Q1 2022 Taysha Gene Therapies Inc Earnings Call

Yeah.

Good morning.

Good morning, welcome to taste. The gene therapy is the first quarter of 2022 financial results and corporate update conference call. At this time all participants are in a listen only mode. Following management's prepared remarks, we will hold a brief question and answer session.

Operator: Welcome to Taysha Gene Therapy's first quarter 2022 Financial Results and Corporate Update conference call.

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

Operator: This concludes today's conference.

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

As a reminder, this call is being recorded today, May 16, 2022.

As a reminder, this call is being recorded today may 16 2022.

Dr. Kimberly Lee: I'll now turn the call over to Dr. Kimberly Lee, Chief Corporate Affairs Officer.

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

Please go ahead.

You may disconnect your lines at this time.

Good morning, and welcome to take the first quarter 2022 financial results and corporate update conference call. Joining me on today's call are <unk> session. The second Tatius, President founder and CEO Tetra fish passage, 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 session and instead.

Thank you for your participation.

Sections will follow at that time.

Dr. Kimberly Lee: Good morning and welcome to Taysha's first quarter 2022 Financial Results and Corporate Update conference call.

Later today teacher and issued a press release announcing financial results for the first quarter ended March 31st 2022, a copy of this press release is available on the company's website at your 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 expected timing and results of clinical trials for a part of candidates our expectations regarding the data necessary to support regulatory approval of tissue, one 'twenty and then Michael.

Saturday and market opportunity for those programs as well as tissue manufacturing plants.

This call May also contain forward looking statements relating to <unk> growth and future operating results discovery and development of product candidates strategic alliances and intellectual property as well as matters that are not historical facts or information.

Krish, which may cause patients actual results to differ materially from those stated or implied in such forward looking statements.

These risks included searches fees related to the timing and results of clinical trials and preclinical studies of our product candidates our dependence upon strategic alliances and other third party relationships our ability to obtain patent protection for our discoveries limitations imposed by patents owned or controlled by third parties and the requirements of substantial funding to conduct our research.

And development activities.

So I listened to discussion of the risks into states 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 today of this live broadcast may 16th 2022 tisha entertains 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.

Dr. Kimberly Lee: Joining me on today's call are Ari Seshan II, Taysha's President, Founder and CEO,

Paul.

I would now like to turn the call over to our President founder and CEO Ari session second Ari.

Dr. Sudesh Prasad, Chief Medical Officer and Head of R&D, and Kamran Alam, Chief Financial Officer.

Thank you Kim good morning, and welcome everyone to our first quarter 2022 financial results and corporate update conference call.

After a formal remark, we will conduct a question and answer session and instructions will follow at that time.

Since our last update we have continued to advance our core development programs with particular focus on China, Kona neuropathy, or Gan and Ret syndrome.

Earlier today, Taysha introduced a press release announcing financial results for the first quarter and then March 31st, 2022.

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

In March we were pleased to initiate clinical development of patient one O two under a Cta approved by health, Canada for the first and the only gene therapy in clinical development for ret, which affects over 350000 patients worldwide.

We look forward to reporting preliminary phase one flashed two clinical safety and efficacy data by year end.

We were also pleased to recently received orphan drug designation for Tisha 120, <unk> honor to work with the from the European Commission further highlighting the unmet need for treatment options in Gan and the potential Acacia one 'twenty to provide a disease modifying treatment for these patients.

We look forward to providing a regulatory update by mid 2022.

As we look ahead, we remain focused on executing on our strategic pipeline prioritization initiatives and expect our current capital resources, along with full access to our existing term loan facility to fund operating expenses and capital requirements into the fourth quarter of 2023.

Please note that on today's call, we will be making forward-looking statements,

I'll now turn the call over to Sue to provide a more detailed update on our clinical programs. So yes. Please go ahead.

Thanks, Alright.

including statements relating to the safety and efficacy and the therapeutic and commercial potential of our investigational product candidates.

As already noted we have made significant recent progress in its own small clinical programs for GAAP.

Threats and try them and expect exciting milestones throughout the remainder of the year.

These statements may include the expected timing and results of clinical trials for our product candidates,

I will begin with ret syndrome.

our expectations regarding the data necessary to support regulatory approval of Taysha 120,

Tisha wanted to deliver a transgene metope too, which is a protein essential for new rental development and function.

and the regulatory status and market opportunities for those programs, as well as Taysha's manufacturing plans.

The challenge in junior replacement therapy, or make pizza is finding the appropriate balance of sufficient physiological expression to correct the deficiency.

Whilst also avoiding over expression and the associated toxicity.

This call may also contain forward-looking statements relating to Taysha's growth and future operating results,

To do this takes you wanted to regulate the expression of Mac P. Two using a novel micro RNA responsive also regulatory elements platform known as M. IRA.

discovery and development of product candidates, strategic alliances and intellectual property,

as well as matters that are not historical facts or information.

Police Sibley licenses Taisha developed by doctors Cyrus Senate I'm, Stephen Gray of Ut Southwestern Medical Center.

Iraq provides sophisticated regulation of transgene expression on a cell by cell basis, ensuring controlled expression that avoids excessive levels of Mac P too.

Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements.

We recently initiated clinical development of taste, you wanted to under an approved Cta by Health Canada.

These risks include uncertainties related to the timing and results of clinical trials and preclinical studies of our product candidates,

our dependence upon strategic alliances and other third-party relationships,

And further supports this promising program, we presented positive I N D C J, enabling preclinical data at the International Ret Syndrome Foundation Scientific conference and ascend Ret syndrome National patient advocacy summit. These.

our ability to obtain patent protection for our discoveries, limitations imposed by patents owned or controlled by third parties,

and the requirements of substantial funding to conduct our research and development activities.

These data supported the C J acceptance, including a pharmacology study in rats knockout mice assessing the efficacy of Taishan, one I too.

And a six month at G. L. P. Toxicology study in nonhuman primates exploring safety by distribution of mechanism of action of Taisha wanted to come.

Collectively these preclinical results confirm the ability of Taisha, one O two to regulate transgene expression to within the appropriate physiological levels.

This week, we will have a presence at the 25th annual meeting of the American Society of gene and cell therapy, or I S. G. C. T. While we will be presenting the safety and by distribution data and in Hps as well as safety data in a rash. These.

These presentations will further support the ability of our M. I wrap platform to control gene expression and address the challenge of ensuring appropriate levels of might be two expression that have limited effective therapeutic development with other gene replacement strategies.

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.

I've already indicated there are over 350000 patients estimated to suffer from restauranteur and worldwide spanning patients as young as six months into adult Hood.

This conference call contains time-sensitive information that is accurate only as of today of this live broadcast, May 16, 2022.

Taysha undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances

after the date of this conference call, except as may be required by applicable securities law.

RA Session II: I would now like to turn the call over to our President, Founder, and CEO, RA Session II.

Currently there are no disease modifying therapies to treat this devastating condition.

We are excited to advance taisha, one or two in their reveal phase one two clinical trial is the first gene therapy in clinical development for Ret syndrome.

RA?

RA Session II: Thank you, Kim.

RA Session II: Good morning and welcome, everyone, to our first quarter 2022 Financial Results and Corporate Update Conference Call.

The reveal study is an open label dose escalation randomized multicenter study that will examine the safety and efficacy of <unk>, one or two in adult female patients with ret syndrome.

Since our last update, we have continued to advance our core development programs,

with particular focus on Jynexonal neuropathy, or GAN, and Rett syndrome.

Up to 18 patients will be enrolled in.

In March, we were pleased to initiate clinical development of Taysha 102 under a CTA approved by Health Canada

In the first cohort a single five <unk> 14 of total V. G dose of Taishan, one or two will be given interest equally.

The second cohort will be given a 115 total V G dose of <unk> 102.

as one of the first and only gene therapy in clinical development for Rett, which affects over 350,000 patients worldwide.

Key assessments will include ret specific and global assessments quality of life, Biomarkers and neurophysiology imaging assessments.

Saint <unk> mother, and Child University Hospital Center in Montreal, Quebec, Canada has been selected as the initial clinical trial sites under the direction of Doctor Elsa Russian Y'all assistant Professor neuroscience, and pediatrics and principal investigator.

We look forward to reporting preliminary Phase 1-2 clinical safety and efficacy data by year-end.

We look forward to reporting preliminary first in human data by the end of 2022.

Takes you one or two has been granted wrap pediatric disease designation and orphan drug designation from the FDA and more recently orphan drug designation from the European Commission.

We were also pleased to recently receive Orphan Drug Designation for Taysha 120 for Jynexoneuropathy from the European Commission,

further highlighting the unmet need for treatment options in GAN,

Turning to tissue in 'twenty for the treatments of Gan earlier. This year, we reported positive clinical efficacy and safety data for the high dose cohort of 3.5 E. 14 total V. G delivered interests equally as well as long term safety and durability across all therapeutic doses.

and the potential of Taysha 120 to provide a disease-modifying treatment for these patients.

Treatment with Taishan, one 'twenty achieved a clinically meaningful and statistically significant slowing or halting disease progression across all therapeutic dose cohorts that was further confirmed by long term data demonstrating sustained durability.

Notably nerve box he data provided new evidence of active regeneration of nerve fibers following treatment with tissue on 'twenty.

In addition, we observed preservation of visual acuity as measured by the log Moscow and optical coherence tomography.

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

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

Lastly, there was no evidence of dorsal root ganglion inflammation or thrombocytopenia.

We recently completed a commercially representative G M P. Bachelor Tayshaun 'twenty and release testing for this batch is currently underway.

Also in April Taisha, one 'twenty received orphan drug designation from the European Commission further support the large unmet need for treatment options in Gan.

