Q3 2022 Taysha Gene Therapies Inc Earnings Call

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[music].

Thank you for standing by.

Welcome to Acacia gene therapies third quarter, 2022 financial results and corporate update conference call.

At this time all participants are in listen only mode. Following management's prepared remarks, we will hold a brief question and answer session.

A reminder, this call is being recorded today November eight 2022.

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

Good morning, and welcome to tissue third quarter 2020 financial results and corporate update conference call. Joining me on today's call are already session. The second patient President founder and CEO , Doug Just Jewish Prasad Chief Medical Officer, and head of R&D and can't went along Chief Financial Officer. After our formal remarks, we will conduct a question and answer session and instructions.

I'll follow at that time.

Today patient issued a press release announcing financial results for the third quarter ended September 30th 2022 a copy of this press release is available on the company's website and through our SEC filings.

Please note that on today's call, we will be making forward looking statements, including statements relating to the safety and efficacy and the therapeutic and commercial potential of our investigational product candidates as well as the strategic investment by Astellas.

Statements may include the expected timing and results of clinical trials for our product candidates our expectations regarding the data necessary to support regulatory approval of Taishan 120, and the regulatory status and market opportunity for tissue when 20 tissue, one or two in patients other clinical programs as well as the potential benefits of the strategic investment by Astellas, including the potential.

First tell it to exercise any of the options we granted to them.

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

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

East West included charges related to the timing and results of clinical trials and preclinical studies of our product candidates.

Dependence upon strategic alliances and other third party relationships, our ability to obtain patent protection for our discoveries limitations imposed by patents owned or controlled by third parties and the requirements of substantial funding to conduct our research and development activities for lessons description of the risks and uncertainties that we face. Please see the reports that we have filed with us.

Securities and Exchange Commission. This conference call contains time sensitive information that is accurate only as of the date of this live broadcast November eight 2022.

<unk> 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 quiet be required by applicable securities law.

I would now like to turn the call over to our president founder and CEO Ari session the seconds alright.

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

I'm very proud of what the company has accomplished in the past few months.

The strategic investment from Astellas and they successfully completed public follow on offering has strengthened our balance sheet and extended our cash runway into the first quarter of 2024.

We are excited about the recent strategic investment from Astellas to support the development of tissue 120 for giant XOMA neuropathy again in case of 102 for Ret syndrome.

The partnership with Astellas underscores the therapeutic and market opportunity of these two programs and importantly, further validates our scientific approach of combining established gene therapy technology with innovative targeted payload design.

Under the terms of the agreement Astellas will make a 50 million dollar investment and patience in exchange for 15% of patients outstanding shares pre follow on financing.

As well as an exclusive option to license the worldwide development manufacturing and commercial rights to Tisha 120 in Gan for a period of time after receipt of the formal type b into phase two meeting minutes from the FDA.

Astellas will also receive an exclusive option to license the worldwide development manufacturing and commercial rights to tissue, one O two and ret syndrome for a period of time. After we provide astellas access to certain clinical data from the planned rep female pediatric study.

Astellas will also receive a right of first offer related to a change in control of T shirt for a period of time after receipt of the rec clinical data package.

To further strategically aligned the two companies Astellas will also receive one board observer seat on the tissue board of directors, enabling us to leverage astellas clinical and commercial expertise.

Economics associated with the potential licenses will be negotiated by both companies.

At a later date should Astellas decides to exercise any of these options next slide.

We believe we have selected the best possible partner in a Dallas a premier biopharmaceutical company that has built global R&D manufacturing and commercialization capabilities instead.

Astellas has a dedicated leader in the field of gene therapy with large scale fully integrated in house GMP manufacturing.

Building upon its Dallas this acquisition about dentists. This partnership fits strategically within their long term vision of expanding its gene therapy capabilities and enhancing focus on genetic regulation.

So ultimately bring new transformative gene therapies for serious genetic diseases with limited treatment options.

We believe at Telus with clinical development and commercialization experience combined with patients capabilities and know how of gene therapy.

It will help us achieve our shared objectives.

We look forward to this partnership and the potential to bring life changing treatments to patients around the world.

In 2023, we expect to provide an update on the regulatory pathway for <unk> 120 engaging in January .

Boeing are type b into phase two meeting with the FDA. In addition, we intend to disclose preliminary clinical data for Acacia one O. Two from the first cohort of adult patients with Ret syndrome, and initiate a phase one slash two clinical study for T shirt, one O two and female pediatric patients with <unk>.

Ret syndrome in the first half of 2023.

I will now turn the call over to <unk> to discuss our clinical programs. So yes.

Yeah.

Thank you all right and good morning, everyone. Our two lead clinical programs have generated a significant amount of compelling evidence I have exciting upcoming milestones that could support a potential to make life changing impacts for patients worldwide.

I'll begin with a recent update on Tcl 120th again.

Argon program includes a comprehensive and robust clinical package that is supported by evidence generated across multiple clinical functional neuro physiological and pathological endpoints. These include the MFN such two motor function assessment, demonstrating clinically meaningful slowing of disease progression across all therapeutic dose.

