research and patient advocacy activities.

Kamran Alam: We also incurred an increase of $13.9 million in professional fees related to legal, insurance, investor relations, communications, accounting, personnel recruiting, market research, and patient advocacy activities. Net loss for the 3-month-end of December 31, 2021 was $50.4 million or $1.32 per share as compared to a net loss of $18.3 million or $50 per share for the 3-month-end of December 31. 2020. The net loss for the full year ended December 31, 2021 was $174.5 million or $4.64 per share compared to a net loss of $60 million or $3.40 per share for the full year ended December 31, 2020. As of December 31st, 2021, Taysha had $149.1 million in cash and cash equivalents.

Net loss for the three months ended December 31, 2021 was $54 million or $1 32 per share as compared to a net loss of $18 $3 million or <unk> 50 per share for the three months ended December 31st.

2020.

Net loss for the full year ended December 31, 2021 was $174 $5 million or $4 64 per share compared to a net loss of $60 million or $3 40 per share for the full year ended December 31 2020.

As of December 31, 2021 piece, you had $149 $1 million in cash and cash equivalents, our strategic pipeline prioritization initiative, along with existing cash and financing under the current debt facility is expected to extend cash runway into the fourth quarter of 2023 and with that I'll.

Kamran Alam: Our strategic pipeline prioritization initiatives, along with existing cash and financing under the current debt facility, are expected to extend cash runway into the fourth quarter of 2023. And with that, I will hand the call back to RA. Thanks Kamran.

I'll hand, the call back to Ara.

R.A. Seshan II: This year we are focused on strategic pipeline prioritization initiatives for GAN and Rett syndrome and our plans to conduct small proof-of-concept studies in CLN1 disease and SLC13A5 deficiency. We anticipate several potentially value-creating catalysts this year, including a regulatory update, for Taysha 120 in GAN by mid-year, and preliminary clinical data for Taysha 102 in Wretland. 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 our mission to develop curative gene therapies to eradicate devastating monogenic CNF. I will now ask the operator to begin our Q&A session. Operator.

Thanks Cameron this year, we are focused on strategic pipeline quota based on initiatives for Gan and Ret syndrome, and our plans to conduct small proof of concept studies in Seattle in one disease and SLC 13, eight five deficiency.

We anticipate several potentially value, creating catalysts this year, including a regulatory update quotation at 120, and Gan by mid year and preliminary clinical data for Acacia one O two in Ret syndrome.

I would like to give special thanks to the continued support and dedication of our rotation employees board of directors.

Advisory Board collaborators and the patients and advocates who remain our motivation every day to continue our mission to develop curative gene therapy to eradicate devastating monogenic CNS disease.

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

Thank you at this time, we'll now be conducting a question and answer session.

Operator: Thank you. At this time, we'll now be conducting a question and answer session. And if you'd like to ask a question today, please press star 1 from your telephone keypad and a confirmation tone will indicate your line is in the question queue. You may press star 2 if you would like to remove your question from the queue, from distance using speaker equipment. It may be necessary to pick up your handset before pressing the star key.

Do you like to ask a question today. Please press star one from your telephone keypad.

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Operator: So that we may address questions to as many producers as possible, we ask you to limit yourself to one question. One moment, please, while we poll for questions.

One moment, please while we poll for questions.

Thank you and our first question comes from the line of Celgene Richter with Goldman Sachs. Please proceed with your question Hey.

Operator: Thank you. And our first question comes from the line of Salveen Richter with Goldman Sachs. Hey, good morning. This is Elizabeth on behalf of Salveen.

Hey, Good morning. This is elizabeth on for solving them just given the strong data that you had for a G. M. Two this year I guess why choose to de prioritize that program.

Hi, Elizabeth Good morning, hopefully you can hear me okay.

R.A. Seshan II: Just given the strong data that you had for GM2 this year, I guess, why choose to deprioritize that program? Hi Elizabeth, good morning. Hopefully, you can hear me okay. You know, I think it really boils down to really focusing on a couple of key value drivers this year, just with the uncertainty in the capital markets from a fundraising perspective. I think it was really imperative to put the company in the best possible position for when red data would be available as, you know, that's a pretty big opportunity. We're talking about 350,000 patients worldwide and really the significant medical need there. You know, what I would say is that I think there's always the opportunity to, you know, take another look at prioritization.

I think it really boils down to really focusing on a couple of key value drivers. This year just with the uncertainty.

In the capital markets from a fundraising perspective, I think it was really imperative to put the company in the best possible position for when that data would be available as you know that's a pretty large opportunity. We're talking about 350000 patients worldwide and really the significant unmet medical need there what I would say.

Is.

I think theres always the opportunity to take.

Another look at prioritization.

R.A. Seshan II: You know, once we see external factors stabilized somewhat, but I think this is really, this was extremely important to make sure that the company itself was put in the best possible position to preserve cash runway, but also value creation. Obviously, the focus on GAN is pretty evident because we're going to be embarking on regulatory pathway discussions, and then, you know, RET is just such a large opportunity and one that we're going to be the first and only gene therapy in development where a lot of other companies haven't made it that far. We thought it was just prudent for us to focus there. So hopefully that answers your question. Thank you. Are there any questions from the line of Jun Lee with Jewish security?

Once we see external factors stabilized somewhat but I think this is really this was an extremely important to make sure that the company itself was put in the best possible position.

To preserve cash runway, but also value creation, obviously to focus on Gan.

Pretty evident because we're gonna be embarking on regulatory pathway discussion and then.

It's just such a large opportunity and one that we're going to be the first and only gene therapy in development, where a lot of other companies haven't made it that far we thought it was just prudent for us to focus there. So hopefully that answers your question.

Thank you.

Our next question is from the line of June Lee with <unk> Securities.

Hi, Thanks for taking our questions.

R.A. Seshan II: Hi, thanks for taking our questions. In addition to restructuring, would you also consider monetizing some of the non-core programs via outlicensing or partnering? And then also, our understanding is that the term loans from SVB are contingent upon you having three active programs. So, in addition to GAN or RED, do you plan to have a third program so active? Thank you. Hey, Jim.

In addition to restructuring would you also.

Consider monetization of some of the noncore programs.

We are out licensing or partnering and then also our understanding is that the term loans from SBB Leerink FCB is contingent upon you having three active programs. So in addition to again or do you plan to have a third program still active thank you.

Hey, Dan Good morning, Thanks for the questions I'll take the last question.

R.A. Seshan II: Good morning. Thanks for the question. So, I'll take the last question first. So, I think as we stated, you know, there will be a key focus on GAN and Rett syndrome, but we're also going to be continuing development on CLN1, CLN7, and SLP1385. So, in total, there's five active programs.

So I think as we stated.

There will be a key focus on Gan and ret syndrome, but we're also going to be continuing with development.

I see.

So you're all in one ceiling seven and then it'll be 13.

<unk> five so in total Theres five active programs I think what we've decided to do was essentially paused work on additional clinical programs as well as programs moving from preclinical into the clinic and that's really where I think the prioritization Cain Bryan So we significantly meet the required.

R.A. Seshan II: I think what we've decided to do is essentially pause work on additional clinical programs as well as programs moving from preclinical into the clinic, and that's really where I think the prioritization came from. So, we significantly meet the requirement for that loan facility, and that was actually just validated as we filed the case. You're your first question around B.D.

Or that.

That loan facility and that was actually just validate it.

As we Bob.

Okay.

R.A. Seshan II: opportunities. I think, you know... As the former head of VD in my former career, I think we are always open to having conversations around VD. I think for us, what would be important is to, if we were to do a deal, is to find a partner that either has an opportunity for us to reach markets that we don't necessarily have or to accelerate programs that we cannot. What I will say is there's active discussions around, you know, potentially looking at opportunities for ex-U.S. territory types of deals that could accelerate clinical development and speed to market in certain parts of the world.

Your first question around <unk>.

<unk> opportunities.

No.

He is the former head of BD.

In my career I think we are always open to having conversations around B D. I think for US what would be important is to if we were to do a deal just to find a partner that either has an.

<unk> for us to reach markets that we don't necessarily have or to accelerate programs that we cannot what I will say is there is there is active discussions around.

Potentially looking at opportunities.

For ex U S territory type of deals.

That could accelerate clinical development and speed to market in certain parts of the world, but I think this is something that will always kind of keep us draw.

R.A. Seshan II: But I think this is something that we'll always kind of keep as dry powder. I think we will always look at ways to, you know, ways to bring in non-diluted forms of capital while accelerating our programs. I think that's always a prudent thing to do. So really good question. Our next question comes from the light of Mike Ols with Morgan Fanny. Please excuse me.

My powder I think we will always look at ways to.

To bring a non dilutive forms of capital.

Capital, while accelerating our programs I think thats always a prudent thing to do so so really good question.

Our next question is from the line of Mike <unk> with Morgan Stanley . Please proceed with your question.

Hey, guys. Thanks for taking the question.

R.A. Seshan II: Hey guys, thanks for taking the question. Just with respect again, maybe you can just give us an update on your current thinking on the path forward there in the US. In the past, you had mentioned analytic comparability as one of the potential scenarios there, and I'm just curious if you've done that analysis yet or are you waiting to get feedback from the FDA before you move forward with that? Thanks, Mike. A really good question.

With respect again, maybe you can just give us an update on your current thinking on the path forward there in the U S.

And in the past you had mentioned.

Analytic comparability is one of the potential scenarios, there and I'm just curious if you've done that analysis, yet or are you waiting to get feedback from the FDA before you move forward with that thanks.