And potentially expedited support and regulatory approval.

As a reminder, tissue in 'twenty previously received orphan drug wrap pediatric disease designations from the FDA.

Partnerships with genetics testing, Lisa gene Dx to sponsor the inclusion of a genetic marker for Gan testing and the gene D. S routine hereditary neuropathy screening panel free of charge are ongoing as well as our collaboration with the hereditary neuropathy Foundation on the shelf for a tooth association centers of excellence.

Health care professionals and patient efficacy groups to help raise awareness early diagnosis of gap.

We remain well positioned to further advanced tissue on 'twenty through regulatory approval and believe the comprehensive gene therapy dataset generates the dice and Gan office tasteful 20, a potentially derisk regulatory path. So it meets most registration requirements of the S. D E and M. A.

We look forward to our continued discussions with major regulatory agencies on potential registration pathways for tissue in 'twenty and anticipate providing a regulatory update by mid 2022.

We look forward to providing a regulatory update by mid-2022.

At the upcoming S. G C T meeting Doctor ratio Bailey assistant Professor in the Department of Pediatrics at U T. S. W will be presenting data on vagus nerve delivery of Taishan, one 'twenty to treat the autonomic nervous system dysfunction in Gan.

There will also be other presentations on some of our earlier stage programs, including preclinical data and tell what party.

<unk> Willi syndrome, and Angelman syndrome.

There will also be a symposium on innovative approaches and translational strategies and gene therapy development.

In addition to expected regulatory feedback potential in 'twenty in Gam by mid 2022, and first in human preliminary phase one two safety and efficacy data for <unk> 102, and Ret syndrome by year end, we remain focused on continued clinical development of the first generation construct for <unk>.

As we look ahead, we remain focused on executing on our strategic pipeline prioritization initiatives

All in seven disease in partnership with Ut southwestern and under the leadership of Dr. Ben Greenberg, Vice chair of clinical and translational research and the principal investigator during the course of 2022.

Clinical development of <unk>, one one night and sale in one disease Ultra remains ongoing and we intend to initiate clinical development for a small proof of concept study potential one O five and SLC third Tonight five deficiency.

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

and expect our current capital resources, along with full access to our existing term loan facility,

Cameron.

Thank you Sue yet this morning, I will discuss key aspects of our financial results for the first quarter ended on March 31 2022.

to fund operating expenses and capital requirements into the fourth quarter of 2023.

RA Session II: I will now turn the call over to Suyash to provide a more detailed update on our clinical programs.

More details can be found in our Form 10-Q, which will be filed with the FCC shortly.

Suyash, please go ahead.

As indicated in our press release today research and development expenses were $37.8 million for the three months ended March 31, 2022, compared to $23 $9 million for the three months ended March 31, 2021.

Thanks, RA.

The $13 9 million dollar increase was primarily attributable to an increase of $9.3 million in employee compensation, which included $2.2 million of severance and one time termination costs in connection with the strategic re prioritization of programs completed in March 'twenty, 'twenty, two and 1 million.

There's a noncash stock based compensation.

Additionally in the three months ended March 31, 2022, we incurred an increase of $2.9 million of expenses and research and development manufacturing and other raw material purchases.

We also incurred an increase of $1.7 million in third party research and development consulting fees, primarily related to G. L. P toxicology studies and clinical study activities.

General and administrative expenses were $11.5 million for the three months ended March 31, 2022 compared to $8 $2 million for the three months ended March 31, 2021.

The increase of approximately $3.3 million was primarily attributable to $2.9 million of incremental compensation expense, which included zero point $4 million of severance and one time termination costs and zero point $7 million of noncash stock based compensation.

We also incurred an increase of zero point $4 million in professional fees related to insurance Investor Relations Communications accounting and market research now.

Net loss for the three months ended March 31, 2022 was $50 $1 million or one dollar and 31 cents per share as compared to a net loss of $32 million or <unk> 87 cents per share for the three months ended March 31, 2021.

As of March 31, 2022, Tisha had $96 $6 million in cash and cash equivalents. This cash balance excludes $12 million in gross proceeds generated from the sale of common shares under our existing aftermarket facility or ATM in April .

Current cash and cash equivalents, along with full access to our existing term loan facility is expected to fund operating expenses and capital requirements into the fourth quarter of 2023.

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

Thanks Cameron.

As RA noted, we have made significant recent progress in advancing our clinical programs for GAN and Rett syndrome

Our focus for 2022 continues to be on executing across our core development programs and I am extremely proud of our team's progress and accomplishment this quarter.

and expect exciting milestones throughout the remainder of the year.

We continue to maintain a strong cash position that should provide runway into the fourth quarter of 2023.

We would like to thank our patient employees board of directors Scientific Advisory Board collaborators and the patients and advocate for their ongoing support of our mission to develop curative gene therapies to eradicate devastating monogenic CNS disease.

I will begin with Rett syndrome.

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

Taysha 102 delivers a transgene for MeCP2, which is a protein essential for neuronal development and function.

The challenge in gene replacement therapy of MeCP2 is finding the appropriate balance

of sufficient physiological expression to correct the deficiency,

Thank you if you'd like to ask a question. Please press star one on your telephone keypad, a confirmation tone will indicate your line is in the question queue.

You May press star two if you'd like to remove your question from the queue for participants using speaker equipment and may be necessary to pick up your handset before pressing the star keys in the interest of time, we ask that you each keep to one question.

whilst also avoiding overexpression and the associated toxicity.

Our first question comes from the line of June Lee with True Securities. Please proceed with your question.

To do this, Taysha 102 regulates expression of MeCP2 using a novel,

microRNA-responsive auto-regulatory element platform, known as MiRARE,

Hi, Good morning, and thank you for taking my question. This.

that is exclusively licensed at Taysha and developed by Drs. Sarah Sinnott and Stephen Gray of UT Southwestern Medical Center.

MiRARE provides sophisticated regulation of transgene expression on a cell-by-cell basis,

ensuring controlled expression that avoids excessive levels of MeCP2.

This is Matthew.

For June so what is the probability by which you think FDA might ask you to have efficacy data on new patients using a commercial grade material and how long would you say Oh, what do you think it takes to provide such data. Thank you.

We recently initiated clinical development of Taysha 102 under an approved CTA by Health Canada.

Hey, good morning. Thank you for the question you know I think we've gone through this when we actually presented the definitive data set earlier this year really around kind of the current scenarios and how we look at them. We essentially you know.

Cut them in two parts, one being ex U S. One being the U S, particularly for the F. D. A week that breaks down to about three scenarios are the first being being able to immediately file off the data that we've generated thus far again, we reported data.

In further support of this promising program, we presented positive IND CTA-enabling preclinical data

From all therapeutic dose cohorts include in the high dose of 3.5 V to the 14th earlier this year, where we really see really nice efficacy and safety durability and now we have really nice pathological data with the biopsies showing a nerve fiber regeneration, which which essentially we view as a game changer.

at the International Rett Syndrome Foundation Scientific Conference

and ASCEND Rett Syndrome National Patient Advocacy Summit.

These data 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 primates

exploring the safety, biodistribution, and mechanism of action of Taysha 102.

Collectively, these preclinical results confirm the ability of Taysha 102

to regulate transgene expression to within appropriate physiological levels.

This week, we will have a presence at the 25th Annual Meeting of the American Society of Gene and Cell Therapy, or ASGCT,

where we will be presenting the safety and biodistribution data in NHPs, as well as safety data in rats.

These presentations will further support the ability of our MiRARE platform to control gene expression

and address the challenge of ensuring appropriate levels of MeCP2 expression

that have limited effective therapeutic development with other gene replacement strategies.

And so we're pretty excited about this data set not only because we show clinical but we show really nice clinical data, but also epic.

Safety and efficacy data, but also really the biopsy data in the natural history, which essentially has been going on for.

Or close to 10 years and each patient rolling over from the natural history study provides three levels of control.

The patient has a comparison between their own pre treatment and post treatment performance.

Because it's such a large natural history study over 50 patients at this point, we're able to show age matched controls and then you're able to compare the entire cohort.

Two a patient's performance. So we're really excited again about the breadth of the data.

As already indicated, there are over 350,000 patients estimated to suffer from Rett Syndrome

As I mentioned, our base case is most likely that the F D. A.

worldwide, spanning patients as young as 6 months into adulthood.

Currently, there are

no disease-modifying therapies to treat this devastating condition.

We are excited to develop

Ask you to dose a few more patients using the commercial grade material.

And this is a similar pathway of what they asked abaxis to do during the registration of the old Gen Summer most likely you would be what we would consider a handful of patients you know somewhere between probably three to five patients. Those patients are already identified so from a timing perspective, this week, which Jordan.

Taysha 102 in the REVEAL Phase 1-2 clinical trial as the first gene therapy in clinical

Any type of a recruitment effort to get these patients into the study because essentially they would roll over from the natural history study. So these patients are already identified and our partners at <unk>.

development for Rett Syndrome.

The REVEAL study is an open-label, dose-escalation,

randomized, multi-center study that will examine the safety and efficacy of Taysha 102 in adult

The NIH is under the leadership of the Carson bottoming who've done a fantastic job keeping that steady moving in in the wealth of data that we've generated from from that study. So we really see the difference between filing immediately based off the current dataset and dosing a few more patients were probably looking at about a six month time difference, it's not a huge.

Time difference because again, we don't have to go out and identify patients are those patients are already identified and so we think by dosing a few more patients that would probably set us up for.

An approval towards the end of 'twenty 'twenty. Three this begins the F D. A scenario the EMA our going in position is that we meet all the requirements for conditional approval and the hope is to initiate a MAA filing by the end of the year. We would also ask just shifting focus back to the F. D. A.