Co host compared to natural history decline with a durability of effect observed up to five years post dosing.

The progressive loss of visual acuity towards blindness as assessed by longwall stabilized after treatment with Taishan 120 <unk>.

This was supported by the findings in retinal nerve fiber layer thickness or are in F. L. As assessed by optical coherence tomography, which demonstrated stabilization on prevention of further restful tissue loss following taishan 120 treatment.

Electric geologic nerve conduction studies support Recoverability stabilization and in some cases improvements in sensory response in patients treated with Taishan 120.

Nerve biopsies confirmed that treatment with Taishan, one 'twenty result, inactive regeneration of nerve fibers and.

And lastly, CMC comparability testing validated thus all clinical and commercial grade material or comparable via our release assays on next generation sequencing.

We have a type b under phase two meeting scheduled with the FDA via teleconference. On December the 13th which will enable us to have discussions regarding a pathway to our bailey filing.

We expect receipt of the formal meeting minutes by mid January at which time, we will provide an update.

Next slide please.

We continue to work with regulatory agencies with the goal of achieving conditional approval in Europe and accelerated approval in the United States based on M E and F D. A industry guidance for gene therapies, and neuro degenerative diseases.

Based on key registrational requirements from regulatory agencies, including the FDA and EMA, we have outlined some possible scenario for approval.

In Europe , we believe there is potential to false conditional approval based on current data set for MAA guidance documents.

In the U S. The first scenario is immediate filing for approval based on the current dataset and comparability.

The second scenario, which we view as a base case cheeses dosing a few more patients to demonstrate comparability of clinical effects between clinical and commercial grade material, which was a similar approval pathway is old Jasmine and spinal muscular atrophy.

The loss scenarios to initiate a new pivotal trial, which we think is unlikely given the recently published final guidance document on human gene therapies for neuro degenerative diseases on the extensive long term safety and efficacy dataset available.

Next slide please.

Let's move on now to take you wanted to the first and the only gene therapy in clinical development for Ret syndrome type.

<unk> you want us to utilize is the novel micro RNA or M. O M. I RNA responsive ultra regulatory element platform to regulate transgene expression genotypic Lee on a cell by cell basis.

The totality of preclinical data generated to date for tissue when I two represents the most robust data package supporting the clinical advancement of a gene therapy Inrush syndrome.

This includes preclinical data in neonates, Loretta knockout mice, demonstrating near normalization of survival.

Normalization of body weight, a normalization of behavior as assessed by the Bird school.

Pharmacology data demonstrated significant improvement in survival Baldy White, Multifunction, a respiratory health across treatment ages and rats knockouts mice.

Toxicology data supported a favorable safety profile of Taisha, one O two and wall tile rats up to doses fourfold over the clinical starting dose.

Nerve conduction studies remain at the normal range signifying no evidence of dorsal root ganglion inflammation or other neuropathy deterioration and lastly, toxicology data in nonhuman primates demonstrated at all doses studied well tolerated, while showing broad by distribution to the brain and spinal cord.

Importantly, NH piece studies demonstrated that the Downregulates <unk> M. I wrap platform worked well with low levels of RNA, a minimal expression of Mac P. Two and wall type cells, which have normal preexisting levels of Mike P too.

These full preclinical studies together represent a comprehensive and robust package supporting the clinical advancement of Taisha, one O two for Ret syndrome.

Our first in human Phase one two trial of tissue on the two four syndrome also known as the reveal study is ongoing considering lot Polish it with Astellas and our attempt to provide them with a more comprehensive data sets. We now expect to report preliminary clinical safety and efficacy data I mean, it's our first cohort and includes up to six adult patients with ret.

Syndrome in the first half of 'twenty 'twenty three.

Also in the first half of 'twenty to 'twenty, three we intend to initiate a female pediatric study in ret syndrome.

As a reminder, taisha one or two has received orphan drug and wrap pediatric disease designations from the FDA and has been granted orphan drug designation from the European Commission.

In summary, we believe we have a compelling and robust clinical package for <unk> 'twenty and Gan.

And preclinical package for Taisha, one O two and Ret syndrome, we are extremely excited about the strategic investment or support from Astellas and look forward to providing additional updates in the first half of 'twenty 'twenty three for our two lead clinical programs.

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

Cameron.

Thank you Sue just this morning, I will discuss key aspects of our financial results for the third quarter ended September 32022, more details can be found in our Form 10-Q, which will be filed with the FCC. Shortly as indicated in our press release today research and development expenses were $16 $4 million for the three months ended September 30.

2022, compared to $39 $5 million for the three months ended September 32021.

The $23 $1 million decrease was due to a reduction of $11 $7 million in research and development GMP manufacturing and other raw material purchases.

Additionally, we incurred $6 $7 million less expense and third party research and development consulting fees, primarily related to non clinical GOP toxicology studies, and a decrease of $4 $7 million in employee compensation expenses.

General and administrative expenses were $8 $7 million for the three months ended September 30 of 2022 compared to $11 $2 million for the three months ended September 30 of 2021.