Thanks, Mike really good question, so really I think it boils down to three scenarios.

R.A. Seshan II: So, really, I think it boils down to three scenarios in the United States with GAN, and XUS is kind of slightly different. I think there's a clear pathway when you start to think about the EMA, which opens up the rest of the world, which references the EMA. But particularly for the FDA, it boils down to three scenarios. I think two are higher probability, one is less probable, but certainly could always be a route that the FDA asks you to go down. Scenario one would be if the FDA allows you to file for analytical comparability, essentially doing an analytical bridging study between the clinical material and the commercial-grade material.

And in the United States with Gan in ex U S is kind of slightly different I think there's a clear pathway. When you start to think about the EMA, which opens up the rest of the world who references the EMA, but particularly for the FDA. It boils down to three scenarios I think two or higher probability one is less a probability, but certainly could always be a route.

That the FDA asked you to go since.

Scenario, one would be if the <unk>.

<unk> allows you to file with analytical comparability essentially doing.

In analytical bridging study between B.

Clinical material and the commercial grade material in order to what we would say increase the probability of success.

R.A. Seshan II: So, in order to, what we would say, increase the probability of success of this option, what we decided to do was keep the manufacturer of this program at the same CDMO partner that manufactured the clinical program or using the same cell line, same media, same downstream purification, and same facility. So, essentially, it's a life-for-life process, and we wanted to make sure we held these things constant because we wanted to be able to increase that probability. This, I would probably say, would probably not be the FDA's preferred route. We haven't had that conversation with them yet.

This option.

What we've decided to do with Jeep.

Manufacturer of this program at the same CMO partner, then maybe back to the clinical program, we're using the same cell line.

Save.

<unk> media has seen downstream purification.

So these are the so essentially it's a like for like process and we wanted to make sure. We held everything constant because we wanted to be able to increase that probability.

This one I would probably say would be.

Not the Fda's preferred route we havent had that conversation with them, but if you just look at the comp and the closest comp to this would be the experience of soldiers.

R.A. Seshan II: But if you just look at the comps, and the closest comp to this would be the experience of Zolgensma, that would more align to option two. And I would say option two is probably our base case, and this is essentially what we're planning for internally. And this would be somewhat of a bridge between, you know, doing an analytical filing on analytical comparability and doing a new study. This is essentially where you would dose a handful of patients under the current IND and protocol using commercial-grade material. The goal would ultimately be to propose to the FDA filing a rolling submission, essentially filing the preclinical data first. That's not changing.

That would more aligns option too and I would say option two is probably our base case and this is essentially what we're planning for internally and this would be somewhat.

Bridge between doing a analytical filing on analytical comparability and doing a new site. This is essentially where you would dose a handful of patients under the current IND.

And protocol using the commercial grade material the goal would ultimately be to propose to the FDA.

Following a rolling submission essentially falling the preclinical data first that's not changing that's all there then starting to supplement the filing with the clinical data that's already been generated which we now have seven years worth of data safety and efficacy data that's been generated that we've seen long term durability.

R.A. Seshan II: That's all there. Then starting to supplement the filing with the clinical data that's already been generated, which we now have seven years' worth of data, safety, and efficacy data that shows we've seen long-term durability, dose response, good safety, and efficacy across the board. And then supplementing that data with new data generated with the commercial-grade material. What I will say is the engineering run for the commercial-grade material has just completed, and the yields are phenomenal.

Dose response, good safety efficacy across the board.

Supplementing that data with new data generated with the commercial grade material. What I will say is the engineering run for the commercial grade material just completed and the yields are phenomenal and we've just kicked off our GMP run for the validation batch of which is ultimately the commercial grade material that will be released in Q3. So we.

R.A. Seshan II: And we've just kicked off our GMP run for the validation batch, which is ultimately the commercial-grade material that'll be released in Q3. So we're actually quite excited that we've made significant progress along with our CDMO partner there. The third scenario, which we think is somewhat unlikely and would be against the FDA's guidance that they issued last year for the development of gene therapy in neurodegenerative diseases, is for them to go back and ask for an additional study. Here, the natural history is pretty well elucidated.

We're actually quite excited that we've made significant progress along with our CMO partner there the third scenario, which we think is somewhat unlikely it would be against the FDA guidance issued last year for the development of gene therapy and Neurodegenerative diseases.

R.A. Seshan II: We have three sources of comparatives. Each patient in the interventional trial rolls over from the natural history study. So each patient acts as their own comparator. There's also using the full cohort, natural history cohort, as a comparator. And because the natural history data was so extensive, Because the natural history data was so extensive, you could actually find age-matched controls within that natural history cohort to act as a comparator.

To go back and ask for an additional study here is the natural history is pretty well loose the data we have the resources the comparative each patient in the interventional trial rolled over from the natural history study.

So that's the the lease breaks and access their own comparator.

There's also using the full cohort natural history cohort as a comparator.

And because the natural history data with so extensive.

Because of the natural history data was so extensive.

You can actually find age matched controls.

It within that natural history cohort to act as a comparator. So we're pretty fortunate that the level of robustness of the data the long term durability of the data. We now have pathological change, where we actually see regeneration of nerve fibers.

R.A. Seshan II: So we're pretty fortunate that the level of robustness of the data, the long-term durability of the data, we now have pathological change where we actually see regeneration of nerve fibers, you know, from biopsies that were taken pre- and post-treatment. So we feel pretty good about the data set that we're going to go in and talk to regulators about. This should be extremely compelling. But those would be the three scenarios in the U.S. Ex-U.S., we think this lines up perfectly for the conditional approval pathway based on the data set today, and that's going to be our conversation with the EMA regulators later this year. Farting's questions coming from the line of Jack Allen with Baird. Please answer them.

You know from biopsies that were taken pre and post treatment.

We feel pretty good about the data set that we're going to go in and talk to regulators about this should be extremely compelling, but those would be the three scenarios in the U S. Ex U S. We think that lines up perfectly for the conditional approval pathway based off the data set today and that's going to be our conversation with the regulators later this year.

Our next question is coming from the line of Jack Allen with Baird. Please proceed with your question.

Alright. Thank you so much for taking the questions and congratulations on all the progress I guess the first one I wanted to stick in Gan and talk about tissue on 20, <unk>, maybe you could provide a little bit more context around the gating factors surrounding a gaining regulatory clarity or do you have a meeting on the calendar with the FDA in.

R.A. Seshan II: Hi, thank you so much for taking the questions and congratulations on all the progress. I guess the first one I wanted to stick in again and talk about Taysha 120. Maybe you could provide a little bit more context around the gating factors surrounding gaining regulatory clarity here. Do you have a meeting on the calendar with FDA and any comments around when you may have clarity around the timeline in greater detail than mid 2022.

Any comments around when you may have clarity around the timeline.

In greater detail than mid 2022 and then I was just curious how the genetic testing program is going as well any comments you can make around our early findings from that and if you would consider presenting that data I think it would be quite interesting to see a little bit more insight into the epidemiology of Dan as well.

R.A. Seshan II: And then I was just curious how the genetic testing program is going as well. Any comments you can make around early findings from that, and if you would consider presenting that data? I think it would be quite interesting to see a little bit more insight into the epidemiology of GAN as well. Thanks, Jack, for the questions.

Thanks, Jack for the question, but I think the easy answer is the current guidance is.

R.A. Seshan II: I think the easy answer is the current guidance for regulatory feedback is mid-year 2022, so I think we're going to probably just stop at that guidance without any further level of specificity. You know, obviously, as the agencies recover from, you know, COVID and meeting requests associated with COVID approval, they're continuing to approve the vaccines associated with that. Getting meetings on the books and having those meetings actually stay on the book has been, you know, somewhat of a..., somewhat of an issue.

Regulatory feedback it is mid year 2022, so I think we're going to probably just stopped.

At that guidance without any further level of specificity.

Obviously as the agencies recover from Covid and.

Media requests associated with Covid approval, they're continuing to approve.

Vaccines associated with that getting meetings on the books and having those meetings actually stay on the book.

It has been somewhat.

Hum.

So somewhat of an issue, but what I will say I think we're comfortable with the guidance.

R.A. Seshan II: But what I will say is that we're comfortable with the guidance of mid-2022. And so, we'll essentially stop there with any further detail around guidance. And once we have more specificity, I'll be happy to give that to you. Or once we have that feedback in hand, I'll be happy to give that to you.

Our 2022, and so we'll essentially stopped there with any further detail around guidance and what we.

Have more specificity happy to give that to you are once we have that feedback in hand happy to give that to you.

R.A. Seshan II: And I think what was pretty interesting about some of the information that we've received is that certainly there are more patients out there than I think the epidemiology that's in the literature actually lets on. Just anecdotally, we had a pretty interesting situation where we were speaking with an investor on a Friday afternoon.

As far as the genetic testing panel.

We've actually gone quite well and I think it's what was pretty interesting about some of the some.

Some of the information that we've received it certainly there is theres more patients out there that I think the epidemiology thats in the literature actually lights on.

Anecdotally.

We had a pretty interesting situation, where we were speaking with an investor on a Friday afternoon, we get a call on Saturday.

R.A. Seshan II: We get a call on Saturday. And essentially, the investor's colleague next-door neighbor was diagnosed with GAN. So, that kind of gives you a little bit of context that I think now that the data set is out there. And I think, you know, having the positive data set out there and the availability potentially of additional patients being dosed, you know, patients tend to find you. And this is just normal for rare disease.