Based off the current dataset, we would ask the F D a.

As a default to initiate a rolling submission based off of the data that we've generated the preclinical data won't change.

The clinical dataset is it would be near final what they asked us to dose a few more patients. So we would be able to start the review of the current dataset and obviously, we would have completed.

The release testing and the analytical panel for or commercial grade material, which we've already.

<unk> completed the manufacturer of this current currently undergoing release testing and we're quite excited about not only the yields but also the product purity from that run. So that's kind of our going going in strategy, we're going to go in and.

And ask for approval based off the current dataset, but our base case would be dosing a few more patients that would immediately rollover from the NIH natural history study and so this is something we previously stated before and it continues to be our base case.

Yeah.

Thank you. Our next question comes from the line of Gil Blum with Needham <unk> Company. Please proceed with your question.

Good morning, and thanks for taking my question, maybe another quick one on tissue on 'twenty.

What more is there to do a commercial grade product.

What more things do you need to do there and maybe you can give us an idea of how many patients can be treated with this batch. Thank you yeah.

Actually a really good question Gil.

Thanks for asking and I'll start in and see US Please chime in if you'd like.

But essentially theres not much more to do on this commercial grade material we initiated.

The manufacturing run earlier this year, we have now completed that manufacturing line. It was quite successful both from a yield perspective, and a purity perspective.

The current analytic that we Brian around comparability to the original clinical material are spot on and those tests continue to be ongoing the team's leadership team along with Fred's team are continuing to work on key assays key released assay that will support the BLA, including the definitive.

Potency assay, which the team has made significant progress on which I'm quite pleased about and just to give you an idea.

On just the yields are from from this run but the team has done just a fantastic job around manufacturer ability and depending it and depending on the dose and I'll just go with the high dose of 3.5 to the 14th where over 50 patients worth of drug and so that gives you an idea around just one the shrink.

Our platform. This is using our head to 93 suspension.

Triple plasmid transfection platform that we use across.

The entire portfolio, but also just really the strength of the team that we havent CMC, so I couldnt be even more proud so.

What we'll do is the the this run will continue to go undergo release testing stability testing and whatnot and the team will continue to gather data to support the BLA, but really this the progress that the team has made in this manufacturer of this commercial grade material has gone it's.

It it's gotten even better as we could imagine so I'll stop there. So yes do you have anything to add.

No.

I would just echo the fact that.

You know the batch is made there was plenty.

Plenty of product managers are high yielding.

Rob.

It released test testing is underway looking at the characterization of that product.

And it's all looking.

Very promising thus far are alright quite correct.

Thing Radio's outstanding is to finalize the potency assay and just to remind you.

Yeah.

Sensually exists to demonstrate that the molecule that we're administering closely mimics what's effectively.

In the clinical settings. It does in a lab setting in every language to be tested that treat chronic surplus character that need to be met and the SBA and the regulators are pretty keen to ensure that we make on the longer the basis is consistent and highly <unk>.

Level of quality and as already said, we have made a lot of progress in finalizing that.

So everything is looking great.

Or at least testing is underway and the drugs that are available to be treating patients imminently.

Thank you. Our next question comes from the line of solving with their with Goldman Sachs. Please proceed with your question.

Hey, good morning, guys and thank you for taking our question. This is Elizabeth on for solving maybe just switching over to Rod if you could comment on the nature of the first clinical data, we expect to see and how many patients. We can expect to see data from them and then a second one from us or what.

What kind of assumptions.

Has have been baked into the <unk> 23 cash runway guidance. Thank you.

Sure Let me take the question about the clinical trial.

And then Kevin Laura can handle the second question. So with regard to the right clinical trial. This is a trial in adults Cmos with Ret syndrome.

female patients with Rett Syndrome.

Up to 18 patients will be enrolled.

Mind, you, we just felt given.

Just given the.

Concerns about potential over expression, which we which we share with US you kind of regulate very nicely and on HB data, we still want it to be a little bit conservative.

And.

So we're starting off in adults on the cloud move into children pediatric females with Arete.

Some point thereafter, and then we want to provide a small studies boys.

Very rare population of boys with rats. Shortly thereafter now in terms of expectations with regard to what we're going to have coming out of the clinical trial data from the adult study, which we anticipate sharing data from them by the end of the year. The likelihood is going to be safety data and perhaps some preliminary efficacy data and whatnot.

In the first

cohort, a single 5E14 total VG dose of Taysha 102 will be given intrathecally.

The second

So at the moment.

cohort will be given a 1E15 total VG dose of Taysha 102.

We will as is the case for these.

Key assessments will include

Studies with the products you have to stagger dosing, we call them. Several places all at once with a personal patient leave at that period of time.

And then dose the second patient after a DMC review and then leave it pretty tough for dice in the next patient.

So my guess is it's going to be a small number of patients safety data by the end of this year potentially some preliminary efficacy data will start to see some early signs of that but I think that's why we're that's what we're focusing on for the clinical trials.

With regard to assumptions, alright, and Camden tie that question.

Sure and thanks Louise for the question I was actually talking on mute. So just to reiterate what would see US mentioned you know we're quite excited about the ret data.

Rett-specific and global assessments, quality of life, biomarkers, and neurophysiology and

imaging assessments.

St. Justine Mother and Child University Hospital Centre in Montreal,

Quebec, Canada, has been selected as the initial clinical trial site under the direction of

Dr. Elsa Rossignol, Assistant Professor, Neuroscience and Pediatrics, and Principal

The preclinical dataset that supports the the C. T. A and again are really excited about what this means to the rec community being the first and only gene therapy are actually in clinical development for for Ret syndrome, and I think just to echo what see as she mentioned it will really be on the totality of data the amount of the <unk>.

Investigator.

We look forward to reporting preliminary first-in-human data by the end

of 2022.

Taysha 102 has been granted a rare pediatric disease designation, an orphan drug

designation from the FDA, and more recently, orphan drug designation from the European Commission.

Turning to Taysha 120 for the treatment of GAN, earlier this year we reported positive

Mt.

Endpoints that are that are being collected or are immense both from physician reported red Red syndrome outcomes patient reported outcomes respiratory measures. Obviously, some some neurodevelopmental measures as well as movement. So it's really going to be you know a whole whole.

[noise] of endpoints that we'll share including safety and safety is going to be probably one of the most important ones because there's always this notion around over expression and the data from our in Hp's study or an H B Tox study not only demonstrated the safety of our of our construct at all.

clinical efficacy and safety data for the high-dose cohort of 3.5E14 total VG delivered

Doses up to four fold above what the starting dose will be in the clinical setting, but also proof of mechanism the ability to down regulate the expression of <unk> in the presence of wild type <unk>.

And the presence of wild type <unk>, two and so again for us. It's it's quite exciting but certainly this is one of the reasons why we decided to start into adult so I would probably characterize it similarly the way. That's so yes did it it'll be on the totality of data it'll be safety with some preliminary efficacy in there.

On from an assumption perspective on cash runway the way that we're thinking about this is we have you know with the full a drawdown of our current term loan facility from Silicon Valley Bank, we have the ability to be able to extend runway into Q4 of 2023.

With our exist along with our existing cash and that's kind of the assumption that the base case assumption. That's gone in as you are aware, we executed on a a pipeline prioritization exercise earlier this year, which we announced at our yearend earnings call, which also included.

A rip up 35% and in essentially a kind of a right sizing based off of a clear focus on two key programs and that's our Ret syndrome program and are John if someone Allopathy program, which were both quite excited about and then taking two of the additional clinical development assets and moving those from more of a registration.

Directed trial to more of a proof of its kind of small proof of concept studies that being selling wine and then S. O C 13, eight five what I would also say, though is again I'm quite I'm quite excited about the progress that the team has made just in the short period of time and really.

The ability to be able to get through this.

This prioritization analysis and kind of reap will focus the company and still execute is just been something that I I've been immensely proud of it it's not easy for anyone out there and.

In biotech and in particularly in gene therapy, but the team is really nose to the grind and executing and so for US all of this has been baked into our cash analysis and we continue to look at ways to augment and extend runway.

Thank you. Our next question comes from the line of Kevin did either with Oppenheimer and company. Please proceed with your question.

Hey, great. Thanks for taking our questions just under again regulatory update the Ari can you comment on your confidence sort of above that that mid 2022 update timeline I guess sort of underlying this question is is it reasonable to conclude that.

Had the necessary meetings with FDA and other regulatory agencies are waiting for feedback at this point or are there kind of opened scheduling.

Components.

Could it impact that timeline and caused some uncertainty.

Yeah. Thanks, Kevin for the question and good morning, So I think we're confident in reiterating that guidance.

Around.

That the mid 2022 from a from a regulatory feedback perspective.

Again, I think you know most people go in to have conversations with the F. D. A.

The EMA in a in a COVID-19 environment and other regulatory agencies in a COVID-19 environment. You know, obviously theres been some flex there there's been a little bit of flex in and scheduling, but with that being said we're quite excited.

And the promise of the dataset that we presented thus far the reproducibility of that data you know and the fact of the matter that the product is is not only efficacious, but durable and faith at multiple doses.

Including a really robust natural history study and now.

Really you know now the beginnings of what would be a really nice data package from a module three perspective from a CMC comparability.

Comparability. So we're gonna go in with that dataset and and obviously our goal and strategy is to be able to to to file off of the current data set and as a default base case, we we essentially default to be prepare to dose a few more patients with the commercial grade material. So we're re.

Reiterating that guidance, we've done that in our communications and and look forward to updating you guys here closer to the two later this year, but but again mid year 2022.

<unk> is our guidance around having that be back in here.