The decrease of approximately $2 $5 million was primarily due to a reduction of $1.3 million in professional fees related to pre commercialization recruiting and patient advocacy activities. Additionally, compensation expense decreased by $1 $2 million compared to the same period in 2021 net loss for the three months ended the para 30th.

2022 was $26 $3 million or <unk> 64 per share as compared to a net loss of $51 $2 million or $1 35 per share for the three months ended September 30 of 2021 as of September 32022, the company had cash and cash equivalents of $34 $3 million, which does not include the recent 50.

Million dollar strategic investment from Astellas or the net proceeds of $25 $6 million generated from the follow on offering closed in October 2022, we expect that the existing cash and cash equivalents along with the investment from Astellas and the net proceeds received from the public offering will enable funding of operating expenses and capital.

<unk> requirements into the first quarter of 2024, and with that I will hand, the call back to our a the next six to 12 months will be a busy time for T shirt on December 13th we are scheduled to have a teleconference with the FDA to discuss the pathway to a BLA filing for Acacia 120 in Gan.

We expect to provide a regulatory update on the program. Once we receive the final meeting minutes from the FDA likely in mid January of 2023.

In the first half of 2023, we anticipate clinical data for tissue one O. Two from the entire first cohort of adult patients with Ret syndrome.

And intend to initiate a female pediatric study in breast syndrome.

We look forward to providing updates on our progress throughout the year.

We will now open the call for questions.

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Our first question is from Gil Blum with Needham and company. Please go ahead.

Good morning, everyone and thanks for taking our question so.

So maybe maybe one on astellas here.

Can you remind us if astellas has experience and manufacturing AAV nine.

Genetic medicine, I can't remember exactly what the dental sector was thank you.

Hey, Joe Good morning, Thanks for the question, maybe I'll start and I'll turn it over to the Fred because he had extensive experience with the gene therapy manufacturing.

Manufacturing group over at audiences and actually took a tour of the new manufacturing site in Sanford. So the original astellas programs in Pompe, a N and M. S tubular myopathy, those or a V. Eight programs not a benign programs, but what I will say is the manufacturing is nearly identical.

So they're using <unk> to nine three triple plasmid transfection and suspension just like we are and as we were actually building on our facility that we now pause the layout was almost identical and so we feel like there's a significant opportunity to be able to leverage that asset.

As a collaboration moves forward I'll pause there Fred maybe you want to give some insight.

Sure Yeah. Thanks, Alright.

Certainly agree with you I think a while.

While Astellas is main experiences an AAV platform manufacturing approach that Astellas is taking and we are developing it to Asia really complementary.

Our intention that as we move forward our programs that it's really our knowhow that will follow these programs through in partnership with Astellas or independently. So I think.

It's still again very well suited to our collaborations.

Thanks for the question.

The next question.

It's from <unk> Yang with Jefferies. Please go ahead.

Mac Chandler on for Yaron. Thank you for taking the question.

Just wanted to know with with Astellas option for patients in 'twenty available for a period of time following the receipt of those minutes are there any specified outcomes from the end of phase two meeting or is that tied to meeting.

With the FDA for opt in or are you expecting.

Anything there.

Good morning, it's a it's a really good question. So what we've shared with Astellas is the the the full dataset from that study as presented to the F. D. A and we've also shared with the range of possible outcomes that we've laid out for you guys and what we kind of consider the base case that would be you know to do.

A few more patients let's call. It three to five four you know somewhat of a period of time hopefully around six six months or less in order to show in order to kind of demonstrate clinical comparability.

And that's something that we've been consistent within our communication with them. One thing I will say is I can't speak for Astellas and how they would make their decision, but this is the way that we framed the conversation with Astellas and they are fully aware and understand you know.

How either one of those scenarios could play out I think what's most important to them is the fact that this is a severe neurodegenerative disease with with no treatment alternatives. The fact that the dataset here is as robust as it possibly could get for gene therapy asset also the fact that we have not only.

The long term safety, but long term durability long term efficacy functional endpoints pathological endpoints and and really one that I think leads itself ultimately to a high probability of success of an eventual approval. So I think that's the way that they're there for a minute versus you know one.

<unk> outcome or another but again I think that's probably a better question posed to astellas, but.

The way that I've laid it out to you today is the way that we framed it for them.

The next question is from Gila mix shifts with Chardan. Please go ahead.

Hi, Good morning, Thanks for taking my question I'm wondering if you could give some color on how a potential registrational trial design would be similar or different from the ongoing phase one or two in <unk> syndrome and <unk>.

So the control group patient types, and then points and if you have any and.

And understanding of.

Among the several functional outcome buckets, if there are any particular ones that carry more weight.

Arizona experts in this space.

Hey, good morning, Thanks for the thanks for the question I'll turn that question over to <unk> to discuss how we're thinking about a pivotal design for ret syndrome. So yes.

Sure. Thank you for the question Yeah, I think it's an interesting one.

We actually know amazing pool to the adult study.

Currently this clinical trial is ongoing and we intend to strike with the pediatric study in the first half of next year I think a registration enabling study will really focus on the pediatric population more than anything I think this is the P population.

