Q3 2021 Taysha Gene Therapies Inc Earnings Call

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Welcome to the <unk> gene therapies third quarter 2021 financial results and corporate update conference call. At this time, all participants are in a listen only mode.

Operator: Therapy's third quarter 2021 financial results and corporate update conference call. At this time, all participants are in a listen-only mode, following management's prepared remarks.

Following managements prepared remarks, we will hold a brief question and answer session. As a reminder, this call is being recorded today November 10th 2021.

Operator: We will hold a brief question and answer session. As a reminder...

Operator: This call is being recorded today, November 10th, 2021. I will now turn the call over to Dr. Kimberly Lee, Senior Vice President of Corporate Health.

Now I'll turn the call over to Dr. Kimberly Lee Senior Vice President of corporate Communications and Investor Relations. Please go ahead.

Kristen Kluska: Vice President of Corporate Communications and Investor Relations, please go ahead.

Thank you good morning, and welcome to take his third quarter 2021 financial results and corporate update conference call. Joining me on today's call are are a session. The second patient President CEO and founder Dr. C. S Prasad Chief Medical Officer, and head of R&D, and Kamran Alam Chief Financial Officer after their formal remarks, we welcomed.

Kristen Kluska: Thank you. Good morning, and welcome to Taysha's third quarter 2021 Financial Results and Corporate Update conference call. Joining me on today's call are Ari Sesham II, Taysha's President, CEO, and Founder, Dr. Suyash Prasad, Chief Medical Officer and Head of R&D, and Kamran Alam, Chief Financial Officer. After our formal remarks, we will conduct a question and answer session, and instructions will follow at that time.

A question and answer session and instructions will follow at that time.

Earlier today <unk> issued a press release announcing financial results for the third quarter ended September 30 of 2021, a copy of this press release is available on the company's website and through our SEC filings.

Kristen Kluska: Earlier today, Taysha issued a press release announcing financial results for the third quarter ended September 30th, 2021. A copy of this press release is available on the company's website and through our SAC 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 our product candidates, our expectations regarding the data necessary to support regulatory approval of Taysha 120, and the regulatory status and market opportunity for those programs, as well as Taysha's manufacturing plans.

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 our product candidates our expectations regarding the data necessary to support regulatory approval of <unk> 'twenty.

And then my other toy status and market opportunity for those programs as well as Texas manufacturing plant.

Kristen Kluska: This call may also contain forward-looking statements relating to Taysha's growth and future operating results, research and development, and product candidates, strategic alliances, and intellectual property, as well as matters that are not of historical fact or information. Various risks may cause patients' actual results to differ materially from those stated or implied in such forward-looking statements. These risks include uncertainties related to the timing and results of clinical trials and preclinical studies of our product candidates, 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.

Call May also contain forward looking statements relating to <unk> growth and future operating results discovery and development and product candidates, which he did your 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. These risks and 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 our ability to obtain patent protection for discoveries.

Patients imposed by patents owned or controlled by third parties and the requirements of substantial funding to conduct our research and development activities for a list and description of the risks and uncertainties that we face. Please see the reports we have filed with the Securities and Exchange Commission. This conference call contains time sensitive information that is accurate only as of the date of this live.

Kristen Kluska: 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. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, November 10, 2021. 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. I would now like to turn the call over to our President, CEO, and Founder, R.A. Seshan II. R.A.?

<unk> November 10th 2021 patient undertakes no obligation to revise or update any forward looking statements choice about the events or circumstances. After the date of this conference call, except as may be required by applicable Securities law.

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

Thank you Ken Good morning, and welcome everyone to our third quarter financial results and corporate update conference call.

Mahdi Goudarzi: Thank you, Kim. Good morning and welcome everyone to our third quarter financial results and corporate update conference call. It has been a busy quarter with positive regulatory discussions for several programs, obtaining an exclusive license for the CLN7 program and collaborating with UT Southwestern on a next-generation CLN7 construct, partnering with GeneDx, the Hereditary Neuropathy Foundation, and the Charcot-Marie-Tooth Association on increasing awareness for gynecological neuropathy and hosting investor webinars featuring disease overviews from key opinion leaders, as well as program highlights for CLN1, Rett, and Angelman syndrome.

It has been a busy quarter with positive regulatory discussions for several programs obtaining an exclusive license for the ceiling seven program and collaborating with UT southwestern on a next generation field and seven construct partnering with G X the hereditary neuropathy Foundation and the Sharklet Marie tooth.