Thank you. Our next question comes from the line of Jack Allen with Baird. Please proceed with your question.

Hi, Thank you so much for taking the questions and congratulations on all the progress.

intrathecally, as well as long-term safety and durability across all therapeutic doses.

I wanted to shift gears back to rat really briefly and talk about the dose. There I know you mentioned that you're starting at five either the 14th Turtle D. G and then moving up to $1 15.

I guess the preclinical.

Packaged showed safe yet forex.

The first dose I was just curious.

Was there.

In the preclinical package, where you did see tolerability issues and how much coverage do you think you have to dose escalated as we moved through the study based on the existing preclinical package.

Okay. Thanks, Yeah, Great question and good morning, I'll turn it over to see us to to answer that question.

Treatment with Taysha 120 achieved a clinically meaningful and statistically significant slowing

Yeah, Hi, Jeff. Thanks, Thanks for the question so.

It's a really important question you know the dose selection for the clinical trial for a gene therapy study getting it right. The first time is really important because you've got to make sure you get enough drug to make sure the drugs affects it but also make sure there's no safety or tolerability issues. Once you give them the drink therapy drugs, you can't take it away.

or halting of disease progression across all therapeutic dose cohorts,

that was further confirmed by long-term data demonstrating sustained durability.

Notably, nerve biopsy data provided new evidence for active regeneration of nerve fibres

following treatment with Taysha 120.

In addition, we observed preservation of visual acuity

as measured by the Logmar scale and optical coherence tomography.

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

and no dose-limiting toxicities.

All adverse events related to immunosuppression

or study procedures were comparable to other gene therapies and transient in nature.

Lastly, there was no evidence of dorsal root ganglion inflammation or thrombocytopenia.

Yeah, So it's a really critical.

and release testing for this batch is currently underway.

We recently completed a commercially representative GMP batch of Taysha 120

Also, in April, Taysha 120 received orphan drug designation from the European Commission,

further supporting the large unmet need for treatment options in GAM,

and potentially expedited support in regulatory approval.

Decision that needs to be made.

As a reminder, Taysha 120 previously received orphan drug and rare pediatric disease designations

And in particular rats why there is this.

from the FDA.

Partnerships with genetics testing leader GeneDx to sponsor the inclusion of

a genetic marker for GAN testing in the GeneDx Routine Hereditary Neuropathy Screening Panel

Risk of over expression toxicity, you have to get the amounts of protein being produced.

Appropriate.

These appropriate physiological limits enough to make sure youre, having efficacy, but not so much protein that causes toxic side effects because of that we actually did a very very disciplined preclinical package, which included a mouse pharmacology study so a mouse model of pharma.

free of charge are ongoing, as well as a collaboration with the Hereditary Neuropathy Foundation

and the Charcot-Marie-Tooth Association's Centers of Excellence, health care professionals,

and patient advocacy groups to help raise awareness on the early diagnosis of GAN.

We remain well positioned to further advance Taysha 120 through regulatory approval and

believe the comprehensive gene therapy data set generated to date in GAN offers Taysha

Nicole just studying did.

We did a rat toxicology study who didn't NIH painful supported study all of the studies with very extensive and very comprehensive.

120 a potentially de-risk regulatory path that meets most registration requirements

of the FDA and EMA.

We look forward to our continued discussions with major regulatory

Mouse study was over 250 mice, the rat study with over 120 rats and H piece to this 24 and H P's.

agencies on potential registration pathways for Taysha 120 and anticipate providing a

The mouse Pharmacology study is why you'd look for dosage strengths to be efficacious and we're able to we were able to identify that very clearly in terms of demonstrating enough drug, causing an improvement in survival Mitra assessments respiratory assessments and other assessments. So the five year 14 total.

D. G does is above that level.

And then on the other end both in the rack talks on that.

H P talks we tested doses up to an equivalent to two E 15 total D. G human equivalent so that's for the starting dose and to answer your question specifically there was no adverse events.

Note the $2 15 days, so it's possible we could go even higher than that but we didnt test hard and not because we didnt think there'd be a need to go.

The $2 15, simply because we saw efficacy at a much lower amount in the mass pharmacology study.

regulatory update by mid-2022.

And I think it was that combination of studies that really persuaded a health.

Health, Canada to allow the CCA to be opened.

There's one other important piece around the sell HP study the cause is really really important and I'll actually be discussing.

At the upcoming ASGCT meeting, Dr. Rachel Bailey, Assistant

Discussing this a poster presentation at.

G C T.

I think its tomorrow Tomorrow, Wednesday, Tuesday, actually yeah, because I think it Tuesday.

Professor in the Department of Pediatrics at UTSW, will be presenting data on vagus

nerve delivery of Taysha 120 to treat the autonomic nervous system dysfunction in GAN.

There will

There will also be other presentations on some of our earlier stage programs, including

also be a symposium on innovative approaches and translational strategies in gene therapy

And I actually presented to stay to the Big Ret syndrome.

preclinical data in telepathy, Prader-Willi syndrome, and Angelman syndrome.

development.

In addition to expected regulatory feedback for Taysha 120 in GAN by mid-2022,

and first in human preliminary phase 1-2 safety and efficacy data for Taysha 102 in Rett syndrome

by year end, we remain focused on continued clinical development of the first generation

Scientific conference that's organized by the ISR are about three or four weeks ago.

And the other should be Tulsa, just three things it shows a full absence of any.

When you come to the task effects.

Which.

Which is important for kohl's hardly clinical dose. It also shows really excellent by distribution.

Types throughout Brian on the spinal cord, so you're getting back to coffee numbers.

And a very nice range, one to two coffees particular gene I'm in different parts of the brain and the spinal cord and the ganglia in the peripheral nervous system and it also shows correspondingly low levels of or a night and day.

Don't forget these are wild type of niche piece, so well.

That means that you're getting great delivery.

<unk>.

Into the brain spinal cord, but actually very tight down regulation, meaning not much RNA being produced which is appropriate given us a whatsapp envelope. So that NH piece that he shows safety says about distribution, but the mechanism of action and another sale, but going through that data in more detail. The S. T. C. T makes it tomorrow, so that group of studies.

<unk> was really very persuasive to how candidates will last with the seats yet.

Yeah.

Thank you. Our next question comes from the line of Ian song with BTG. Please proceed with your question.

Hi, Thank you very much for taking the question. This is actually a follow up question on just what you said.

Now through us so on Ret syndrome has anyone looked at comparability between nonhuman primate and human patients in terms of our power distribution and also given that this is not cross correction to be expected. So are.

Are there any data to suggest the transduction efficiency or do you have an estimate on how many cells where needed to be transfused to see a reasonable efficacy.

So two very good questions.

So the first question was about the translate stability of NXP budge because of human participation you thought it's a good question no one's done it specifically in Iraq. What we've done is we've shown very nice participation with our ret program with niche equal dosage without an H P, which is of course smaller than your humor.

Being bumped the anatomy is very similar and it's probably the best corollary looking at budget in any handle.

The old model to the human and we get really hot spot distribution throughout the brain and the spinal cord injury equal days of injection.

Now in the human setting the only way to really ascertain but distribution is in the sub situations. It if a patient was passed away.

And to look at DNA, and RNA and protein and that's not individual and that just happened very early on and one of the gang patience.

One of our lives I scan patients, who sadly passed away through progression of disease state that has been presented by costs and polymer and I'm Stephen Gray at the S. G. C teammates for a few years ago and they showed that wasn't interest equal dose of the AAV nine gene therapy for gap, you actually got nice parts distribution although.

It's a low level because it was a low dose throughout old targets, all the tissues and the other thing I will say from what we learned from the gown program and it doesn't get countless AAV 9293, and they seem to be.

They could be delivered so lots of similarities to the Ret program. The only thing I'll say about Gan is.

Is that we've demonstrated more recently in January .

January .

Presentation that we see improvements in the peripheral nerves and the net boxes now these windows BOP sees the performed in the radar superficial nerve which is the.

The risk of what this means is that drug is getting down into the peripheral nervous system down the risk for us.

And then should equal dose of injection. So for those reasons, we're confident that an interest equal doses of drug.

We'll actually deliver.

Drug in restaurant drove very nicely to all the tissues that needs to be transfused, which helped Brian .

In particular, the spinal cord and bright stuff.

Especially after the first question. The second question you had was about.

What proportion of cells.

It needs to be transducer and.

Difficult to know, but we certainly believe that.

With this 50 50 ratio of mosaics versus.

Versus non <unk>.

Sorry, wildfire versus null sells in the metastatic setting we certainly know that if we transition some of the cells, you're going to get some clinical benefit and the likelihood is the more cells. That's all no. The trustees the batch of clinical benefit you get so.

Our approach once again is to give a high dose of drug interests equally to enhance distribution and we know we have confidence that given giving high dose of drug you still see a nice downregulation of the protein being produced which for the wild type cells. So.

Once again, we don't know exactly how many cells neatly trustees, but I think a small number will give you some better but a large and that will give you more benefits, but we're quite confident giving high doses to enhance by distribution because we see all that package working nicely.

Hopefully that answers your question Gabe.

The only thing that I would add to that too.

Two what you mentioned are just two examples.

I would say you know the preclinical dataset that that we've been able to generate particularly the N. H P. Dataset really gives us the opportunity to maximize transduction efficiency and so you just mentioned this.

Before I just wanted to reiterate this the fact of the matter is that we didn't see we didn't observe talks at any dose that was actually given including to each of the 15, you always have the ability to be able.