That is of interest.

But that also will be applicable to the wider population because we do feel that the gene therapy will be applicable to all populations.

Across the age spectrum and Ret syndrome.

In terms of differences between registration, enabling pediatric study and a an adult study the buckets of the site the bucket so assessments and the same I E. One big bucket is looking at seizures.

How frequently the seizures Hum.

So there are they how long haul like how can we reduce the burden that another bucket is looking at specific ret tight behavioral assessments, such as the ret syndrome functional style, the restaurateur and behaviour questionnaire and there's two or three of US that we include in the study in the pediatric study.

Another big bucket is looking at autonomic features of disease I E. The respiratory outcomes, which we've demonstrated very clearly and improvements in the in the animal studies in which we know from a patient perspective is incredibly distressing to both adults with the disease and children with this disease.

We also looked at communication capability as a bucket and also a mix of different biomarkers.

Exploratory CSF of blood based biomarker or E. G. You officially electrical biomarkers. So the buckets of the science from the analysts to the children. Some of the specific assessments are a little bit different I E. There are some specific assessors are more relevant for children or adults. One example would be the base.

These developmental assessments, which looks at development progression across early childhood classes scatter will be included within the actual pediatric study that is not in the adult study.

So I think there's a lot we can learn from the adult study that moves into the pediatric study I do think that the.

The likelihood is a registration enabling study and we're looking a long way out right.

A registration enabling study will most likely be in the pediatric population.

But the buckets five points all generally the site.

I'll stop there.

Thanks, so much.

Thanks for the question.

The next question is from Joon Lee with <unk> Securities. Please go ahead.

Hi, Good morning. This is Maggie on for June .

Congrats on the quarter and deal with Astellas.

About the buffering capacity and my rare system, what is the range of tolerate a viral copy numbers or sell.

And basically what is the expected translate the ability of the outcomes.

Adult patients to pediatrics.

The same dosing use.

This group thank you.

Okay. Thanks for the question I'll ask two years to answer the question and answer yes, just to clarify I think the question was you know is there a limit and sell copy number or.

Or kind of genomes per cell and the M. I rare platform and how that actually responds would be the first question. The second question would just be the translate ability from a dose perspective from the.

B the adult population into the pediatric study.

Sure so yeah.

Two very very good questions off to say you know the first question is a really interesting one.

The the way the culture was designed it was still over engineered.

So there are six micro RNA binding sites.

And the actual construct itself plus an additional three in the untranslated region of the construct these are binding sites sit down regulatory micro RNA now you only need one to be Frank to be able to keep the.

Level.

Pizza too.

Within the appropriate physiological range, but because of this issue of maybe I saw getting two three or four coffees, Steve Gray, our chief scientific adviser in partnership with Sarah Senate Bill 10 kind.

Kind of an overabundance of these regulatory micro RNA binding sites in there.

Just to make sure we really are truly going to make to make sure that we do not express any met P. J.

Now the exact.

Number of genome copies, we got to know that what we do know from the toxicology studies is that we've given a full fold dose over.

The initial starting dose initial stocks and this is a $5 14 total D. G and then both <unk> and Hps and the rats over three and six month period. We gave we gave three type season, both toxicology studies all the way up to two E 15 human equivalent.

So we know that sort of four fold over dosing.

The initial clinical starting dose you actually see.

Minimal.

Adverse well no adverse tosco logical findings.

And we know that there's high numbers of <unk> gene copies getting T cells with niche vehicle dose, but not as high so we have.

Confidence that getting into the 514 level.

And the humans, which is far below the highest is getting the toxicology studies is not catch results and over expression.

Yeah.

I had the answer to your first question. The second question about dose translate the bullets say from.

Philtrum adults or models down to children.

In this case.

It's very interesting you know most of the time when you give a drug systemically.

Do you have you touched on the BG per kilo basis. So for example, a six year old Boy will Germany, why 20 kilos. So if you're giving on that one of the 14 Beachy potato you'd love to call out that by the 20 kilos that heat waves.

And obviously, a larger boy or girl, a 12 year old who may wait 30, 35 gave us enough what my wife Sixty-seventh English. So you multiply that number and do the dice translates ability on the white.

It's different for a CNS delivered drug and ensure they can deliver drugs because.

Giving the gene therapy and didn't do a very limited space and the other thing that's different is this.

Children develop from babies through total hoods and see teenage years that all goodness all grow at different rates and the one that grows the fastest illness. The biggest in proportion to the rest of the body.

Is the right answer.

So it does translate the ability is only really an issue between the H zero full once Charles his four years of age the CSF volume and Brian all in all pretty similar to adults and so we've done lots of animal modeling and we've done a lot of looking at the literature and we've got an approach for.

Hum.

Moderating the pediatric and the adult thanks, Susan activation of about four years of age we give every patient whether the children and adults.

Same dose below the age of four we race show the dose down dependent on both the CSF bogey and the and Bryan volume and we've got a very thoughtful way of doing this and that's been discussed with the FDA and other regulators so that very much in agreement.