And essentially the Investor colleague next door neighbor was diagnosed with Gan so that kind of gives you.

A little bit of context, but I think now that the data set is out there and I think you know having deposit.

The positive data set out there and the availability potentially additional patients being dosed.

Patients tend to find you and this is normal for rare disease and this is what we're seeing.

Our next question is coming from the line of Kevin <unk> with Oppenheimer.

R.A. Seshan II: And this is what we're seeing. Our next question is coming from the line of Kevin DeGeter with Oppenheimer. Okay, great. Thanks for taking our questions. Maybe a two-part question with regard to manufacturing. You know, can you provide enough days to whether, you know, the strategic refocusing has, you know, any impact on the build out of it and how it affects manufacturing capacity and then kind of, within the cash runway assumption, you know, how should we think about catbacks to investment manufacturing. Thank you for your time.

Okay, great. Thanks for taking our questions maybe.

Two part question with regards to manufacturing.

You know can you provide an update as to whether you know the strategic refocusing has any impact on the build out of in house manufacturing capacity and then kind of.

Within the cash runway assumption, how should we think about how capex and investment in manufacturing.

Yeah, Kevin Thanks for the question, obviously manufacturing is strategically important to the company, particularly as we are embarking on to wanting a validation run for a commercial grade material second an extremely large and.

R.A. Seshan II: Yeah, Kevin, thanks for the question. Obviously, manufacturing is strategically important to the company, particularly as we're embarking on one of the validation runs for commercial grade materials, second, an extremely large indication in right syndrome. So what I'll say is, again, manufacturing continues to be strategically important to the company. We think it's one of the aspects that sets the company up and differentiates the company from some of our peers out there.

Extremely large indication in ret syndrome. So so what I'll say it again manufacturing continues to be strategically important to the company. We think it's one of the aspects that sets the company up.

And differentiates the company from <unk>.

Some of our peers out there and so that disease that remains a strategic focus.

R.A. Seshan II: And so that could be the remaining strategic focus. It's for if you remind me of your second question. Yeah, within the cash runway guidance, you know, how should we think about, you know, maybe cumulative cash fax or some other metric across that time frame. Yeah, I think Kevin, we're not going to provide additional guidance around what we've already provided around expense management and cash management, where cash extends until Q4 of 2023.

Sorry could you remind me of your second question.

Second part was just yeah.

Within the cash runway guidance you know how should we think about you know maybe cumulative capex or some other metric across that timeframe.

Yeah, I think Kevin we're not going to provide additional guidance around what we've already provided around expense management and cash management, where cash extends until Q4 of 2023, but I think again just to answer your question CMC.

R.A. Seshan II: But I think, again, to just answer your question, CMC, for a gene therapy company and to continue with our history, understanding where the bulk of the management team and board came from, you know, controlling your own destiny remains a key strategic focus of the organization. So I think that's where we'll probably stop from a guidance perspective. Thanks. Our next question is from the line of Gil Blum with Needham & Company. Hello everyone, can you hear me?

For a gene therapy company and they continued with our history.

Standing where the bulk of the management team and board came from.

You know controlling your own destiny remains a key strategic focus of the organization. So.

I think that's where we'll probably stop from a guidance perspective.

Thank you. Our next question is from the line of Gil Blum with Needham <unk> company.

Hello, everyone can you hear me.

R.A. Seshan II: Yep, we can hear you. Okay, maybe just kind of a general question about RAS here. So, because it's a relatively larger indication, would you also expect the studies to be larger or more expensive on that account? Thank you. Hi Gil.

Yes, we can hear you.

Okay.

Maybe just kind of.

General question about.

Sure so because it's a relatively larger indication.

So expect those studies to be larger or more expensive to that oh.

Thank you.

R.A. Seshan II: That's a very insightful question. And I think, as you can, the larger the opportunity, obviously, the larger the study. I'll pause and let Suya stand there.

Hi Gil.

Very insightful question and I think as you can the larger the opportunity obviously the larger the study I'll I'll pause and let's see you guys to answer but I think the short answer to your question is yes, and I think when you start to look at the strategic prioritization. This is one of the reasons why.

We did we've done what we've done to put ourselves in the best position in order what do we have ret data.

This is the organization broadly understanding the development cost per rep. Both on the clinical side, but also on the CMC side are going to be quite extensive I'll stop there and let's see.

Chairman.

R.A. Seshan II: But I think the short answer to your question is yes. And I think when you start to look at the strategic prioritization, this is one of the reasons why, you know, we've done what we've done to put ourselves in the best position in order, when we have RET data, to position the organization broadly, understanding the development costs for RET, both on the clinical side, but also on the CMC side, are going to be quite extensive. But I'll stop there and let Suya chime in.

Sure.

Great question Bill.

Essentially what I want to say that the studies.

Dr. Suyash Prasad: Sure, um, great questions, Bill, and, uh, essentially you're right. I want to say that... And we think what I will say is that the Central Trial Court was always going to be big. And it's been a few reasons, we're in the first of all, it is a huge month of opportunity as you bore you there.

Size of the clinical trial program as a whole.

It's been two reasons first of all it is.

The huge market opportunity.

Dr. Suyash Prasad: There's also a little bit more focus on the safety matters with regard to, given the fact that there's a risk of overexpression of NET-P2. And so you've got to be a little bit more cautious and safe. That's why as a whole, we're really going to start our clinical trial, as you will have heard from Mehdi this week, we now have an open CTA in Canada, which we are very excited about and ready to start facing patients.

The old site.

A little bit more focus on our site on our site.

With regard to what.

Given the.

The risk of over expression to let's say go they're living more closer to the site.

That's why Oh, we're really going to stop the trial as you will have heard from other this wait and see.

C J caliber, which we're very excited about.

Ready to start dosing.

Thanks, guys.

Dr. Suyash Prasad: And as a whole, we're going to start with an adult study. Prove and safety, looking at some gloomy accuracy. Ashley Does, a handful of outlets with Van, moved into a pediatric girl study, where the bulk of the patients were better and where we think that the greatest opportunity for improvement will be, although we think all patients with Rett will improve regardless of age.

As a whole we're going to start with a pilot study.

Primarily safety they looked at some preliminary efficacy.

Dose levels will boldly into a pediatric study.

Well the bulk of the patients with Brent So we think that the greatest the greatest opportunity.

Although we think all patients with the threat will improve regardless of age.

Dr. Suyash Prasad: And then shortly after that, we will also start a pediatric boy's study, which is a somewhat unusual thing to do given that there are only a small number of boys around, but the boys, you'll probably remember, have no MECCP2 or so on, so they're very severely affected. The vast majority of them die in utero, and only a handful of them survive, so there may be only two or three hundred boys in the world with it, but we can do some kind of rescue study there and demonstrate an improvement, and, of course, because they have no MECCP2, you're not so worried about over-expression toxicity in these boys; it could actually provide a potentially expedited path to conditional approval.

Shortly after that we will also start a pediatric voice.

Somewhat unusual things do take a look at.

A small number of voice, but the boys.

You'll probably remember.

Domestic fuel swaps are very severely affected the vast majority of the R&D.

He's right outlook will survive.

So it May then be till 300 voice in the world with the digital kind of rescue spoke with them.

On the strength of the frameworks and of course, because I've learned to not so worried about over expression consist in these boys it could actually provide the potential that the Gulf coast.

Additional critical so that's how we're approaching the right situation as a whole yes, the only thing that I would add to what <unk> just mentioned.

Dr. Suyash Prasad: So that's how we're approaching the Rett situation as a whole. Yeah, the only thing that I would add to what C.S. As I just mentioned, when you start to think about the Rett boys, not only do they offer an accelerated pathway to approval just because of the nature of the phenotype, but the biology of the boys is quite similar to the biology of the animal models that we have for Rett. Essentially, the industry standard animal model for Rett is the knockout mouse model.

When you start to think about the Rep boys not only do they offer a an accelerated pathway to.

To an approval just because of the nature of the phenotype. The biology of the boys are quite similar to the biology of the animal model that we have already essentially.

The industry standard animal model for Rep is the knockout mouse model essentially that model.

R.A. Seshan II: Essentially, that model has no MECCP2, and that's basically what we're seeing in the boys in the biology of their disease. And so, as C.S. mentioned, there really is less of a concern around over-expression, but I think when you start to look and correlate the IND-enabling pharmacology studies one-to-one, you see, we're seeing across a number of different functional outcomes, respiratory outcomes, motor function, and a number of other functional assessments.

<unk> has no <unk>, that's basically what we're seeing.

And the boys.

And the biology or their disease and so as soon as you mentioned there really is less of a concern around over expression, but I think when you start to look and correlate.

The IMD, enabling pharmacology studies one to one.

We're seeing multiple age groups.

A significant improvement across a number of post the functional outcomes.

Victoria outcome.

Motor function.

R.A. Seshan II: And again, when you even dose earlier in the neonates, we're seeing a normalization of survival or preliminary data suggests a normalization of survival. So, this gives us a lot of confidence that, you know, the opportunity and really our goal is to not leave a patient behind here in this population. It's a large indication.

And a number of other functional assessment and again when you even dose earlier in the neonates, we're seeing a normalization.

Survival or preliminary data suggests a normalization of survival so let's see.

Gives us a lot of confidence that the opportunity and and really our goal is to not leave a patient behind here in this population the large indication Jeff.

Associated with the girls, we're talking about 350000.

Patients worldwide. So it's a massive indication.

The massive indication but.

For us.

It's more important to make sure that all patients are addressed.