To increase dose to really maximize our transduction efficiency and to be able to get really nice bio distribution, we see nice bio distribution at the levels that we're starting it but again, if we wanted to be able to maximize that we obviously have the ability to be able to go higher than the second point that I just wanted to make and I think it's something that that does get overlooked.

construct for CLN7 disease in partnership with UT Southwestern and under the leadership

Is a nice correlation to our ceiling.

of Dr. Ben Greenberg, Vice Chair of Clinical and Translational Research and Principal Investigator

<unk> study, which is being done under our collaboration with our partners at UT southwestern this is again a membrane bound protein similar to Mac P. Too. So it's not there is no cross correction here and we've shown the ability to be able to dose patients up to when each of the 15.

during the course of 2022.

Clinical development of Taysha 118 in CLN1 disease also remains

ongoing and we intend to initiate clinical development for a small proof of concept study

for Taysha 105 in SLC13A5 deficiency.

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

Cameron: review our financial results.

And to be able to do that successfully and safely and safely. So some of that early preliminary data was presented at world Symposium earlier this year and since that data has been presented Ah theres been an additional patient that has been dosed at the high dose, which is one of the 15th so again I think I.

Cameron?

Cameron: Thank you, Suyash.

This morning, I will discuss

key aspects of our financial results for the first quarter ended on March 31, 2022.

More

I like to remind the field around the number of first that's really come out of this collaboration.

details can be found in our Forum 10 queue, which will be followed with the SEC shortly.

With Pacer and Ut southwestern where you have the first thing are equally dose gene therapy and history, that's our Johnny on the rock with the study the first gene therapy in development for Ret syndrome. You now have the first gene therapy with the self regulatory feedback loop in clinical development to control expression.

On a cell by cell basis are the first to be able to dose a <unk> at one each of the 15 and to be able to do that safely and to demonstrate safety of and a benign construct so that it just in the short period of time that the company's been in existence Ah Theres been a number of firsts that had been.

As indicated in our press release today, research and development expenses were $37.8 million

<unk> generated.

And it's something that I'm very proud of and I and I always remind our employees to be proud of.

The number of first for the field of gene therapy, that's been generated by the company and our partners at Ut southwestern.

for the three-month ended March 31, 2022, compared to $23.9 million for the three-month

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

ended March 31, 2021. The $13.9 million increase was primarily attributable to an increase

Hey, good morning, guys. Thanks for taking the question I wanted to circle back with regards to the spend I'm wondering if you can offer a little bit more clarity on perhaps the breakdown between R&D and G&A and R&D I think you made an earlier comment too about kind of exploring additional channels for monetization. Just wondering if you could kind of expand on.

A little bit thanks, guys.

Sure. Thanks, Laura Good morning, So I'll start with your last question first really around just ways that we're thinking about extending.

of $9.3 million in employee compensation, which included $2.2 million of severance and

one-time termination costs in connection with the strategic reprioritization of programs

completed in March 2022, and $1 million of non-cash stock-based compensation.

Additionally, in the three months ended March 31, 2022, we incurred an increase of $2.9

Extending cash runway, obviously, you know having business development opportunities continue to remain an opportunity for us to be able to go and bring in non dilutive forms of capital you know what I would say to that is that you know we're constantly looking at potential strategic collaborations.

million of expenses in research and development, manufacturing, and other raw material purchases.

We also incurred an increase of $1.7 million in third-party research and development consulting

fees, primarily related to GLP toxicology studies and clinical study activities.

Financial and administrative expenses were $11.5 million for the three months ended March

31, 2022, compared to $8.2 million for the three months ended March 31, 2021.

The increase of approximately $3.3 million was primarily attributable to $2.9 million

of incremental compensation expense, which included $0.4 million of severance and one-time

<unk> with parties, whether those are regional collaborations our collaboration around specific assets you know.

But it's something that we consistently look at it and we've been fortunate.

You know two to essentially get a lot of calls after we've made our announcement in and at the year end earnings call and so you know we can't continue to explore those as a potential way of bringing in non dilutive capital. What I would also say is again, we look very carefully around which probe.

Brands that would continue in and what the company would actually focus on from a clinical development perspective, and essentially what we decided to do is once you know for programs that have hit proof of concept we essentially.

Ceased with those and and for and again for the ones that are currently in clinical development and haven't yet hit proof of concept. We will continue to move forward with those until we hit that milestone, particularly with a focus on C. O N. One and S. O C 13, eight five going away from that registration speed to registration pathway, which is gonna be a lot.

More expensive from a CMC perspective, and a clinical development perspective, and really just again continuing to validate the platform from a proof of concept perspective, and then still focus with our two lead programs on the fastest pathway to approval and that's a giant Exxon and neuropathy.

And our and our Ret syndrome program, which where we we continue to be all in on but still doing you know.

From a totality of our portfolio really looking with an eye to preserve cash and and a long term runway and so that's the way that that we're kind of looking at looking at this I think you know again as I mentioned earlier, we we executed on a strategic pipeline prioritization earlier this year.

Which is starting to play out where essentially we pause.

Our work on a lot of our preclinical programs and essentially kind of begin re.

Reconstituted a number of our clinical programs continuing to move them forward done for an apple to to preserve cash runway and I think youll start to see our R&D expense come down.

Over over the next few quarters and start to get to a certain run rate as we get into the second half.

The year that we'll be able to the whole constant our ways to augment that obviously, if there was a turnaround in the capital markets. You know, we we should be able to we should be able to go and raise capital through our currently available ATM, which we've already done since our year end earnings.

Call, we've been able to successfully draw down.

Some capital from that ATM that extended cash runway and we will continue to be strategic in the way that we look at that but I would probably say non dilutive forms of capital. Our current term loan facility, which again allows us to have cash into Q4.

2023, and then obviously the ability to be able to tap our ATM, which we've already done I think all of those things be inconsistent are ways that we would look to extend the runway maybe a cameron you'd want to comment.

On just the breakdown between R&D and G&A.

Yeah sure happy to thanks, Alright, and thanks for the question Laura So over 75% of our operating expenses, our R&D related and as already mentioned because of their strategic pipeline prioritization effort, we will be able to reduce that R&D expense burn significantly over the next coming quarters.

As a result of pausing research and development activities on our preclinical programs as well as.

Significant reduction in our CMC expenses ultimately as a reminder, we conducted six GMP batches last year.

Some of which were completed in Q1 of this year in terms of product release, and we're only doing GMP manufacturing on our Gan program. This year. So you can expect a significant reduction in our expense year over year and in subsequent quarters. As a result, so again a lot of a lot of nice work.

So really focus our resources and our efforts primarily on of course gamma graph.

Thanks Kamran.

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

Hi, Thanks for taking my questions.

A couple on the Ret syndrome, a clinical trial, what is the waiting period for safety observation.

Patient one is dosed.

And how how would you or certain whether there is a Mac P. Two overexpression associated toxicity.

Even that.

Mcafee to duplication syndrome share a lot of the same manifestations are with the ret syndrome. Thank you.

Yeah. Good morning, I'll turn that question over.

Too soon to provide some context so yes.

Sure. So the stock is cyclically is.

Eight weeks.

Dose appropriate view of the eight week time point discussions the DMC will ensue.

And in the absence of any safety issues.

We will then go ahead and dose the next patient.

But that's that's between patients wanted to as time progresses, the staggering changes in a clinical trial of course.

You need less stack rank as the study progresses.

Specifically with regard to signs of overexpression toxicity. It's a good question on this one we discuss at length, both with regulators and with key opinion leaders.

And the bottom line is the most.

Most patients all patients in the adult study certainly liked in the pediatric study will be in the phase three of Ret syndrome are either stable or not declining.

May recollect that this.

This full phases to the clinical progress of patients with ret.

This is why they get a diagnosis.

This too is when there's a rapid decline in functionality phase III is that when they are in a stable phase <unk>.

Stay with the right call points level of functioning.

And then.

It can be in place for years, sometimes decades, and then they end up until the late deterioration face all patients in the study will be the phase III are stable. So what we're looking for clinically is any kind of acceleration okay. Because it's.

Because there was such a pull stay stable for a while if there's any deterioration seen in terms of ret syndrome trial.

It is a rather than Europe neurological features is likely to be <unk> over expression.

Correct. The Ret syndrome now moving that's a definite that we wouldnt because we cant biopsy brain tissue of course and in the clinical trial in patients, but the way we're observing specific pizza of refreshing toxicity is about looking for a change in the mental status and the change of neurological space.

It's us and your behavioral states us.

And central nervous system peripheral nervous system.

Deterioration.

After dosing with a gene therapy are likely to be due to progression to Brett.

It could be due to over especially toxicity that feature it.

Having settled what we anticipate is highly unlikely given already HP talk states and I'll wrap top states and while we gave very high doses of the.

The drug for cold of the presumed clinical dice and sold no toxicity, even at that high level.

Thanks, so much.

Thank you, ladies and gentlemen, we've come to the end of our time allowed for questions I'll turn the floor back to Mr session for any final questions comments.

Thank you operator and again, thank you for everybody for joining our Q1 call today as we iterate as we iterate. It earlier the company has performed quite nicely coming out of Q1, and Archie Puget pipeline prioritization also a refocus on continuing to move forward, our Gan program, our Ret program.

termination costs, and $0.7 million of non-cash stock-based compensation.

We also incurred an increase of $0.4 million in professional fees related to insurance,

investor relations, communications, accounting, and market research.

Net loss for the three months ended March 31, 2022, was $50.1 million, or $1.31 per

share, as compared to a net loss of $32 million, or $0.87 per share, for the three months ended

March 31, 2021.

As of March 31, 2022, Tayshia had $96.6 million in cash and cash equivalents.

This cash balance excludes $12 million in gross proceeds generated from the sale of

common shares under our existing at-the-market facility, or ATM, in April.