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Increasing awareness for giant exponent, wrathy and hosting Investor Webinars featuring disease overviews from key opinion leaders as well as program highlights for sealing one reps and Angelman syndrome, I would elaborate on some of our recent key achievements and review our expected upcoming milestones following.

Mahdi Goudarzi: I will elaborate on some of our recent key achievements and review our expected upcoming milestones. Following this, I will turn the call over to Suyash and Kamran for updates on our pipeline developments and financial results, respectively.

This I will turn the call over to Sue <unk> cameras for updates on our pipeline developments and financial results respectively.

Mahdi Goudarzi: In October, we were pleased to announce an exclusive option from UT Southwestern to license a clinical stage CLN7 program, an AAV9 intrathecally-dosed gene-replacement therapy that was invented by our chief scientific advisor, Dr. Stephen Gray. UT Southwestern is currently running a clinical proof of concept trial with the first generation construct, and we expect to have preliminary clinical data, including safety data from the first patient ever dosed intrathecally with 1e to the 15th total VG by the end of this year. We are collaborating with UT Southwestern to develop a next-generation construct that will provide improved potency, safety, packaging efficiency, and manufacturability over the first generation construct.

October we were pleased to announce an exclusive option from Ut southwestern to license a clinical stage C O. When seven program in AAV, nine, particularly dose gene replacement therapy.

That was invented by our chief scientific adviser Dr. Steven Gregg.

UT southwestern is currently running a clinical proof of concept trial with the first generation construct and we expect to have preliminary clinical data, including safety data from the first patient ever dose <unk> with one each of the 15 total vg by the end of this year.

We are collaborating with Ut southwestern to develop a next generation construct that will provide improved potency.

Safety packaging efficiency and manufacturer ability over the first generation car scrubbed.

Mahdi Goudarzi: Construct design is anticipated to be completed by year end, with initiation of a planned pivotal trial using the next generation construct in 2022, with reference to human proof of concept data generated from the first generation construct. To support patient education, disease awareness, and advanced newborn screening initiatives for CLN7, we have provided a grant to Batten Hope, a leading CLN7 patient advocacy group. Currently, there are no approved treatments for this severe neurodegenerative lysosomal storage disease.

Our store design is anticipated to be completed by year end with initiation of a planned pivotal trial using the next generation construct in 2022 with reference to human proof of concept data generated from the first generation construct.

To support patient education disease awareness and advanced newborn screening initiatives for ceilings seven we have provided a grant to batten hope a leading ceiling seven patient advocacy group.

Currently there are no approved treatments for this severe neurodegenerative lysosomal storage disease.

And we are excited to work with Ut southwestern and support Baton hope to further advance this promising clinical stage program.

Mahdi Goudarzi: And we are excited to work with UT Southwestern and support Batty Hope to further advance this promising clinical stage program. With the addition of the CLN 7 program, we expect to have five clinical stage programs by the end of this year, including Dynaxon for Neuropathy, GM2 Gangliosidosis, CLN 1, and Rett Syndrome. As our programs mature, we continue to make progress on the regulatory front.

With the addition, with the addition of the ceilings seven program, we expect to have five clinical stage programs by the end of this year, including John excellent neuropathy G O <unk> gangliosidosis ceiling, one and ret syndrome.

As our programs mature we continue to make progress on the regulatory front.

This past quarter, the European Commission granted orphan drug designation for T shirt, one O. One for G. M to Acacia one O two for Ret syndrome, Acacia one O five for S. L. C 13, API related epilepsy.

Mahdi Goudarzi: This past quarter, the European Commission granted orphan drug designations for Keisha-101 for GM2, Keisha-102 for Rett Syndrome, and Keisha-105 for SLC-13A5-related applications. Year-to-date, we have had nine regulatory interactions with multiple agencies across our portfolio and plan to submit additional requests for end-of-phase meetings for gynecological neuropathy before the end of this year. We anticipate reporting clinical data for several programs by the end of this year. For GAN, in September, we submitted an end-of-phase meeting request for Taysha 120 to a major ex-U.S. regulatory agency and look forward to submitting additional requests to multiple regulatory agencies by the end of this year.

Year to date, we have had nine regulatory interactions with multiple agencies across our portfolio and plan to submit additional request for interface meetings for Xilinx Ananda wrapped up before the end of this year.

We anticipate reporting clinical data for several programs by the end of this year.

For Gan in September we submitted an interfaith meeting request rotation at 122, a major ex U S regulatory agency and look forward to submitting additional request to multiple regulatory agencies by the end of this year.