R.A. Seshan II: Just associated with the girls, we're talking about 350,000 patients worldwide, so it's a massive indication. It's a massive indication, but for us, I think it's more important to make sure that all patients are addressed. Our next question comes from the line of Laura Tiko, with web-bushed securities, please just- Hey, good morning, guys. Thanks very much for taking the question. I guess I wanted to circle back on the cash runway. And with the changes, I just wanted to clarify how long the cash runway was extended. And as it relates to the GAN program, I just want to understand the base case scenario.

Our next question comes from the line of Laura Chico with Wedbush Securities. Please proceed with your question.

Hey, good morning, guys. Thanks, very much for taking the question I guess I wanted to circle back on the cash runway and with the changes I just wanted to clarify how how long the cash runway was extended and as it relates to the Gan program I just want to understand the base case scenario you have.

R.A. Seshan II: So you have around 120, and you walk through the options there, RA. But I guess how would cash runway change if we had to go through kind of that extreme scenario where there was an additional study requested? Thanks very much.

Around 120, and you walked through the options there are a but I guess, how would cash runway change. If we had to go through kind of that extreme scenario, where there is an additional study requested thanks very much.

Thanks, Laura I'll take your second question first Mike.

R.A. Seshan II: Thanks, Laura. I'll take your second question first, because it's top of mind. So, when you start to think about if the FDA came back with an option of doing a pivotal study in GAN, just because of the patient population, it would be a pretty small study. We would essentially roll over patients that are currently in the natural history study. There's about 50-plus patients in the current natural history study, of which about 40 of them haven't been dosed.

So when you start to think about it the FDA came back with an option of doing a pivotal study in Gan.

Just because of the patient population that would be a pretty small study.

We would essentially rollover.

Rollover patients that are currently in the natural history study, there's about 50 plus patients in the current natural history study of which about 40 of them haven't been dosed. So the patients are there. So there is no kind of need to go search for patient, but you wouldn't have to do some type of big patient finding opportunity.

R.A. Seshan II: So, the patients are there. So, there is no kind of need to go search for patients, but you wouldn't have to do some type of big patient-finding opportunity. So, but ultimately, ultimately... The catch one way would be really minimally impacted.

So, but ultimately ultimately.

The cash one way would be really minimally impacted I think.

R.A. Seshan II: I think, you know, when you start to think the clinical development for gene therapy trials, these trials are relatively small and the cost associated with conducting these trials are relatively small. The bit cost is associated with the production of G&P manufacturing, right? And the use of external third parties to do that, which is what makes having your own manufacturing facility so strategically important because just one being able to get a plot at a high quality manufacturer and the cost to do that are pretty high.

Are you starting to think of.

Clinical development for gene therapy trials these trials.

Relatively small and the costs associated with conducting these trials are relatively small the bit cost is associated.

<unk> with the production of GMP manufacturing right and.

The use of external third parties to do that.

Is what what makes having your own manufacturing facility.

Particularly important because.

One of them being able to get a slot at a high quality manufacturer and the cost to do that.

Are pretty high.

R.A. Seshan II: The difference between scenario one, which would be to do analytical comparability, the base case, which would be to dose a few more patients under the current protocol with commercial grade material once it's available, and the third scenario, which if you had to do, if you had to do another complete study, the cost would be, I would say, from scenario two to scenario three are pretty much the same because you've already embarked on the production. G&P material that's commercially validated, so your commercial grade material, that's where the big costs are.

Between scenario, one which would be to do analytical comparability the base case, which would be the dose a few more patients under.

The current protocol with commercial grade material once it's available and the third scenario, which if you had to do.

If you had to do another complete study the cost of our I would say both scenarios you just never know who you are pretty much the same because you've already embarked on the production.

R.A. Seshan II: So it really would have minimal to no impact on cash runway, the difference between honestly scenario one, two or three because you're already doing the big cost impact, which is manufacturer of commercial grade G&P material. So that's your, that was your second question. Your first question was around the extent to the cash runway. I think we previously got it to cash being into the second half of 2023.

<unk> materials that commercially.

That's commercially validated so your commercial grade material, that's where the big cost. So it really would have minimal to no impact on cash runway. The difference between honestly scenario, one two or three because youre already doing the big cost impact, which is a manufacturer of commercial <unk> GMP material.

So that's that's your board that was your second question. Your first question was around the extension of cash one way I think we previously guided guided too.

Cash being into the second half of 2023, we essentially have been fortunate to extend cash runway.

R.A. Seshan II: We essentially have been fortunate to extend the cash runway by quarter into 2024. Our next question comes from the line of Yoon Jung with BTIG. Please proceed. Hi, good morning.

By quarter into 2020.

Into Q4 of 2023.

Our next question comes from the line of young Chung with BTG. Please proceed with your question.

Hi, Good morning. Thank you very much for taking the question. So on the Ret syndrome I assume it's a dose finding study. So was curious how are you going to what kind of a markers will allow you to decide that you are getting close to the optimal dose and also on the efficacy readout and any potential sit.

R.A. Seshan II: Thank you very much for taking a question. So on the red syndrome, I assume it's a dose-finding study so it was curious how are you going to or what kind of markers will allow you to decide that you are getting close to the optimal dose. And also the efficacy readout any potential signal for efficacy. And I think we, Previously talked about the potential biomarkers and the EEGB one of them and them. I'm curious, would that be included in the data readout by year and any additional markers? Sure, let me make a couple of comments.

No for efficacy and I think a week.

Previously you talked about the potential biomarkers and the E E. G. P. One of them and I'm just curious would that be included in the data read out by year end any additional markers.

So let me make a couple of comments.

Dr. Suyash Prasad: The two posters, you're on the defense, the Lincoln Study and Adults, the MLs of Web, the initial start event is a Friday 14th total VG dose, and there's a provision to escalate up to the 2015 total future. Now I think the most simple thing here is that we have an incredibly robust, It's what, you know, allow us to have the CTA open and we've had a lot of track reports with the regulators of some of the details.

The.

The dose that you're on the business the license stuffing in adults.

With what the initial softness Bobby Bolting total BG does.

Escalate up to the $1 15, BJ now I think the most important thing here is that we.

An incredibly robust preclinical package.

It's well.

Allowed us to have the CGI open without the other.

With the regulators on some of the details.

And the.

Is it like a neighborhood.

Dr. Suyash Prasad: And the prequel package, the idea made with the help of a group of hackers, was designed out of three studies that built on many, many years of work. The, So, the most important study from a dose binding perspective is our pharmacology study, which we ran in 252 mice with Rex and Joe, wild-type mice, so 12 cohorts. 21 cohorts, and we looked at a number of different doses, a number of different age time points of dosing mice, and the whole spectrum of parameters, all of which translate nicely to clinical outcome measures. For example, we looked at the gait of these mice, the importance of performed practice, multiplicity of breathing, and a whole host of other assessments.

This is andre.

The bolt on many many years of what Steve O'brien Cyrus football.

So the most important study for Us Army perspective.

Apologies public, which we ran in the children 52.

Mice with Brexit very ballpark wise.

With 12 cohorts.

So I told you one cohorts.

We looked at a number of different bases among the different age it's fine.

Mike.

So spectrum all.

<unk> all of this translate not plentiful.

So let's just for example look at gates these laws important.

Great.

I'm hopeful.

Subsequent well not particular study were able to elicit a minimally effective dose.

Dr. Suyash Prasad: From that study, we were able to elucidate the minimally affected cells. And then, on top of that, we also ran our toxicology studies, both in WETS and NHTs. And the important data was, of course, the NHT data, the viral distribution data, and importantly, we found that with an elevated dose, four-fold over the clinical starting dose, we actually had perfectly clean tox, and our toxicology with no adverse findings, and we have very high levels of DNA, showing good viral distribution, but correspondingly low levels of mRNA, so mechanistically showing that our regulation is working.

And then on top of that we also.

Ram.

Toxicology studies, but the ramp.

AIDS.

The important data with a full scale basis.

Based on the published data and importantly.

It does.

Oh, Paul Auvil clinical starting dose we actually have.

Separately clean socks.

And the bulk sales culture is alive.

The findings on behalf.

Alright highlights of DNI showed good participation.

Following the low levels of online so mechanistically shrunk down regulation of working with anybody from the Hong Kong study on the toxicology study.

Dr. Suyash Prasad: So we took the MEP from the pharmacology study and the toxicology study, the male observable adverse event level, and you can actually hone in on a very good starting dose. And, as I say, the starting dose is 5 and 14, and we got to 1 and 15. Neither of those showed any appreciable toxicity, and we expect both to be efficacious. That's how we selected them. In terms of actual measures, we've got a whole host of actual measures. But you do know, of course, that there are no official, well-known, well-understood biomarkers in serum or in the CSF.

Hello.

Good stuff guys.

As I said as long as as far as in 14. It was up to 115 north of those shows.

<unk> toxicity.

I expect both to be efficacious.

We selected the dose and sales of our commercial offers.

You know both of those.

Official while not well understood by Marcus and serum or CSI, we all looked at a whole host of that spot market as we all know.

Dr. Suyash Prasad: We are looking at a whole host of exposure biomarkers. We are looking at EEG as a potential biomarker as well, and a whole host of different clinical endpoints, the RSPQ, the CGI, the RET-Candida Proxia score, as well as broader efficacy measures such as the brainstem function, restoration, looking at seizure frequency, how many seizures, what's the frequency, what triggers them. So we're going to be guiding our dose selection on the absence of a safety signal, and just in general, progress from a clinical perspective. As I say, EEG will be using the old exposure biomarkers. We're not making any decisions around the biomarkers.