But as I say I think the vast majority of patients who will be enrolling in the pediatric study will probably be over the age of three or four and it's likely we're not going to change that dose that fall because the size of a three or four year old.

Child reaches three or four years of age they've reached the brine sizable adults. So it's likely to be the way the car pediatric critical decided this country. It's the same $5 14 total BG stuffs index, sorry that was too long answers, but hopefully I gave you.

Comprehensive answers to your questions.

Thanks Louis.

The next question is from Celgene Victor with Goldman Sachs. Please go ahead.

Hi, good morning, and thanks for the question. This is Mason on for Celgene Hum along the end points that are given for the first clinical data in ret, What's your view on the bar for success and what threshold you would view as clinically meaningful thank you.

He made some good morning. Thanks. Thanks for the question, maybe I'll just give a start and then we'll turn it over to see used to give kind of a more detailed answer I think the way that we've looked at these initial clinical studies is certainly safety is going to be extremely important and more so important in the rat population the way that the construct as designed and so.

Fish went into this in great detail is to really make sure that patients.

That patients get the level of <unk> that they need and actually to be not only a significant improvement across you know kind of.

The spectrum of disease, but also make sure that we were able to do that safely in the presence of wild type <unk> B, two and keep in mind. These patients with ret syndrome are mosaics, meaning 50% of their sales are normal and 50% of their cells are a kind of know or not producing <unk> two.

And to also give you a little bit further detail in the diseases.

Too much med D too is toxic and so the way that the concept with design is to express the level of magnitude that's needed in a genotypic manner on a cell by cell basis, and so most importantly confirmation that the construct is doing that.

The way that it's been proven in the animal models both the.

The knockout mouse.

The rats as well as Indian HP theres going to be extremely important and I think as we look across the spectrum of disease from a from an efficacy perspective are in the initial study, it's really going to be the totality of data across the spectrum.

So yes laid out some of those key endpoints that we'll be looking at them, but for us it kind of Holistically. The study safety, making sure that the down regulatory micro Ernie.

Construct is working well and then the totality of efficacy I'll pause there, but let's see if maybe you have something to add.

I could have been a little bit more color on everything you say is absolutely accurate and in fact, so the question is exactly the right questions to be asking first and foremost we've got to clear the bar safety is already says.

Secondly, we do have we are expecting to the heightened state preliminary efficacy what I will say to set expectation is that when you look at Apple plus the children. We expect the children's do back when the adults from an efficacy perspective, when we say that for two reasons first of all in general.

Treating the developing brain.

Seems to result in better clinical outcomes.

As a functional outcomes in animal studies.

And adult Brian .

All site from our animal studies, while we did a very large pharmacology study dosing many different ages of retinal cardiac myosin. It was clear that the younger mice performed better than the older mice. So that's one thing one important point I'll make them.

But I think from a clinical meaningfulness perspective, we spend a lot of time told them to patients and families and it's clear that subtle improvements some of which if that translates in the adults from the animals to the humans will be beneficial for example.

I've already mentioned the autonomic.

Dysfunction is breathing dysrhythmia thoughts are both children and adults with red hat and its ultimate dysfunction in the brain. When you have these alternating periods of very rapid breathing wishes correlate to what huddled around so let's see and then.

Hypoxic excess where they don't agree that's all for wallet and start to go a little blue Cyanosed and this causes incredible stress on the families and so anything that can help moderate even back dysfunctional rhythm.

Subtle way and which we saw significant improvements in animal models, I think would be clinically meaningful for patients.

Families. In addition, if we can reduce the seizure burden a tool where we can bring in some function I would say.

A modicum of functionality and and hand function. For example, all these things will be clinically meaningful, but I think another way to look at it is we're looking at many many different commission because this is a global neurological developmental disease and even the subtle change across several different measures will be very very <unk>.

Tactful to a.

Patients and their families.

The next question is from Mike <unk> with Morgan Stanley . Please go ahead.

Okay.

Everyone and thanks for taking the question.

Just given the importance of the pediatric ret data to Astellas decision can you maybe comment on what the trigger is to starting the pediatric study in the first half of 2023.

Just curious if youre looking to the adult study in terms of a certain number of patients or a certain level of follow up.

Prior to deciding to start the pediatric study thanks.

Hey, Mike.

Good morning, and thanks for the question, maybe I'll just start and maybe I'll just take that question in the interest of time, you know I I.

I think ultimately the main trigger for starting that pediatric study is really getting some some level of patient experience and follow up in the adult study and for US. We don't think that that's a large number of patients, but we do want to make sure that that level of experience is going to be.

For.

Multiple months of follow up and really for US. It's a safety issue, we want to make sure that that down regulatory micro RNA those binding sites in that construct.

And my real platform is doing exactly the way that we designed it in a way that it performed in the preclinical studies, that's essentially what we're looking for what I'll also say for the pediatric study in the pediatric study is going to be a global study. The goal is to do this study in multiple countries around the world.

And for US, it's really going to be around laying out kind of the right sequence of the filings.

Filings of both Dth, and then B I M B a.

In the United States will also kind of play a role.

For the way that different sites.

Come online, but for US really is the main kind of a gateway to us is just getting.