Again, we have up to six years of longitudinal data in individual patients and collectively 55 patient years of clinical safety and efficacy data from our ongoing clinical study.

Mahdi Goudarzi: Again, we have up to six years of longitudinal data in individual patients and collectively 55 patient years of clinical safety and efficacy data from our ongoing clinical study. We also have eight years of robust longitudinal data from a natural history study being conducted at the NIH by Dr. Carson Bonner. There has been consistency in the strength of data across multiple functional and biomarker inputs, including the MFM32 scale, vision assessments, and nerve biome.

We also have eight years of robust longitudinal data from the natural history study being conducted at the NIH by Doctor Carsten bottoming.

There has been consistency and the strength of data across multiple functional and biomarker endpoints.

Including the M. S M 32 scale vision assessments and nerve biopsies.

We look forward to reporting clinical safety and functional M. S. N 32 data for <unk> 'twenty from the high dose cohort of 3.5 each of the 14 total Vg in December.

Mahdi Goudarzi: We look forward to reporting clinical safety and functional MSM32 data for Taysha 120 from the high-dose cohort of 3.5e14 total VG in December, where we believe continued clinically meaningful slowing of disease progression similar to that achieved with the lower dose cohorts would be considered confirmatory of disease modification. For Taysha 101, the first Bicistronic Vector in the clinic in history, which is designed to express the subunits of hex We remain on track to report preliminary clinical safety data and hexane enzyme activity data in the plasma and CSF in December of this year. Based on natural history, 2 to 4 percent hexane enzyme activity in the plasma normalizes survival and significantly improves the clinical phenotype of GM2 gangliosidosis.

Where we believe continued clinically meaningful slowing of disease progression similar to that achieved with the lower dose cohorts would be considered confirmatory of disease modification.

<unk> one on one the first bias dystonic vector in the clinic in history, which is designed to express the subunits attacks a enzyme.

And the endogenous one to one ratio.

We remain on track to report preliminary clinical safety data and hexane enzyme activity data the plasma and CSF in December of this year.

Just on natural history, two to four per cent per se enzyme activity in the plasma normalizes, the Bible and significantly improves clinical phenotype of <unk> gangliosidosis.

We anticipate preliminary clinical safety data and xa enzyme activity in the plasma and CSF for Acacia one O. One N G M. Two gangliosidosis.

Mahdi Goudarzi: We anticipate preliminary clinical safety data and hexane enzyme activity in the plasma for NCSF, Cretaceous-101, and GM2 gangliosidosis in December from the ongoing Canadian study. We believe a hexane enzyme activity level of at least 5% in the plasma will be considered disease-modifying based on natural history. Regarding the safety profile, preclinical data demonstrated intersecretly delivered Taysha 101 was safe and well-tolerated in GM2 knockout mice. Due to the severity of the disease and unmet medical need, we are currently assessing the need for a U.S. study to support global registration.

In December from the ongoing Canadian study.

We believe xa enzyme activity level of at least 5% in the plasma will be considered.

Disease modifying based on natural history.

Regarding the safety profile preclinical data demonstrating interest equally deliberate patient one O one was safe and well tolerated in G. M. Two knockout mice.

Due to the severity of the disease, an unmet medical need we are currently assessing the need for U S study to support global registration.

We're seeing for our ceiling seven program, we anticipate preliminary clinical data, including safety data for.

Mahdi Goudarzi: For our CLN7 program, we anticipate preliminary clinical data, including safety data, for the first patient in history to be dosed at 1e to the 15th total VG, interfecally with the first generation construct in December. In parallel, we expect to finalize the design of the second generation CLN7 construct by year-end, and initiate a planned pivotal clinical trial in 2022 with reference to clinical data generated by the First-Generation Con For CLN1, the program currently has an open IND.

So the first patient in history to be dosed at 1% to the 15th total B G.

Equally with the first generation construct in December.

In parallel we expect to finalize the design of the second generation sealed and seven construct by year end.

And initiate a planned pivotal clinical trial in 2022 with reference to clinical data generated by the first generation construct.

Of course, the all in one the program currently has an open I N T.

And an additional C. T E filing pertains to 118 has been submitted quickly.

Mahdi Goudarzi: And an additional CTA filing for Taysha 118 has been submitted. Preclinical data demonstrated that Tayshia 118 was safe and well-tolerated following interfaecal administration in the CLN1 knockout mouse mob. In preclinical models, KCASA-118-treated mice demonstrated superphysiological levels of active PPT1 enzyme with no associated adverse effects, suggesting a wide therapeutic window for clinical dosing.