Current cash and cash equivalents, along with full access to our existing term loan facility,

is expected to fund operating expenses and capital requirements into the fourth quarter

From a speed to registration aspect and then morphing some of our earlier clinical programs to more proof of concept studies I couldnt be prouder of the execution of the team I couldnt be prouder of the focus of the team and we continue to invite you guys to follow the progress that the company continues to make strides later this year with that I wish you guys.

of 2023.

RA Session II: And with that, I will hand the call back to R.A.

Thanks, Cameron.

RA Session II: Our focus for 2022 continues to be on executing across our core development programs, and

I am extremely proud of our team's progress and accomplishments this quarter.

We continue to maintain a strong cash position that should provide runway into the fourth

quarter of 2023.

RA Session II: I will now ask the operator to begin our Q&A session.

We would like to thank our Tayshia employees, Board of Directors, Scientific Advisory Board,

Operator?

collaborators, and the patients and advocates for their ongoing support of our mission to

develop curative gene therapies to eradicate devastating monogenic CNS disease.

Operator: Thank you.

If you'd like to ask a question, please press star 1 on your telephone keypad.

Thank you.

A confirmation tone will indicate your line is in the question queue.

RA Session II: Hey, good morning, Mehdi.

You may press star 2 if you'd like to remove your question from the queue.

A wonderful week many of us, albeit a S E T. So I would ask you guys to cut by say hi.

Thank you for the question.

For participants using speaker equipment, it may be necessary to pick up your handset

We're going

You know, I think we've gone through

before pressing the star keys.

to go in and ask for approval based off the current data set.

this when we actually presented the definitive data set earlier this year really around kind

In the interest of time, we ask that you each keep to one question.

But our base case would be

of the current scenarios and how we look at them.

Our first question comes from the line of June Lee with TruSecurities.

dosing a few more patients that would immediately roll over from the NIH natural history study.

We essentially, you know, cut them in

June Lee: Please proceed with your question.

And so this is something that we've previously stated before and continues to be our base case.

two parts, one being ex-U.S., one being the U.S.

Hi.

Particularly for the FDA, that breaks

Mehdi Goudarzi: Good morning and thank you for taking my question.

And I look forward to seeing many of you there with that.

down to about three scenarios, the first being being able to immediately file off the data

This is Mehdi for June.

that we've generated thus far.

So what is the probability by which you think FDA might ask you to have efficacy data on

Again, we've reported data from all therapeutic dose cohorts,

new patients using commercial-grade material and how long would you think it takes to provide

including the high dose of 3.5E to the 14 earlier this year, where we really see really

such data?

nice efficacy and safety, durability.

In today's call. Thank you.

And now we have really nice pathological data

Thank you.

with the biopsy showing neurofiber regeneration, which essentially we view as a game changer.

Gil Blum: Our next question comes from the line of Gil Bloom with Needham & Company.

Thank you.

And so we're pretty excited about this data set, not only because we show clinical, but

Please proceed with your question.

Yeah.

With that, we'll end today's call.

Thank you. This concludes today's conference you may disconnect. Your lines at this time. Thank you for your participation.

we show really nice clinical data, but also safety and efficacy data, but also really

Good morning, and thanks for taking our question, maybe another quick one on Taysha 120.

It's actually a really good question, Gil.

the biopsy data and the natural history, which essentially has been going on for close to

Sure.

Thanks for asking, and I'll start, and so yes, please chime in if you'd like.

Thank you.

10 years.

So, what more is there to do on your commercial-grade product, you know, what more things do you

But essentially, there's not much more to do on this commercial-grade material.

And each patient rolling over from that natural history study provides three

need to do there, and maybe you can give us an idea of how many patients can be treated

We initiated the manufacturing run earlier this year.

levels of control.

with this batch.

We have now completed that manufacturing run.

The patient has a comparison between their own pretreatment and post-treatment

It was quite successful, both from a yield perspective and a purity perspective.

performance.

The current analytics that we've run around comparability to the original clinical material

Because it's such a large natural history study, over 50 patients at this point,

are spot on, and those tests continue to be ongoing.

we're able to show age-matched controls, and then you're able to compare the entire cohort

The team, CSH's team, along with Fred's team, are continuing to work on key assays, key

to a patient's performance.

release assays that'll support the BLA, including the definitive potency assay, which the team

So we're really excited, again, about the breadth of this data.

has made significant progress on, which I'm quite pleased about.

As I mentioned, our base case is most likely that the FDA would ask you to dose a few more

And just to give you an idea on just the yields from this run, the team has done just a fantastic

patients using the commercial-grade material.

job around manufacturability, and depending on the dose, and I'll just go with the high

And this is a similar pathway of what they

dose, the 3.5E to the 14, we're over 50 patients' worth of drug.

asked Avexis to do during the registration of Zolgensma.

And so that gives you an idea around just, one, the strength of our platform.

Most likely it would be what

This is using our HEC293 suspension triple plasma transfection platform that we use across

we would consider a handful of patients, somewhere between probably three to five patients.

the entire portfolio, but also just really the strength of the team that we have in CMC.

Those

So I couldn't be even more proud.

patients are already identified. So from a timing perspective, this would shorten any

So what we'll do is this run will continue to undergo release testing, stability testing,

type of recruitment effort to get these patients into the study, because essentially they would

and whatnot, and the team will continue to gather data to support the BLA.

roll over from the natural history study.

But really, the progress that the team has made in this manufacture of this commercial-grade

So these patients are already identified in

material has gone even better as we could imagine.

our partners at the NIH, under the leadership of Carson Bonham, and have done a fantastic

So I'll stop there.

job keeping that study moving and the wealth of data that we've generated from that study.

CSH, do you have anything to add?

So we really see the difference between filing immediately, based off the current data set,

No.

and dosing a few more patients.

You know, I think I would just echo the fact that, you know, the batches made, there was

We're probably looking at about a six-month time difference.

plenty of product made.

It's not a huge time difference, because again, we don't have to go out and identify patients.

It was a high-yielding run, and release testing is underway, looking at the characterization

Those patients are already identified.

of the product, and it's all looking very promising thus far.

And so we think by dosing a few more patients,

RA's quite correct.

that would probably set us up for an approval towards the end of 2023.

The only thing really that's outstanding is to finalize the potency assay.

This is, again, the

And just to remind you, you know, potency assay essentially exists to demonstrate on

FDA scenario.

the molecule that we're administering, closely mimics, and works effectively in the clinical

The EMA are going in position is that we meet all the requirements for conditional

settings it does, in the lab setting, and, you know, every lot needs to be tested.

approval.

There's certain predefined acceptance criteria that need to be met.

And the hope is to initiate MAA filing by the end of the year.

The FDA and the regulators are pretty keen to ensure, obviously, that the product we

We would also ask,

make on an ongoing basis is consistent and highly, you know, the appropriate level of

just shifting focus back to the FDA, based off the current data set, we would ask the FDA,

quality.

as a default, to initiate a rolling submission based off of the data that we've generated.

And as RA said, we have made a lot of progress in finalizing that potency assay.

The preclinical data won't change.

So everything is looking great.

The clinical data set would be near final if they asked us to

Release testing is underway, and drugs are going to be available to be treating patients

dose a few more patients.

imminently.

So we would be able to start the review of the current data set.

Thank you.

And obviously, we would have completed the release testing and the analytical panel for

Our next question comes from the line of Salveen Richter with Goldman Sachs.

our commercial-grade material, which we've already completed the manufacture of.

Salveen Richter: Please proceed with your question.

It's

Hey.

currently undergoing release testing.

Elizabeth Webster: Good morning, guys, and thank you for taking our question.

And we're quite excited about not only the yields,

This is Elizabeth on for Salveen.

but also the product purity from that run.

Maybe just switching over to Rhett, if you could comment on the nature of the first clinical

So that's kind of our going-in strategy.

data we expect to see and how many patients we can expect to see data from.

And then a second one from us are what kind of assumptions have been baked into the 4Q23

cash runway guidance?

Thank you.

Sure.

Well, let me take the question about the clinical trial, and then Kamran and I can handle the

second question.

So, with regard to the Rhett clinical trial, this is a trial in adult females with Rhett

syndrome.

To remind you, we just felt given the concerns about potential overexpression, which we show

we can actually downregulate very nicely in our NHP data, we still want it to be a little

bit conservative.

And so we're starting off in adults, and the plan will be to move into children, pediatric

females with Rhett at some point thereafter, and then we want to plan a small study in

boys, the very rare population of boys with Rhett shortly thereafter.

Now, in terms of expectations with regard to what we're going to have coming out of

the clinical trial data of the adult study, which we anticipate sharing data from by the

end of the year, the likelihood is going to be safety data and perhaps some preliminary

efficacy data.

We're not sure at the moment.

You know, we will, as is the case for these first-in-hand studies with these innovative

products, we have to stagger dosing.

We can't dose several patients all at once.

We have to dose one patient, leave it a period of time, and then dose the second patient

after a DMC review, and then leave it a period of time before dosing the next patient.

So my guess is it's going to be a small number of patients, safety data by the end

of this year, potentially some preliminary efficacy data if we start to see some early

signs of that.

But I think that's what we're focusing on for the clinical trial at the moment.

With regard to assumptions, I'll let R.A. and Cameron take that question.

Sure.

And thanks, Liz, for the question.

I was actually talking on mute.

So just to reiterate what Suyash mentioned, you know, we're quite excited about the Rhett

data, the preclinical data set that supports the CTA, and, again, are really excited about

what this means to the Rhett community, being the first and only gene therapy actually in

clinical development for Rett syndrome.

And I think just to echo what Suyash mentioned, it'll really be on the totality of data.