Some level of follow up.

And we've kind of detailed this internally and we we haven't disclosed to the street, but some level of follow up for multiple months.

From a few patients in the adult study would give us the competence to include that into the data package to include that into the data package for the pediatric study and so we're well on our way to doing that and we feel good about the guidance that we've laid out with initiating that study in the first half of next year. So really excited about it and the fact that.

This is a population with significant unmet medical need there's a large number of patients out there so recruitment should not be an issue.

The Red advocacy group puts the.

The prevalence of ret worldwide at somewhere around 350000 patients worldwide. We've calculated in the in the U S and Europe somewhere between around 25000 to 35000 patients I'm.

Just in those two geographies. So the issue around enrollment is a non issue, it's really for us to make sure.

That we're getting meaningful data from both the adult study as a gateway into the pediatric population.

That answers your question, but thanks for the question.

Next question is from David Wang with S. M. D. C. Please go ahead.

Hey, good morning, and thank you so much for taking the question I just had one on <unk>.

In the case of Ret syndrome, if you were to get <unk> over expression too toxic level with the construct can.

Can you just give us an idea about what that toxicity might look like based on your animal studies and then you know how how.

How quickly and definitively would manifest.

Thanks, David for the question, maybe I'll start and then I'll turn it over to see us. So so we didn't see that in our animal studies and again I think so yes laid out you know kind of the extensive package that we put forward to both.

The regulators up in Canada that will be putting into the follow on C. T as in <unk>.

To expand the study geographically, but for US you know I think what we saw was the fact that we were able to dose up to really high doses and.

And we've kind of stopped it at four fold over what the human equivalent starting dose would be to each of the 15. We just didn't go above that because we would never be dosing theoretically above that level, but we didn't see any type of toxic effects I think what we can probably do it in half so yes to answer the question theoretically.

What you would see and it is really informed by the experience of that.

<unk> duplication, most likely most likely so yes, do you want to kind of comment there.

Yeah, I would just reemphasize that we gave very high doses in the toxicology studies. So no evidence of any toxicity teach over expression.

Measured.

And all the tissues in the animals, DNA RNA and protein we've got high levels of T. N DNA, meaning we're getting good distribution of tissue wanted to all the tissues in the NIH paper at very low levels of RNA and correspondingly levels of Mec pizza, meaning the dam regulatory.

System is working well.

We felt that it's a very good question to ask just in case, you see some kind of neurological toxicity, that's totally them.

This took them not predicted.

That looked like and in theory that there's two ways of really drawing that parallel the first is what happens in the clinical situation.

And the second is looking at the animal situation. So in the clinical situation. There is a condition that is met pizza duplication syndrome, where children inherit two copies of it might be to change. So they have doubled the amount of met Pete too and they have associated your behavioral and neurological.

She's relate it to that and in fact, it doesn't look that different to rest and dry.

These are children, who it's actually a little more severe than rats.

Symptoms come on a little earlier, but basically you see a whole host of.

Evidence of developmental regression, a lack of milestones that you get seizures.

Hum.

With ophthalmic nervous system dysfunction as well so so.

From a clinical perspective, you see.

Neurological and neuro behavioral outcomes with our global in nature, and that's also true for the animal situation, where you encourage over expression.

Mac pizza and that in a mouse model. For example, you will see significant near behavioral toxicity and also I draw and survival. Once again I'll emphasize these are highly theoretical we've not seen anything of that nature whatsoever, and I'll rattle toxicology studies and one would think given very high doses.

Thanks, Thanks, David for the question.

The next question is from Jack Allen with Baird. Please go ahead.

Hello, This is benjamin pollution, calling in for Jack Allen.

How quickly could you begin dosing patients with a commercial product to take care of 120, and well the commercial product require a new R&D. Thanks for any color.

Thanks for the question, maybe I'll start and we could turn it over to them. So you have to kind of talk about the regulatory pathway. So as we've disclosed we plan to have a teleconference with the FDA on December 13th.

Type b into phase two meeting and the goal of this meeting is really to lay out.

And detailed the regulatory pathway to approval.

What we've also disclosed is a significant clinical safety and efficacy data across a number of meaningful functional pathological endpoints as well as really nice safety over the over the history of the study and the study has been ongoing this keep in mind. This is the first <unk>.

Gene therapy study in history. The study was initiated in 2015, so we're going on the seventh year of the study.

And there wasn't a run in study of natural history running study that initiated two years before that in 2013 that all patients that were dosed in the interventional trial rolled over from so we really have nice levels of control and comparison.

From kind of a pre treatment.

Experienced in a post treatment experience and so we're going to be going in and discussing the totality of the data effect as well as the manufacturing overview of the cleanup of the the clinical trial material and the commercial material with the F. D. A and we presented data on the commercial.

Material by all of our key quality attributes and release assays as well as in next generation sequencing are the product is biologically indistinguishable and we're really excited about the work that.

Brett and his team are performed on the commercial product so.

That product is available and ready to go what we would do is we're taking the full comp analytical comparability dataset, including the validated potency assay to the FDA for a meeting in December along with all the clinical data that we've laid out before and we're putting that in.