E G.

Biomarkers Wow.

On the whole host of different clinical endpoints the hours he didn't see G E.

Don't see a school.

As wireless.

She measures such as the brain stem function.

Respiration.

Seizure frequency harmonization previously what triggers.

Or would it be the I think the selection of.

The outlets are a safety signal and.

Just in general progress clinical perspective.

<unk> will be using explore hallmark.

Decisions around the bond market is not well understood.

Our next question comes from the line of Susan Chicken with JMP Securities. Please proceed with your question.

Dr. Suyash Prasad: It's not a well-understood. Our next question comes from the line of Silvan Tuerkcan with JMP Securities. Good morning and congrats on all the progress. I just have two quick questions, please. Could you run me maybe in more granularity through your GAN base case in terms of.., getting this into commercial material into a handful of patients. How much will be a handful?

Good morning, and congrats on all the progress.

I just had two quick questions. Please could you run me maybe in more granularity through your base.

R.A. Seshan II: And when could this start? Would it make sense to start right now? Or do you need to wait for your validation run in the third quarter? So how much time till filing? And then my second quick question will be on the CLM-7 program. Now you're going ahead with the first gen construct. Do you think that's good enough or do you just want to get some clinical experience no matter what with this program? Thank you for taking my question. Good morning. Good question.

Base case in terms of.

Getting this into commercial material into a handful of patients how much will be a handful and when could that start when it makes sense to start right now or do you need to wait for your validation run in the third quarter. So how much time to filing and then my second quick question would be on the CLO.

Your line separate program now Youre going ahead with a frist Jim construct.

Do you think thats good enough or do you just want to get some clinical experience no matter what with this program. Thank you for taking my questions.

It's all been good morning. Good question, so starting with the first around the availability of commercially.

R.A. Seshan II: So starting with the first around the availability of commercial GMP material, commercial grade GMP material on GAN. As I mentioned before, we've actually just completed our second engineering run. This was the first with a small scale engineering run at the CDMO partner that went beautifully. The second was the definitive engineering run at scale that also went extremely well. This is we're actually quite fortunate.

Commercial GMP material.

Commercial break GMP material on Gan as I mentioned before.

We've actually just completed that.

Engineering Ryan this was the first with a small scale engineering rung at the CMO partner that went beautifully the second was.

The definitive engineering run at scale that also went extremely well.

R.A. Seshan II: GAN and RET are actually our two highest producing, highest yielding products. And so, you know, one being, you know, on a pathway for regulatory discussion around what the approval pathway looks like. And the second just being a massive indication.

We're actually quite fortunate.

Dan and wrap our actually our two highest producing higher yielding.

Products and so one being.

On a pathway for regulatory discussions.

Round, what the approval pathway looks like in the second guess being a massive indication.

I think this gets really lines up nicely with.

R.A. Seshan II: I think this just really lines up nicely with, you know, how we're thinking about prioritizing our efforts this year. So we're actually quite excited about that. Our definitive GMP run for the commercial grade material just kicked off, and we expect that material to be available in Q3. This would either be the material that would support if we're able to do analytical comparability and the agency agrees with that, that would be scenario one, which would be the best case scenario. This would be the material that would support that DLA.

How we're thinking about prioritizing our efforts this year. So we're actually quite excited about that our GMP definitive.

The definitive GMP run.

For the commercial grade material, just kicked off and we expect that material to be available in Q3. This would either be the material that would support.

We were able to do analytical comparability and B. If the agency agrees with that that would be scenario, one which would be the best case scenario.

This would be the material that would support that that DLA I still think even in the best case, it would be more of a rolling submission because there will be some still some additional work from an analytical perspective.

R.A. Seshan II: I still think even in the best case, it would be more of a rolling submission because there will be some, still some additional work from an analytical perspective that would need to be completed. From a base case, which we consider scenario two, kind of the base case, you would still need this material to be released in order to commence dosing a few more patients under the current protocol. And so kind of what you would do for scenario one, scenario two, and scenario three really are really the same activities. You need commercial grade material.

That would need to be completed.

From a from a base case, which we consider scenario to kind of the base case.

You would still need this material to be released in order to commence dosing a few more patients.

Under the current protocol and so kind of what you would do for scenario one scenario to a scenario of three.

Really are really the same activities you need commercial grade material, you're going to either under scenario, two and three need to dose additional patients with commercial grade material under scenario. One do you need a commercial grade material in order to support the BLA.

R.A. Seshan II: You're going to either under scenario two and three need to dose additional patients with commercial grade material. Under scenario one, you need the commercial grade material in order to support the DLA in order to eventually commercialize the product. So, you know, all the activities are the same, but from a timing perspective, we expect that material to be released in Q3 of this year. But as I mentioned, the two engineering runs, small scale and large scale engineering runs, kicked off and completed quite nicely.

In order to eventually commercialize the product. So all the activities are the same but from a timing perspective, we expect that material to be released in.

In Q3 of this year, but if.

As I mentioned, the two engineering run small scale and large scale engineering run.

Kicked off and completed quite nicely and we've recently kicked off.

R.A. Seshan II: And we've recently kicked off the commercial grade GMP run. So we're pretty excited about the progress there and the prioritization. Our next question is from the line of Kristen Kluska with Kantor.

The commercial grade GMP run so we're pretty excited about the progress there.

The prioritization.

Our next question is from the line of Kristen <unk> with Cantor. Please proceed with your question.

Good morning. This is Rick on for Kristen. Thank you for taking our question in terms of the prioritized programs announced today could you. Please talk a little bit about the potential for grants or other non dilutive funding opportunities around these indications for example, we understand their federal funding Bill was recently passed supporting funding for.

R.A. Seshan II: Thank you for taking our question. In terms of the prioritized programs announced today, could you please talk a little bit about the potential for grants or other non-delutive funding opportunities around these implications? For example, we understand that a federal funding bill was recently passed supporting funding for RET syndrome research. Thank you. Thank you. No, it's a really good question.

Or ret syndrome research. Thank you.

No.

R.A. Seshan II: I think, you know, for RETT, obviously, RETT and GAN are squarely within the activities that we have prioritized, and that's where the bulk of our R&D investments are going. But certainly, we always look for additional opportunities for non-dilutive financing, whether that's through grants, government grants, or advocacy grants we've done in our history. We just haven't spoken a lot about them, but what we've done in the past is collaborate very closely with advocacy groups where they funded a lot of the early proof of concept work.

Really good question I think.

Obviously ready Dan are squarely within the activities that we have prioritized and thats, where the bulk of our R&D investments are going but certainly we always look for additional opportunities for non dilutive financing either that's two grants government grants advocacy grants we've done in our history.

We haven't spoken a lot about them, but what we've done in the past they collaborate very closely with advocacy groups, where they funded a lot of the early proof of concept work.

R.A. Seshan II: And we've kind of taken a program over once we've gotten to a definitive animal proof of concept in order to do the IND-enabling top studies and the IND-enabling pharmacology studies and kind of win the big dollars that you need associated with GMP manufacturing before you go into a clinical trial. So.

And we've kind of taken a program over once we've gotten to a definitive.

Animal proof of concept in order to do the IND, enabling.

Tox studies, and the IND, enabling pharmacology studies and kind of when the big dollars that you need associated with GMP manufacturing before you go into a clinical trial. So.

R.A. Seshan II: So these things are always top of mind. And in our history, I think we've always looked for ways to bring in non-dilutive forms of financing, particularly even more important in a situation where the market is, from a macro perspective, a little bit uncertain, right? Geopolitical downturns and a number of other issues that are macro that aren't specific to the company.

So these things are always top of mind and in our history. I think we always look for ways to bring in non dilutive forms of financing, particularly even more important.

Situations, where the.

Marketed from a macro perspective is a little bit uncertain right geopolitical.

<unk> sector and a number of other issues that are that are macro that are arent specific into the company.

R.A. Seshan II: Including looking at potential business development opportunities, particularly with programs that we see broad therapeutic potential, but unfortunately just haven't hit our level of prioritization. Now again, we always have the opportunity to revisit that, you know, if and when situations change. But today, what I would say for clarity, the company is focused on the guidance that we've given you guys today. So that's just, that's where we are. But I think to your question, we always look for non-dilutive ways, along with our partners at Advocacy, along with our partners at UT Southwestern for non-dilutive funding.

Including looking at potential business development opportunities, particularly with programs that we see broad therapeutic potential.

But unfortunately that haven't hit.

Our level of prioritization now again, we always have the opportunity to revisit that.

If and when situations change, but today, what I would say for clarity. The company is focused on on the guidance that we've given you guys. Today. So that's just that's where we are but I think to your question we always.

Look for non dilutive way, along with our partner that advocacy along with our partners at Ut southwestern for non dilutive funding I.

R.A. Seshan II: I just wanted to answer Sylvan's second question and apologize to Sylvan for skipping over it around the CLN7. To clarify, the CLN7 program has actually gone quite well. As C.S.

I just wanted to answer building.

Second question and apologize building for four skipping over at around.

C L. <unk> survey to clarify the field of seven programs have actually gone quite well.

R.A. Seshan II: mentioned, we've recently dosed the fourth patient, which is the third patient dose at 1E to the 15th, which is the highest dose ever given inter-fegally in a gene therapy trial. Patient safety was reported at World Symposium earlier this year. These patients continue to do well. And ultimately, I think you guys have heard me say this before, if it's not broke, don't fix it.