The amount of endpoints that are being collected are immense, both from physician-reported

Rett syndrome outcomes, patient-reported outcomes, respiratory measures, obviously

some neurodevelopmental measures as well as movement.

So it's really going to be, you know, a whole host of endpoints that we'll share, including

safety.

And safety is going to be probably one of the most important ones because there's always

this notion around overexpression.

And the data from our NHP study, our NHP-TOC study, not only demonstrated the safety of

our construct at doses up to fourfold above what the starting dose will be in the clinical

setting, but also proof of mechanism, the ability to downregulate the expression of

MeCP2 in the presence of wild-type MeCP2.

And so, again, for us, it's quite exciting, but certainly this is one of the reasons why

we decided to start in two adults.

So I would probably characterize it similarly the way that Suyash did, and it'll be on the

totality of data.

It'll be safety with some preliminary efficacy in there.

From an assumption perspective on cash runway, the way that we're thinking about this is

with the full drawdown of our current term loan facility from Silicon Valley Bank, we

have the ability to be able to extend runway into Q4 of 2023 along with our existing cash.

And that's kind of the assumption, the base case assumption that's gone in.

As you are aware, we executed on a pipeline prioritization exercise earlier this year,

which we announced at our year-end earnings call, which also included a RIF of 35%, and

essentially kind of a right-sizing based off of a clear focus on two key programs, and

that's our Rett Syndrome Program and our Gynecological Neuropathy Program, which we're both quite

excited about.

And then taking two of the additional clinical development assets and moving those from more

of a registration-directed trial to more of a kind of small proof-of-concept study, that

being CLN1 and then SLC13A5.

What I would also say, though, is, again, I'm quite excited about the progress that

the team has made just in this short period of time, and really the ability to be able

to get through this prioritization analysis and kind of refocus the company and still

execute has just been something that I've been immensely proud of.

It's not easy for anyone out there in biotech and particularly in gene therapy, but the

team is really nose-to-the-grind in executing.

And so for us, all of this has been baked into our cash analysis, and we continue to

look at ways to augment and extend runways.

Thank you.

Kevin DeDeter: Our next question comes from the line of Kevin DeDeter with Oppenheimer & Company.

Please proceed with your question.

Hey, great.

Thanks for taking our questions.

Just on the GAN regulatory update, Ari, can you comment on your confidence sort of of

that mid-2022 update timeline, I guess sort of underlying this question?

Is it reasonable

to conclude that you have the necessary meetings with FDA now that regulatory agencies are

waiting for feedback at this point?

Are there kind of open scheduling components that could

impact that timeline and cause some uncertainty there?

RA Session II: Yeah, thanks, Kevin, for the question, and good morning.

So I think we're confident in

reiterating that guidance around the mid-2022 from a regulatory feedback perspective.

Again,

I think most people going to have conversations with the FDA and the EMA in a COVID environment

and other regulatory agencies in a COVID environment.

Obviously, there's been a little bit of flex

in scheduling.

But with that being said, we're quite excited in the promise of the

data set that we presented thus far, the reproducibility of that data, and the fact of the matter that

the product is not only efficacious, but durable and safe at multiple doses, including a really

robust natural history study.

And now the beginnings of what would be a really nice

data package from a Module 3 perspective from a CMC comparability.

So we're going to go in with

that data set.

And obviously, our go-in strategy is to be able to file off of the current data

set.

And as a default base case, we essentially default to being prepared to dose a few more

patients with the commercial-grade material.

So we're reiterating that guidance.

We've done

that in our communications and look forward to updating you guys here closer to later

this year.

But again, mid-year 2022 is our guidance around having that feedback in hand.

Thank you.

Jack Allen: Our next question comes from the line of Jack Allen with Baird.

Please proceed

with your question.

Hi, thank you so much for taking the questions

and congratulations on all the progress.

I wanted to shift gears back to Rhett really

briefly and talk about the dose there.

I know you mentioned that you're starting at 5e to

the 14th total VG and then moving up to 1e to the 15th, and that I guess the preclinical

package showed safety at 4x the first dose.

I'm just curious, was there a dose in the

preclinical package where you did see tolerability issues?

And how much coverage do you think

you have to dose escalate as you move through the study based on the existing preclinical

package?

Thanks, Jack.

Great question and good morning.

I'll turn it over to Suyash to answer that question.

Yeah.

Hi, Jack.

Thanks for the question.

So it's a really important question.

You know,

the dose selection for the clinical trial for a gene therapy study, getting the dose

right the first time is really important because you've got to make sure you give enough drug

to make sure the drug's effective, but also make sure there's no safety or tolerability

issues because once you've given the gene therapy drug, you can't take it away again.

So it's a really critical decision that needs to be made.

And in particular for Rhett, where

there is this risk of overexpression toxicity, so you have to get the amount of protein being

produced within these appropriate physiological limits, enough to make sure you're having

efficacy but not so much protein that it causes a toxic side effect.

Because of that, we actually did a very, very disciplined preclinical package, which included

a mouse pharmacology study, so a mouse model pharmacology study.

We did a rat toxicology

study.

We did an NHP toxicology study.

All of the studies were very extensive and very

comprehensive.

The mouse study was over 250 mice.

The rat study was over 120 rats.

And

the HP study was 24 NHPs.

And the mouse pharmacology study is where you look for a dose that's

going to be efficacious.

And we were able to identify that very clearly in terms of

demonstrating enough drug causing an improvement in survival, motor assessments, respiratory

assessments, and other assessments.

So the 5E14 total VG dose is above that level.

And

then on the other end, both in the rat tox and in the NHP tox, we tested doses up to

an equivalent of 2E15 total VG, human equivalent.

So that's fourfold over the starting dose.

And to answer your question specifically, there was no adverse events of any note at

the 2E15 dose.

So it's possible we could go even higher than that.

But we didn't test

higher than that because we didn't think there'd be a need to go higher than 2E15, simply because

we saw efficacy at a much lower amount in the mouse pharmacology study.

And I think it was that combination of studies that really persuaded Health Canada to allow

the CTA to be opened.

And I think there's one other important piece around this NHP study that is really, really

important.

And I'll actually be discussing this at a poster presentation at ASGCT.

I think it's tomorrow, tomorrow, Wednesday, I think it's Tuesday, actually, yeah, I'm

presenting it Tuesday.

And I actually presented this data at the big Rett Syndrome scientific conference that's

organized by the ISRF about three or four weeks ago.

And the NHP toxin does three things.

It shows a full absence of any kind of toxic effects, which is important at four-folds

higher than the clinical dose.

It also shows really excellent bio-distribution from an interstitial dose throughout the brain

and the spinal cord.

So you're getting vector copy numbers in a very nice range, one to two copies per diploid

genome in different parts of the brain, in the spinal cord, in the ganglia, in the peripheral

nervous system.

And it also shows correspondingly low levels of RNA.

And don't forget, these are wild-type NHPs.

So what that means is you're getting great delivery of drug into the brain and spinal

cord, but actually very high down regulation, meaning not much RNA being produced, which

is appropriate given it's a wild-type animal.

So that NHP study shows safety, it shows bio-distribution, but importantly, mechanism of action.

And as I say, I'll be going through that data in more detail at the ASGCT meeting tomorrow.

So that group of studies together was really very persuasive to Health Canada to allow

us to open the CTA.

Thank you.

Our next question comes from the line of Yoon Song with BTIG.

Please proceed with your question.

Yoon Song: Hi.

Thank you very much for taking the question.

This is actually a follow-up question on just what you said just now, Suresh.

So on Rett syndrome, has anyone looked at comparability between non-human primates and

human patients in terms of bio-distribution?

And also, given that this is not cross-correction to be expected, so are there any data to suggest

the transduction efficiency?

Or do you have an estimate on how many cells will need to be transduced to see reasonable

efficacy?

So two very good questions.

So the first question was about the translatability of NHP bio-distribution to human bio-distribution.

You know, it's a good question.

No one's done it specifically in Rett.

What we've done is we've shown very nice bio-distribution with our Rett program with an intradecal dose

into an NHP, which is, of course, smaller than a human being.

But the anatomy is very similar.

And it's probably the best corollary looking at bio-distribution in any animal model to

the human.

And we get really nice bio-distribution throughout the brain and the spinal cord with an intradecal

dose of injection.

Now, in the human setting, the only way to really ascertain bio-distribution is in the

third situation, if a patient was to pass away, and to look at DNA and RNA and protein

in that individual.

And that did happen very early on in one of the low-dose GAN patients who sadly passed

away through progression of disease.

This data has been presented by Carsten Bonnemann and Stephen Gray at the ASGCT meeting a few

years ago.

And they showed that with an intradecal dose of the AV9 gene therapy for GAN, you actually

got nice bio-distribution, although at a low level, because it was a low dose, throughout

all target organ tissues.

And the other thing I will say that we learned from the GAN program, and don't forget, GAN

is AV9, it's ACK293, and it's intradecally delivered.

So lots of similarities to the RET program.

The other thing I'll say about GAN is that we've demonstrated more recently in our January

presentation that we see improvements in the peripheral nerves in the nerve biopsies.

Now these are nerve biopsies that are performed in the radial superficial nerve, which is

a nerve in the wrist.

And what this means is that drug is getting down into the peripheral nervous system, down

to the wrist, from an intradecal dose of injection.

So for those reasons, we're confident that an intradecal dose of drug will actually deliver

drug in RET syndrome very nicely to all the tissues that need to be transduced, which

are brain, in particular, and spinal cord and brain tissue.

Stamm.

That answers the first question.

The second question you had was about, you know,

what proportion of cells need to be transduced.

And it's difficult to know, but we certainly

believe that with this 50-50 ratio of mosaics versus non-mosaics, sorry, wild-type versus

null cells in the mosaic setting, we certainly know that if we transduce some of the cells,

you're going to get some clinical benefit.