In front of the F D. A to really ask the question that are we or are we ready for prime time.

We think that we do do we think that we are based off of their recent guidance that was finalized about a week or two ago.

Which is the development of gene therapy for Neurodegenerative diseases, our program across both the CMC section across the clinical section checks all the boxes.

And it's really the kind of outlined the path forward to approval, that's really going to be the key question. So I think any time after that meeting we're ready to go to dose additional patients if that is the knee, but that may not necessarily be the knee, but we'll have to just wait we'll have to wait on that conversation.

With the FDA in order to inform you guys. Further what we would go back to is our base case is you know kind of scenario, two which means you know.

We would need some level of minimal Ah clinical comparability call. It three patients for six months.

In order to demonstrate clinical comparability. The goal would be is to file some sort of rolling submission as we're generating that data because keep in mind. The CMC data is not changing the clinical data for the most part is not changing and certainly the preclinical data is not changing and there's a lot of data to put forward in it.

In our submission. So you know, we'll inform you guys more.

You know post that meeting.

Sometime in January when we have those official meeting minutes in hand, but our base case is is kind of the providing some level of clinical comparability, most likely three to five patients six months in that range.

Yeah.

Operator.

The next question is from Matt Yeah, nothing to do with Wells Fargo. Please go ahead.

Hi, Thanks for taking my questions. So all the Ret syndrome could you talk about.

From the this panel of endpoints, which might be the earliest of from which you can you'd expect to see signals.

Signals and also if the adult study are three plus three design in that you have the opportunity to expand the treatment cohort.

You see any safety events and lastly.

Is there a pre specified duration now at which point the placebo or <unk>.

Delayed treatment patients are supposed to be crossed over to treatment. Thanks.

Thanks, Thanks, Yaniv for those questions and unfortunately, we're probably going to be able to take.

A couple of those questions to probably I'll do the first when we talk about the design of the study and and I just want to keep in mind. The design of the study for the first court is up to six patients somewhere between three to six patients will be included in that first cohort to just be clear and Ah that would be Ah patients.

<unk> treated drug as well as the delayed treatment Ah patients.

On your on your first question I think it was more so around what do we hope to see burst from an efficacy perspective and in be the adult patients that would give us confidence that that would translate into the rest of the population and so for that question. So yes.

I'll turn it over to you, but maybe it's helped informed by what we saw in the animal studies.

Yeah, and just to clarify yes.

The principal way depress close design is always quite correct that we're having up to six patients in the cohort. However, there is a proviso to extend that further if in case. If indeed, there is some kind of adverse events seen which I've seen that was a relatively common proviso in most of these phase one two clinical trial. So that provides a is that as probably be adapted.

The study design.

And in terms of endpoints that might improve.

I think that.

It's an interesting one I think for the animal studies, what we expect to improve quickly.

The it's the breathing dysfunction that I've already mentioned previously there is this usually ultra 19th passes all.

Rapid and shallow breathing and animal studies, we saw that improve relatively quickly.

That's one possibility, although frankly, we'll wait and see what happens but we.

We assume that's one of the changes that might happen relatively quickly. The other point I would make is that you know the other precedent is.

Is in the.

If you look at the Acadia Trust credit tied to study why they use a an analogue of IGF. One just trying to encourage the growth of sign options are in the brain Whats Your Michigan restaurant drove us even though they saw changes in the clinical global impression of severity scale and in the RSP queue, which is.

Our CAG of a right to dress syndrome General development question and think about it shows improvement relatively quickly now within about four to five weeks you can see the separation from placebo.

So I would say you know what.

We'd be looking for the physiological changes and breathing on some of the global ration drive behaviors.

Proving within a few weeks after dosing, what I will say as a comparison to the Acadia.

Any sort of data is that don't forget with the jeans tactical the whites about two or three weeks to get maximal transgene expression. So it may not be quite as rapid as an IGF one envelope being dosed, but I still think it's going to be we're gonna see a potential signs within a matter of weeks.

I'll start on that.

Thanks, So yes, thanks, Anna for the question.

The next question is from Sami Carlin with William Blair. Please go ahead.

Hi, This is Tiffany on for Sammy. Thanks, So much for taking my question or the Gan one 'twenty program in sort of your base case scenario outcomes. The FDA meeting, where that's most stations for comparability could you provide any color on maybe how quickly you might be all enrolled patients have they already been identified.

And are they also like what sort of range of follow up could you imagine you might reasonably need to demonstrate comparability and just as a quick second do you still have any plans for filing.

Filing.

And the name with it yeah. Thanks.

Hi, Tiffany. Thank you. Thank you for the question.

I could probably answer this relatively quickly. So you know the way that we're thinking about this the way that we're thinking about it.

<unk> hundred 20, and in Gan and kind of what the next stage of development with actually look like these patients have all essentially from the interventional study have all rolled over from the natural history study and so we've dosed 14 patients to date.

12 of those patients in the therapeutic doses and and all of those patients rolled over from the natural history study. So what's really nice is you actually have you know call. It one to one to two even three years are pre treatment experience or kind of natural history decline and.