As mentioned, we recently dosed the patient which is the third patient dosed at 115, which is the highest dose.

Ever given equally in a gene therapy trial patient safety was reported at wells Symposium earlier. This year. These patients continue to be well.

And ultimately I think you guys have heard me say this before it's not broke don't fix it and so we're going to continue to focus solely on the FERC generation construct because ultimately that's going to allow for faster pathway to registration. So that's really what's kind of let it fair, but future development will be focused solely.

R.A. Seshan II: And so we're gonna continue to focus solely on the first generation construct because ultimately that's gonna allow for a faster pathway to registration. So that's really what kind of led us there, but future development will be focused solely on the first generation construct. Thank you both for the questions. Thank you. Our next question is from the line of Yun Yang with Jeffreys.

On the first generation contracts.

Thank you both for the questions.

Thank you. Our next question is from the line of Union with Jefferies. Please proceed with your question.

Thank you. Thank you. Thank you for taking my questions. So I have a question on Gan So talk for the toward the end of last year, you mentioned that.

R.A. Seshan II: Please proceed with your question. Thank you, thank you, thank you for taking my questions. So I have a question about GAN.

R.A. Seshan II: So for the tool in the last year, you mentioned that, I think you're meeting with the ex-U.S. regulatory agency scheduled in January, so have you met with them? I know you are not going to provide an update until mid of this year, but just wanted to check if you have met with them. And also in the U.S., you talked about three scenarios for some time. It sounds like option two could be a likely option when you meet with the FDA. If it is option two, what would be the timing for BLA filing?

The meeting with the extra regulatory ex U S regulatory agency scheduled in January .

And then I know you are not going to provide an update on until later this year, but I just wanted to wanted to tag. If you haven't met with them and I'll say in the U S. So you talked about still be.

Scenarios here for some time it sounded like a option to could it be a likely option when you meet with FDA.

The F D a.

If all you need to option two why would it be the timing for P. L. E filing I think in the past you mentioned in around mid 2023.

R.A. Seshan II: I think in the past, you mentioned around mid-2023, so want to get your updated view on that. And lastly, Ari, you mentioned that your cash one-way has been increased by one quarter, so should we really, Think about... The reduction in workforce by 35% leads to one-quarter extension in the cash runway.

So when I gave you our updated view on that and lastly, I.

I mean, you mentioned that.

One way has been increased by one quarter. So.

She didn't even really.

Think about it.

Cause reduction in work force by 35%.

These tier one corner.

So an indication one way.

Thank you.

R.A. Seshan II: Thank you. Thanks for the question. So, starting with your first question around regulatory, we have previously guided that we did conduct a meeting in late January with an ex-U.S. regulatory authority around scientific advice for our GAN program. We're still awaiting formal meeting minutes from that program or from that meeting. And, you know, once we have all of the formal meeting minutes, both from this regulatory meeting as well as the regulatory meetings that will be scheduled with the U.S. agency and other agencies, we'll make sure to summarize those and provide that guidance and update that guidance once we have the formal feedback. But it would just be premature for me to speak kind of outside of school about meeting minutes.

Thanks for the question so.

With your first question around regulatory we have previously guided that we did conduct the meeting.

In late January with the ex U S regulatory authority around scientific advice for our <unk> program. We are still awaiting formal meeting minutes from that from that program or from that meeting and.

Once we have all of the formal meeting minutes, both from regulatory meeting as well as the regulatory meeting that'll be scheduled with the U S Agency.

And other agencies will make sure to summarize those and provide that guy he's been update that guidance. Once we have a formal feedback but it would just be premature for me to speak kind of outside of school about.

R.A. Seshan II: Certainly, the tone was of a good meeting. It was a long meeting, and they were quite interested.

Meeting minutes certainly the tone was a good meeting.

It was a long meeting they were quite interested.

Data the data obviously.

Laid it out is compelling, but again I want to make sure that we have final meeting minutes in hand before we before we provide any additional feedback on that around Gan, specifically I think you're absolutely right.

R.A. Seshan II: The data, obviously, as we laid it out, is compelling. But, again, I want to make sure that we have final meeting minutes in hand before we provide any additional feedback on that. Regarding GAN specifically, I think you're absolutely right.

We've kind of.

Coalesced around scenario too as the base case, and that's kind of the case that that we are planning for internally what I would say is the difference between scenario too.

R.A. Seshan II: We kind of coalesced around Scenario 2 as the base case, and that's kind of the case that we're planning for internally. What I would say is the difference between Scenario 2, of dosing a few patients under a handful of patients under the current protocol, and Scenario 3, doing a second study, is it's probably six to eight months. There's not much of a gap, really, between either one of those scenarios.

Don't think if you're a patient under.

Ample a patient under the current protocol in scenario three.

Doing a second study.

Probably six to eight months theres not much of a gap really between either one either one of those scenarios. The reason for that is because all the patients are identified.

R.A. Seshan II: The reason for that is because all the patients are identified. You're not going out to have to identify patients. This would essentially be a rollover from the natural history study. As I mentioned, there's already 50-plus patients in the natural history study, of which only 14 of those patients have been dosed. So, you could think about 40 or so of those patients haven't been dosed, and we continue, as I mentioned, to identify patients on an ongoing basis quite successfully. So, from an enrollment perspective, He really will have an issue from a timing around his enrollment.

Going out to half to identify patients this would essentially be a rollover from.

This would essentially be a rollover from the natural history study as I mentioned is already 50 plus patients in the natural history study of which only four.

<unk> of those patients have been dosed. So you could think about 40 or so of those patients havent been dosed and we continue as I mentioned to identify patients.

On an ongoing basis quite successfully.

So from our perspective.

And you really wont have an issue.

From a timing around an enrollment.

More so the timing is associated with the availability of commercial grade material and then as I mentioned that material would be available in Q3. So if you would take scenario two which is very similar to the gold's gym scenario from our previous life.

R.A. Seshan II: More so, the timing is associated with the availability of commercial grade material, and then, as I mentioned, that material would be available in Q3. So, if you would take scenario 2, which is very similar to the Volginsma scenario from our previous life, where essentially, the FDA approved Volginsma on the basis of the original nationwide children study. And then, those original patients, I think it was close to about 10 patients that were dozed in that study.

They're essentially the FDA.

The FDA approval on the basis of the original.

Of the original nationwide children study.

And then those original pace in but I think it was close to about 10 patients that were dosed in that study they didn't allow that.

R.A. Seshan II: They didn't allow a vexas nabartus at the time to supplement the data set with data from the pivotal study with their commercial material that was being delivered from Liberty Bill, which was the commercial manufacturing facility located up in Chicago. And so, this would essentially be the pathway that we are considering as the best case, because it's the best cop that we have out there. This is a rare pediatric life threatening neurodegenerative disease, where there's no therapeutic alternative.

Novartis at the time to supplement the dataset with data from the pivotal study.

With their commercial material that would be delivered.

From Liberty Bill.

Which would be a commercial manufacturing facility located up in Chicago and so this would essentially be the pathway that we are kind of considering as the best case, because it's the best that we have out there. This is a rare pediatric life threatening neurodegenerative disease, where there's no therapeutic alternative.

R.A. Seshan II: In the case of Volginsma, there was actually a therapeutic alternative and approval ahead of that in Spinn-Raza. In the case of Johnny, from neuropathy, there's nothing. And so, you know, certainly in our conversations with advocates, advocacy in our conversations with KOL, we pressure tests that are thinking, and we think this would be the optimal approach to potentially go into. Now, we're going to go in and do our best to convince the agency around scenario 1.

In the case of old games, where there was actually a therapeutic alternative.

Approval ahead of that it's been rather in the case of Johnny come on rapidly Theres nothing.

So certainly in our conversations with advocate advocacy and our conversations with Kols, we pressure tested our thinking and then we think this would be the optimal approach to potentially go in they go into now we're going to go in and do our best to convince the agency around scenario, one, but I think realistically I think.

R.A. Seshan II: But I think realistically, I think what we're going to do is plan for a mid, you know, somewhat of a mid case, which would be scenario 2. That would allow us to either initiate a rolling submission at the end of this year or the beginning of next year, and ultimately lead to an approval either late. And when I say late, into the year 2023 or early 2024 in the US. Obviously, the pathway in Europe is quite different.

What we're going to do with the planned for.

Somewhat.

Of a mid case, which would be the scenario two that would allow us to either.

Instigate a rolling submission at the end of this year or at the beginning of next year.

And ultimately lead to an approval either late.

And when I say late into the year 2023, or early 2020 in the U S.

R.A. Seshan II: We feel strongly that we need guidance around the conditional approval pathway, and that's going to be our goal in our conversation with the EMA regulators is really how to accelerate registration options for this program under the conditional approval pathway. And so that's going to be our goal. And so we want to be in the position, if the regulators agree, which, again, with the data set that we have in hand, we think there's a strong possibility to initiate a rolling submission by the end of this year.

Obviously that the pathway in Europe is quite different we feel strongly that we need.

The guidance around the conditional approval pathway and that's going to be our going in.

Conversation with the EMA regulators.

It's really how to accelerate.

How to accelerate registration option for this program under the conditional approval pathway and so that's going to be our goal and so we want to be in the position if the regulators agree which again with the datasets that we have in hand, we think there is a strong possibility to initiate a rolling submission by the end of this year.

Thank you.

Our next question is from the line of Sami Corwin with William Blair.