And the likelihood is the more cells that are null

that you transduce, the better clinical benefit you get.

So our approach, once again, is to give

a high dose of drug intrathecally to enhance biodistribution.

And we know, we have confidence

that given giving high doses of drug, you still see a nice downregulation of the protein being

produced, which for the wild-type cells.

So once again, we don't know exactly how many cells need

to be transduced, but I think a small number will give you some clinical benefit.

A large number

will give you more benefit.

But we're quite confident giving high doses to enhance biodistribution

because we see our downregulation package working nicely.

Hopefully, that answers your question,

Joon.

The only thing that I would add to what you mentioned are just two examples.

I would say the preclinical data set that we've been able to generate, particularly

the NHP data set, really gives us the opportunity to maximize transduction efficiency.

And so you

just mentioned this before.

I just wanted to reiterate this.

The fact of the matter is that

we didn't see, we didn't observe tox at any dose that was actually given, including

2E to the 15.

You always have the ability to be able to increase dose to really maximize

transduction efficiency and to be able to get really nice biodistribution.

We see nice

biodistribution at the levels that we're starting at.

But again, if we wanted to be able to maximize

that, we obviously have the ability to be able to go higher.

The second point that I just wanted

to make, and I think it's something that does get overlooked, is a nice correlation to our CLN

7 study, which is being done under collaboration with our partners at UT Southwestern.

This is,

again, a membrane-bound protein, similar to MeCP2.

So it's not, there is no cross-correction

here.

And we've shown the ability to be able to dose patients up to 1E to the 15 and to be able

to do that successfully and safely.

Some of that early preliminary data was presented at

World Symposium earlier this year.

And since that data has been presented, there's been an

additional patient that has been dosed at the high dose, which is 1E to the 15.

So again, I think I

like to remind the field around the number of firsts that's really come out of this collaboration

with Tayshia and UT Southwestern, where you have the first intrathecally-dosed gene therapy

in history.

That's our Gynexonal Neuropathy Study, the first gene therapy in development

for Rett syndrome.

You now have the first gene therapy with the self-regulatory feedback loop

in clinical development to control expression on a cell-by-cell basis.

The first to be able

to dose intrathecally at 1E to the 15 and to be able to do that safely and to demonstrate safety

of an AAV9 construct.

So just in the short period of time that the company's been in existence,

there's been a number of firsts that have been generated.

And it's something that I'm very proud

of.

And I always remind our employees to be proud of the number of firsts for the field of gene

therapy that's been generated by the company and our partners at UT Southwestern.

Webster.

Thank you.

Our next question comes from the line of Laura Tico with Wedbush Securities.

Please proceed with your question.

Hey, good morning, guys.

Thanks for taking the question.

I wanted to circle back with regards to the spend.

I'm wondering if you can offer a little bit more clarity on perhaps the breakdown between

R&D and G&A.

And, Ari, I think you made an earlier comment, too, about kind of exploring additional channels

for monetization.

I'm just wondering if you could kind of expand on that a little bit.

Thanks, guys.

Sure.

Thanks, Laura.

Good morning.

So I'll start with your last question first, really around just ways that we're thinking

about extending cash runway.

Obviously, having business development opportunities continue to remain an opportunity for us to

be able to go and bring in non-diluted forms of capital.

What I would say to that is that we're constantly looking at potential strategic collaborations

with parties, whether those are regional collaborations or collaborations around specific assets.

But it's something that we consistently look at.

And we've been fortunate to essentially get a lot of calls after we've made our announcement

at the year-end earnings call.

So we continue to explore those as a potential way of bringing in non-dilutive capital.

What I would also say is, again, we look very carefully around which programs that would

continue and what the company would actually focus on from a clinical development perspective.

And essentially what we decided to do is once for programs that have hit proof of concept,

we've essentially ceased with those.

And again, for the ones that are currently in clinical development and haven't yet hit

proof of concept, we'll continue to move forward with those until we hit that milestone, particularly

with the focus on CLN1 and SLC1385, going away from that registration speed to registration

pathway, which is going to be a lot more expensive from a CMC perspective and a clinical development

perspective, and really just, again, continuing to validate the platform from a proof of concept

perspective.

And then still focus with our two lead programs on the fastest pathway to approval, and that's

our Gynexonal Neuropathy and our Rett Syndrome program, which we continue to be all in on,

but still doing from a totality of our portfolio, really looking with an eye to preserve cash

and long-term runway.

And so that's the way that we're kind of looking at this.

I think, again, as I mentioned earlier, we executed on a strategic pipeline prioritization

earlier this year, which is starting to play out, where essentially we paused work on a

lot of our preclinical programs and essentially kind of, again, reconstituted a number of

our clinical programs, continuing to move them forward, done for an effort to preserve

cash runway.

And I think you'll start to see R&D expense come down over the next few quarters and start

to get to a certain runway as we get into the second half of the year that we'll be

able to hold constant.

Ways to augment that, obviously, if there's a turnaround in the capital markets, we should

be able to go and raise capital through our currently available ATM, which we've already

done since our year-end earnings call.

We've been able to successfully draw down some capital from that ATM that extended cash

runway, and we'll continue to be strategic in the way that we look at that.

But I would probably say non-diluted forms of capital, our current term loan facility,

which again allows us to have cash into Q4 2023, and then obviously the ability to be

able to tap our ATM, which we've already done.

I think all those things being consistent are ways that we would look to extend runway.

Maybe Cameron, you'd want to comment on just the breakdown between R&D and G&A.

Yeah, sure.

Happy to.

Thanks, RA.

And thanks for the question, Laura.

So over 75% of our

operating expenses are R&D related. And as RA mentioned, because of the strategic pipeline

prioritization effort, we'll be able to reduce that R&D expense burden significantly over

the next coming quarters as a result of pausing research and development activities on our

preclinical program, as well as significant reduction in our CMC expenses.

Ultimately,

as a reminder, we conducted six GMP batches last year, some of which were completed in

Q1 of this year in terms of product release.

And we're only doing GMP manufacturing on

our GAN program this year.

So you can expect a significant reduction in our CMC expense

year-over-year and in subsequent quarters as a result.

So again, a lot of nice work

to really focus our resources and our efforts primarily on, of course, GAN and RETS.

Thanks, Kamran.

Thank you.

Our next question comes from the

Yanan Zhu: line of Yan and Zhu with Wells Fargo.

Please proceed with your question.

Yanan Zhu: Thanks for taking my questions.

A couple on the RETS syndrome clinical trial.

What

is the waiting period for safety observation once patient one is dosed?

And how would you

ascertain whether there is MEK-P2 overexpression associated toxicity, given that the MEK-P2

syndrome share a lot of the same manifestations with RETS syndrome?

Thank you.

Hi, Yan.

And good morning.

Suyash: I'll turn that question over to Suyash to provide some context.

Suyash?

Sure.

So the stagger specifically

is eight weeks. So after a patient's dose, they'll review at the eight-week time point

and discussions with DMC will ensue.

And in the absence of any safety issues, we will then go

ahead and dose the next patient.

But that's between patients one and two.

As time progresses,

the staggering changes in the clinical trial, of course, need less staggering as the study

progresses.

Specifically, with regard to signs of overexpression toxicity, it's a good question.

And it's one we've discussed at length, both with regulators and with key opinion leaders.

And the bottom line is this.

Most patients, in fact, all patients in the adult study,

certainly, and like in the pediatric study, will be in the phase three of RETS syndrome,

i.e.

they're stable.

They're not declining.

You may recollect that there's four phases to

the clinical progress of patients with RETS.

The first is where they get the diagnosis.

The

phase two is when there's a rapid decline in functionality.

Phase three is when they're in

a stable phase, i.e.

stable with a very compliance level of functioning.

And then they can be in that

phase for years, sometimes decades.

And then they end up into a late deterioration phase.

So all patients in the study will be in the phase three, i.e.

they're stable.

So what we're looking for clinically is any kind of deterioration, okay?

There is such a poor state and they've been stable for a while, if there's any deterioration

seen in terms of Rett syndrome type behaviors or rather neurological features, it's likely

to be due to overexpression than a progression of Rett syndrome.

Now will we know for definite?

No we wouldn't because we can't biopsy brain tissue of course in a clinical trial in patients,

the way we're observing specific MEK P2 overexpression toxicity is by looking for a change in the

mental status and the change of neurological status and neurobehavioral status and central

nervous system, peripheral nervous system deterioration after dosing with the gene therapy

because that's unlikely to be due to progression of Rett, it's likely to be due to overexpression

toxicity of MEK P2.

Having said all that, we anticipate that's highly unlikely given our NHP tox data and

our Rett tox data where we gave very high doses of the drug fourfold over the presumed

clinical dose and saw no toxicity even at that high level.

Thanks, T.S.

Thank you.

Operator: Ladies and gentlemen, we've come to the end of our time allowed for questions.

I'll turn the floor back to Mr.

RA Session II: Session for any final questions and comments.

Thank you, operator.

And again, thank you for everybody for joining our Q1 call today.

As we iterated earlier, the company has performed quite nicely coming out of Q1 and our strategic

pipeline prioritization.

Also a refocus on continuing to move forward our GAN program, our Rett program from a speed

to registration aspect and then morphing some of our earlier clinical programs to more proof

of concept studies.

I couldn't be prouder of the execution of the team.

I couldn't be prouder of the focus of the team.

And we continue to invite you guys to follow the progress as the company continues to make

strides later this year.

With that, I wish you guys a wonderful week.

Many of us will be at ASGCT, so I would ask you guys to come by, say hi, and I look forward

to seeing many of you there.