We were able to compare that with the post treatment intervention and kind of this ongoing stabilization.

In disease, which was which was really clear across a number of the key endpoints not only clinically meaningful but statistically significant we're talking about the M. S. N 32, we're talking about visual acuity, we're talking about retinal nerve fiber thickness.

What's also really interesting is the fact that we have biopsy then and this is really kudos to the NIH and the fact that they.

They just designed a very robust study and the fact that they were able to take pipe biopsies pre and post so pre dosing and then after dosing up to one year and we see the clearly see and a statistically significant manner the REIT.

Generation of nerve cost clusters in kind of this active regeneration.

Which is really exciting so.

Again functional endpoints pathological endpoints.

You know.

We feel really good about the dataset and you couple that with the fact that we have commercial scale material. That's biologically are indistinguishable from our clinical trial material. So again I think.

All things considered we feel pretty good going into that meeting and Ah about proposing what a accelerated pathway could look like a two approval Ah patients have been identified because keep in mind, we've only dosed, we've only dose 14 patients over the history of the study and theirs.

Round 50, plus patients in the natural history dataset are right now and so essentially.

Essentially we could roll patients over.

From that natural history study into.

The clinical trial in order to meet whatever.

The requirement of the FDA have laid out for us in order to in order to.

We generate the data needed for regulatory filing we'll know more here are relatively quickly. The meeting is in December we'll get the meeting minutes and in in January and we'll provide that guidance, but I think if you look at the recent finalized our guidance.

That the FDA has laid out laid out around the development of gene therapy for Neurodegenerative diseases, and you look over this program both from a safety and efficacy perspective as well as the natural history perspective, the program checks all the boxes. So so that takes your your but hopefully that answers your question in the U S.

In Europe . It is absolutely our intention to eventually file an MAA in Europe , we do think that pathway will be further that pathway would be further clarified based on our conversations with the FDA because whatever you would do in the U S. You would want to also Uh huh.

That agreement with the regulators in Europe , So you're only doing it once in order to support that MAA, but we see are the pathways on an almost a parallel ah ah kind of parallel path, but.

But we would certainly want to make sure whatever we would need to do that would support registration in the U S that would also be an agreement that we could get with Europe .

Hopefully that answers your question.

The next question is from Whitney <unk> with Canaccord Genuity. Please go ahead.

Hey, guys.

Follow up on the Ret study update in the first half of next year. I guess can you can you talk about what what you mean, when you say complete cohort that will be getting is it.

Is there a specific amount of follow up you are waiting for in all of the patients or are we waiting for early data from the delayed a.

The delayed treatment control or just kind of help us understand what what you think or what you. When you say when you say complete excuse me what you mean, when you say complete cohort Inc.

Sure. Thanks Whitney for the question. So what I would just reiterate is the fact that that that that first cohort is up to six patients most likely somewhere between three to six patients.

And what what we're.

Trying to make sure is that we have enough patients and enough robust follow up from those patients in order to inform the initiation of the pediatric study that that's really what what what we're trying to define here and that's kind of how we see complete and that's somewhat of a subjective answer but.

The way that we're looking at this is three to four patients, including a delayed treatment patients that could act as kind of a real time level of control keep in mind, the natural history and Ret syndrome is probably some of the most well characterized natural history data out of any disease and the patient advocacy groups, who led the way here have done a fantastic.

Tastic jobs, but you also have that dataset.

To compare to but but really for us its getting too you know three to six patients, including a delayed treatment patient enough data enough follow up in order to inform the initiation of the pediatric study and for US we feel like we will have enough comfort for that.

To file the IND or Cta for the pediatric study to initiate that study in the first half of next year.

That's all the time, we have for questions I'll turn the call back over to Mr session for closing remarks.

Thank you operator, and again I just thank everybody for joining the call. This morning, it's been a quite interesting quarter for Tisha and the company I couldn't be prouder of the way that the company has responded it's a very tough market and I think we could all agree it it's quite interest.

The market and we've been into this cycle for for over a year now almost two years and I just couldn't be prouder of the resilience of the employees of taste showed the resilience of the patient community. The fact that they supported us been with us encourage that and we really want to thank them and so I think we're starting to now see the tide turn.

We're starting to see that pace of spirit rise and we're really excited about the next few months and what that has to offer Cretaceous starting with the type b into phase two meeting we will have in December with the FDA, we're quite excited to go into that.

Into that meeting and to get that to get those meeting minutes to be able to share early next year as well as a continued generating a generation of data in our ret syndrome program and the initiation of the pediatric study in the first half of next year and you know what we're also excited to now be able to share this with the <unk>.

Partner and Estelle, it's one that has a real commitment to patients, but a commitment to gene therapy the modality.

And also innovative medicines and so we're really excited to be embarking on this new journey with our partners Astellas and and look forward to a very fruitful partnership with them with that I wish you guys. A wonderful day go vote go vote go vote.

And we will talk to you guys soon thanks.

Ladies and gentlemen. This concludes today's presentation. Thank you once again for your participation you may now disconnect.

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