R.A. Seshan II: Thank you. Our next question is from the line of Sammy Corwin with William, Hey, guys, thanks for taking my questions. For the RET study, will there be different outcome measures for patients depending on their age or disease stage? And then can we expect any data this year from the CLN1 or CLN7 clinical trials? Thanks. Hey Sammy, good morning.

Hey, guys. Thanks for taking my question.

For the Ret study will there be different outcome measures for patients depending on their age or disease stage and then can we expect any data. This year for me feel N, one or ceiling setting clinical trial.

Hey, good morning. Thanks for the question could you repeat your first question I'm, sorry, we couldn't hear you.

R.A. Seshan II: Thanks for the question. Could you repeat your first question? I'm sorry, we couldn't hear you. Oh yeah, well there are different outcome measures for patients in the reptile depending on their disease state. It's a really good question, so if you want to tackle that first. In general...

Oh, yeah, well there'd be different outcome measures for patients in the trial, depending on their disease stage.

No.

Really good question, so as you might tackle tackle that first one yeah.

And in general.

Yes, yes or no.

Dr. Suyash Prasad: Yes, yes, and no, I just want to say that instead of the day, we're going to be looking at similar broad buckets of efficacy measurements, regardless of age, so we'll be looking at specific WREC assessments such as the RSPQ, such as the motor behavior assessment, the Hound Doge Practical Scale. We'll be looking at certain seizure measurements, EEGs, for example, and seizure values. We'll also look at respiratory assessments, the respiratory distress index, sleep apnea, etc. Communication assessments, the ORCA quality of life assessments, plus a whole host of different biomarkers, which we'll be looking at in the next few slides.

They.

We're going to be looking at.

Similar.

What buckets of efficacy message regardless of that.

Specific breakfast estimates.

It is.

Such as the most behavior assessments and practice fell well below certain Asian Nationals AE Jeans for example, Ctrip will go.

Spirit assessments, the restriction distressing that sleep apnea et cetera.

Can the Acacia assessments.

The.

Okay block assessments across a whole host of different biomarkers.

Richard.

Thank you.

Our next question is from the line of David Ho with F N B C.

Dr. Suyash Prasad: Thank you. Our next question is from the line of David Holm with SMB. Hey, thanks for providing the update and taking my questions. So, I just had a few.

Hey, thanks for providing the update and taking my questions. So I just had a few again going back to the base case for Gan and the regulatory path. There do you have any sense about how many additional patients FDA might ask you to dose and then in terms of the follow up on those patients.

R.A. Seshan II: Again, going back to the base case for GAN and the regulatory path there, do you have any sense about how many additional patients FDA might ask you to dose? And then, in terms of the follow-up on those patients who received the commercial-grade material, what exactly do you need to report? Is it just safety and PK data, or do you need to follow them up and get some efficacy data? Yeah, I think it's a really good question.

Forget who received a commercial grade material what do you exactly need to report is it just safety and PK data or do you need to follow them in and get you know some of them.

Because the data as well.

R.A. Seshan II: And David, unfortunately, you guys cut out a little bit. So we'll go back and answer Sammy's question after we answer your question, David. But your question was really, I think it boils down to what do you think you'll need to show from from an efficacy perspective around the commercial grade material and how long do you think the follow up would be around what you would need in order to prove comparability? Well, I'll tell you the best confidence, again, would be in Zolgensma.

Yes, I think it's a really good question and David.

Unfortunately, you cut out a little bit so we'll go back and answer Sami's question. After we answer.

Your question, David but your question was really I think it boils down to what do you think you'll need to show from.

From an efficacy perspective around the commercial grade material and how long do you think the follow up would be.

R.A. Seshan II: Zolgensma, the FDA allowed us previously to use the top in 10 as a really nice biomarker around activity in kind of comparability between the original clinical trial material and the commercial grade material. Because the top in 10 actually went up pretty uniformly within the first 30 days across all patients. So you know, you're getting really good target engagement.

Around what you would need in order to prove comparability what ill tell you the best pump and that's again it would be installed gentler xeljanz.

The FDA allowed us.

Obviously to use the chop intend as a really nice biomarker.

Around activity and and and kind of comparability between the original clinical trial material.

And the commercial grade material, because the chop intend actually pretty went up it went up pretty uniformly.

R.A. Seshan II: I don't think that's too dissimilar here, where we're using the MSN 32, which is, which is similar in a sense to the top in 10 for older patients. And I think when you look across the entire data set, you do see a really nice kind of stabilization and improvement in disease as compared to the natural history pretty shortly after dosing.

Within the first 30 days across all patient, but you know you were getting really good target engagement I don't think thats to get similar here, where we're using the NFL 32, which is similar and in essence, the chop intend.

For older patients and I think when you look across the entire dataset.

You do see a really nice kind of stabilization.

Jason and improvement in disease as compared to the natural history.

What are you shortly thereafter dosing.

So.

I think using our previous experience experiencing both Janssen I don't think that that is.

Far removed now what I will say this is speculation because we haven't had that discussion but right.

R.A. Seshan II: And so, you know, based on our previous experience in Zolgensma, I don't think that that is, you know, far removed. Now, what I will say is that this is speculation because we haven't had the discussion directly to ask what they're going to ask for. And certainly, we're going to do what they asked us to do, but I think what we'll ultimately do is lean on the extensive safety database that we have. Please stand by; we'll resume with your answer in a moment. Speakers, you may continue with your answer.

What theyre going to ask for and certainly we're going to do.

What they what they asked us to do but I think what will ultimately do is lean on.

The safety database that we.

Please him I will resume with your question I answered a moment Mr. Wang.

Speakers you May continue with your answer where we're supposed to Iran.

Please standby will resume a question answer session momentarily.

Operator: Please stand by, we'll resume our question and answer session momentarily. Please stand by for our question and answer session will resume momentarily. Ladies and gentlemen, thank you for standing by.

Please send my phone a question and answer session will resume.

Momentarily. Thank you.

Ladies and gentlemen, thank you for standing by what we are assuming my question and answer session momentarily. Please remain on the line. Thank you.

Operator: We will resume our question and answer session momentarily. Please remain on the line. I'm sorry, Session, we're just dialing in. We can hear you now, please, therapy.

Okay.

Yeah.

Yeah.

Alrighty assertion ice creams.

Dialing in.

We can hear you now please continue.

Yeah.

Okay.

Jason do their recall.

Hi, operator, so we're going to give this another go we just dialed in just let us know when we.

Operator: Hi, operator. So we're going to give this another go. We just dialed in. Just let us know when we dial out and we just have the phone line available and we'll just pass the phone around. Okay, I can hear you.

<unk> dialogue and we just have the phone line.

Available and we'll just have thrown around.

Operator: You can be heard into the conference again now. We still have Mr. Huang on the line with us for his question. Perfect, perfect.

Give me a lot again.

I can hear you can you can be heard until the conference again now we still have Mr. Huang on the line with his first question.

R.A. Seshan II: David, sorry about this. We're just having some technical issues in the room. But to your question, I was just basically correlating our experience with Zolgensma and the approval pathway to Zolgensma and what the FDA asked us to do as it compared to, you know, trying to use that experience for BAN. So the question was really around what was the extent of the follow-up. The extent of the follow-up in the Zolgensma was really using the CHOP-N10 as a form of comparator for clinical comparability of the commercial-grade material.

Perfect David Sorry about this we're just having some technical issues in the room.

But to your question I would just basically correlating our experience with the June month and.

And the approval pathway to Janssen on what the FDA asked us to do.

That would compare to trying to use that experience.

And.

So the question was really around what was the extent of the follow up.

Then as a follow up in the adult Jamie was really using the chop intend as they compare form a comparator.

Preclinical comparability of the commercial grade material.

R.A. Seshan II: And so we're fortunate to have a similar assessment in the NFM32, which is essentially the CHOP-N10 for the older kids. And, you know, what we're seeing is pretty thoroughly a nice separation between patients that are in the interventional trial compared to the natural history study. And so we think that that could be a useful example and a comparator to provide to the FDA, because you actually see a nice separation relatively quickly

So we're fortunate to have a similar assessment and 32, which is essentially the chop intend.

For the older Kids and what we're seeing is pretty early a nice separation between patients that are Andy interventional trial compared to the natural history study.

So we.

We think that that could be a useful example in a comparator to provide to the FDA because you actually see a nice separation.

R.A. Seshan II: What I'll also say is when you start to look at long-term safety and durability, the patients that we have the most efficacy data on receive the lowest middle dose. It was a dose of 1.2 e to 14.

Relatively quickly.

Also say is when you start to look at the long term safety and durability. The patient that we have the most efficacy data on received the lowest middle dose the dose up.

One point to each of the 14 and I think I think.

R.A. Seshan II: And I think this patient, if they didn't receive the intervention, would have probably succumbed, because where this patient started was actually one of the lower scores on the NFM32. And we've essentially seen a really nice stabilization of disease now going out five years. So I think, you know, with that totality of data, along with the pathology data from the biopsy, along with having a validated instrument that's been used in regulatory approvals before in the NFM32, I think we have a really compelling argument to be able to go in and basically shoot for the, the minimum amount of follow-up if possible, really just to validate that we have active drugs.

This patient.

If they didn't receive the intervention with probably sitcom.

This patient started was actually one of our lower scores on the <unk> 32, and we've essentially seen a really nice stabilization debate now going out five years, So I think with that totality of data along with the.

Apology data from the biopsy.

Along with having a validated instrument that's been used in.

Regulatory approvals before and 32 I think we have a really compelling argument to be able to go in and basically shoot for.

Sure.

The.

The minimum amount of follow up if possible really just to validate that we have active drug that could be somewhere between.

R.A. Seshan II: That could be somewhere between, you know, Ladies and gentlemen, please stand by while we switch. Speakers, please continue on your second, Hi, guys. Please go ahead, you're on your second line. I'm going to disconnect. I'm hearing feedback on the other line. May I disconnect that this time? Yeah, we have to disconnect the other line.

Ladies and gentlemen, please standby, while we switched speakers' lines.

Operator: Yeah, so I think I answered the question ultimately. I think I was just providing some additional commentary. So I think I answered David's question. And again, sorry for the technical difficulties there. Thank you. Please stand by while we resume with the line from Sammy Corwin. Sami, please go ahead.

Speakers. Please continue on your second line.

Hi, guys.

Please go ahead your on your second.

I am going to disconnect Im hearing so so other line may have.

Disconnect at this time.

Yes, we have to disconnect. The other line so.

So I think I answered the question ultimately I think I was at providing some additional.

Commentary, so I think I answered David's question and again, sorry for the technical difficulties there.

Thank you please standby, while we resume with the line of Sami Corwin semi please go ahead.

Yes.

R.A. Seshan II: Oh, guys. Yeah, I think you were just going to answer my question on whether we can accept any data from CLN1 or CLN7. Thanks, Sammy. Yeah, so we've already presented data earlier this year on the CLN7 program. That was on the first three patients that were dosed, the first being 5b to the 14th, the next two that were presented were at the 1E to the 15 dose, and we've mentioned that an additional patient was treated at 1E to the 15.

Oh, Hey, guys. Yeah. I think you were just going to answer my question on if we can expect any data from at one seven.

Thanks, Sami yeah, so we've already.

We've already presented data earlier this year on the sealant and seven program that was on the first three patients that were dosed.

The first being <unk> to the <unk> thousand 14.

The the.

The next two that was presented was at the when it went into the <unk> dose and we've and we've mentioned that in additional patient was treated at one or two won each of the 15 and so we've already reported data on that program and we continue to follow those patients.

R.A. Seshan II: And so we've already reported data on that program, and we continue to follow those patients. On CLN7, what we've decided to do is not guide to the availability of clinical data but to say that we continue, we're kind of morphing this program into, and limiting enrollment to, a proof of concept study, kind of a little bit different of a strategy from kind of a fast pathway to registration type of strategy.

<unk> seven what we've decided to do is to not guide to the availability of clinical.

Clinical data, but to say that we continue we're kind of morphing. This program into you and limiting enrollment to a proof of concept study kind of a little bit different of a strategy from kind of a faster pathway to registration type of strategy and so we will guide to data later this year on the ceiling one pro.

R.A. Seshan II: And so we'll guide the data later this year on the CLN1 program. Thank you. Our final question comes from Yanan Zhu with Wells Fargo; please proceed with, Hi, thanks for taking my question and congrats on the initiation of the Rett Syndrome program, clinical trial. So my first question is about the GAN programs data, because I think R.A. you mentioned about age-matched controls. So far, the MFM32 data you presented is mainly the overall natural history control cohort. So I was wondering what the age-matched controls look like, because I think you mentioned you have enough data there to do the specific HMAC.

Graham.

Thank you.

R.A. Seshan II: And also, if that part of your conversation or package with your regular... Hey Yanan, thanks for the question. So essentially, what I'll say is, those analysis are ongoing. But I think what's important here, we have previously showed data that from the previous doses of patients pre-treatment decline, and their post-treatment stabilization. That's data that we actually shared last year, when we acquired the program. The data that we shared this year was essentially a comparison from the full cohort of natural history that basically shows an 8.07 decline compared to the cohort's experience, depending on that particular dose cohort.

Our final question comes from the line of Yanan, Zhu with Wells Fargo. Please proceed with your question.

Hi, Thanks for taking my question and congrats on the initiation of the Ret syndrome.

R.A. Seshan II: That's the data that we've shared recently. And now the analysis around age mass controls, which is a little bit more extensive, is ongoing. But I think you're absolutely right. This just lends itself to the robustness of the data itself.

Our program our clinical trial.

So my first one my question is.

On the.

On the Gan programs.

Data because I think you mentioned about age matched controls I think so far.

M. F. M 32 data you presented is mainly the overall.

History control cohort. So I was wondering what does the age matched controls look like because I think you mentioned you have enough patient data there to do the specific age match.

And also is that part of your conversation or a package with your regulatory interaction. Thank you.

Hey, yeah. Thanks for the question so essentially what I'll say is those analysis are ongoing but I think what's important here. We have previously show data that are from the previous doses of a pace.

Patients pretreatment decline and their post treatment stabilization that data that we actually shared last year. When we acquired the program. The data that we shared this year was essentially a comparison from the full cohort of natural history that basically shows an eight.

Zero seven decline.

Compared to the cohorts experience depend.

Depending on that particular dose cohort that's the data that we've we've shared recently and now the analysis around age matched controls, which is a little bit more extensive.

Is ongoing but I think you're absolutely right. This just lends itself to the robustness of the data itself.

The fact of the matter that we have access to natural history data that offers three levels of control is extremely extremely compelling. So when you start to look at the data set that we're going to go in and have conversations with the regulators you'll have natural history data three levels of control <unk>.

R.A. Seshan II: The fact of the matter that we have access to natural history data that offers three levels of control is extremely compelling. So when you start to look at the data set that we're going to go in and have conversations with the regulators, you'll have natural history data, three levels of control, biopsy data, functional data across a number of meaningful clinical functions, including MFN-32, including visual acuity, pathology data from the biopsy, but also retinal nerve fiber thickness data, as well as a whole host of sensory endpoints that we haven't presented to the street yet.

The data functional data across a number of meaningful clinical functions, including MFN 32, including visual acuity.

Perhaps the allergy data from the biopsy, but also retinal nerve fiber thickness data as well as a whole host of sensory endpoints that we haven't.

R.A. Seshan II: So we feel, honestly, I think if you asked Suyash, and I'm only answering this because of the technical difficulties that we had, he would probably tell you that he's never gone into a conversation with a regulator with this wealth of data before.

Sent it to the street, yet so we feel honestly I think if you would ask through yes, and I'm only answering that because of the technical difficulties that we had if you add two yes. He would probably tell you that he's never gone into a conversation with the regulator with this wealth of data before.

And and I think this gives us a lot of confidence around the conversation with regulators.

And so that's essentially what I'll say.

You know the level of comp.

Uh huh.

The level of comparison from the natural history. The wealth of endpoints that were collected the pathology data that we have in hand, and what that shows yes really lends itself and it's why we feel.

So I'm confident about our conversations and to be quite honest why we made the decision around prioritization today.

Thank you.

R.A. Seshan II: And I think this gives us a lot of confidence in the conversation with regulators. And so that's essentially what I'll say. The level of comparison from the natural history, the wealth of endpoints that were collected, the pathology data that we have in hand, and what that shows just really lends itself and is why we feel, you know, so confident about our conversations and, to be quite honest, why we made the decision around prioritization today. At this time, we've reached the end of the question and answer session, and I'll now turn the call over to Mr. Sessions rose for a closing remark.

At this time, we've reached the end of the question and answer session I will now turn the call over to Mr sessions for closing remarks.

R.A. Seshan II: Yes, thank you, operator. And first and foremost, we just want to apologize for any of the technical difficulties. I think we got through probably about 80% of the questions before that started to kick in.

Thank you operator, and first and foremost we just want to apologize for.

Any other technical difficulties I think we got through probably about 80% of the questions before that started to kick in so hopefully or our colleagues from the analyst community found found this helpful as well as the broader the broader community, but we really appreciate you guys joining us this morning.

R.A. Seshan II: So hopefully, you know, our colleagues from the analyst community found this helpful, as well as the broader community. But we really appreciate you guys joining us this morning. You know, I think the way we're thinking about 2022 is a year of focus.

The way, we're thinking about 2022 is a year of focus.

R.A. Seshan II: It's a year of operational efficiency. And it's a transformational year, as we potentially transition the company from now, and I say this every year, which is actually quite nice, now from a clinical stage company to a late stage clinical company to a registration company preparing for, you know, our first commercial launch. And so that is an important level of transition. Obviously, we're doing this in uncertain times, from a capital markets

It's a year of operational efficiency and its a transformational year as we potentially transition the company from now in it and I say this every year, which is actually quite nice now from a clinical stage company to a late stage clinical company into a registration company preparing for you know our first commercial launch.

So that is an important level of transition obviously, we're doing this and uncertain times from a capital markets perspective, but I think the.

R.A. Seshan II: But I think the changes that we've made today and announced today have really set the company up to be in the best possible position for when we have both data in hand from our Rett Syndrome program and feedback from regulators around our GAN program. And it puts us, again, in a position of strength.

The changes that we've made today have an announced today has really set the company up to be in the best possible position for when we have both data in hand from our Ret syndrome program and feedback from regulators around organic program and it put us again in a position of strength. So we really didnt.

R.A. Seshan II: So we really want to thank you guys for joining us today and hope you all have a wonderful day and a wonderful rest of the week. So thank you. Thank you to everyone who joined us today. This will conclude today's conference call and webcast. You may now disconnect your lines at this time. We thank you for your participation.

We really want to thank you guys for joining us today and hope you all have a wonderful day and a wonderful rest of the week. So thank you.

Thank you everyone for joining US today. This will conclude today's conference call and webcast. You may now disconnect. Your lines at this time, we thank you for your participation.

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