Preclinical data demonstrated that takes you won 18 was safe and well tolerated following interest equal administration.

And the C O N one knockout mouse model.

In preclinical models, Acacia 118 treated mice demonstrated super physiological levels of active P. P. T. One enzyme with no associated adverse effects, suggesting a wide therapeutic window for clinical dosing.

We plan to initiate the clinical trial by the end of this year and expect to report preliminary clinical safety and P. P. T. One enzyme activity data in the first half of 2022.

Mahdi Goudarzi: We plan to initiate the clinical trial by the end of this year and expect to report preliminary clinical safety and PPT1 enzyme activity data in the first half of 2022. For Taysha 102 in Brett Syndrome, we intend to submit an IND or CTA filing in November, followed by the initiation of clinical development by the end of this year. We have recently obtained preclinical data demonstrating an improvement in survival and respiratory function, as well as motor function, and relevant disease mouse models. We plan to share this data at a later date.

Potato one O two in breast syndrome, we intend to submit and I M D or Cta filing in November.

Followed by the initiation of clinical development by the end of this year.

We have recently obtained preclinical data demonstrating an improvement in survival.

And respiratory function as well as motor function.

And relevant disease mouse models.

We plan to share this data at a later date, notably.

Preliminary data from a G O P. Toxicology study in nonhuman primates demonstrated no adverse findings at the highest dose tested suggesting that the M eyewear platform.

Mahdi Goudarzi: Notably, preliminary data from a GOP toxicology study in non-human primates demonstrated no adverse findings at the highest dose tested, suggesting that the miRARE platform is successfully down-regulating MeCP2 expression to within normal physiological levels. As I mentioned earlier, we will have five clinical programs by the end of this year, and many of those have been a major focus for investors, given the near-term milestone.

He has successfully down regulating mec P. Two expression so within normal physiological levels.

As I mentioned earlier.

We will have five clinical programs by the end of this year.

Any of those have been a major focus for investors given the near term milestones. However, we wanted to highlight a few of these programs and our Investor Mini series, which featured key opinion leaders, who provided a deep understanding of the disease and reviewed preclinical and natural history data to help set the stage for our treatment approach.

Mahdi Goudarzi: However, we wanted to highlight a few of these programs in our investor mini-series, which featured key opinion leaders who provided a deep understanding of the disease and reviewed preclinical and natural history data to help set the stage for our treatment approach. Leaders from patient advocacy organizations also discussed the disease burden of illness from the patient and caregiver perspective and provided real-world context to therapeutic endpoints and insights into how incremental improvements may lead to meaningful benefits for patients and caregivers. We hope you found these events helpful, but if you were not able to attend, the replays are available on our corporate website.

Leaders from patient advocacy organization also discussed disease burden of illness from the patient or caregiver perspective.

And provided real world context to therapeutic end points and insights.

How incremental improvements may lead to meaningful benefits for patients and caregivers. We hope you found these events helpful. But if you were not able to attain the replays are available on our corporate website.

On the manufacturing front, we have completed five successful concurrent GMP manufacturing campaigns for multiple programs to date, which are sufficient to support our planned clinical stage programs. This year.

Mahdi Goudarzi: On the manufacturing front, we have completed five successful concurrent GMP manufacturing campaigns for multiple programs to date, which are sufficient to support our planned clinical stage programs this year. We have received positive feedback from multiple regulatory agencies supporting our three-pillar approach to manufacturing, which includes UT Southwestern, our CDMO partners, as well as our internal 187,000 square foot manufacturing facility located in Durham, North Carolina. We are making solid progress on the build out of our facility, most recently erecting structural steel and completing subfloor piping.

We have received positive feedback from multiple regulatory agencies supporting our three pillar approach to manufacturing, which includes Ut southwestern our CMO partners as well as our internal <unk> 187000 square foot manufacturing facility located in Durham North Carolina.

We are making solid progress on the build out of our facility. Most recently erecting structural steel and completing some lower piping we remain on track to complete the facility by 2023.

Mahdi Goudarzi: We remain on track to complete the facility by 2023. Our translational and bioanalytics labs will also be physically located near our manufacturing facility in Durham to ensure seamless communication between research and manufacturing. Let me conclude by saying that we have accomplished much this quarter but have more to execute on, and we believe our strong balance sheet provides us with the financial and operational flexibility to achieve our numerous value-generating milestones across our programs.

Our translational and bi analytics labs will also be physically located near our manufacturing facility in Europe to ensure a seamless communication between research and manufacturing.

Let me conclude by saying that we have accomplished much this quarter, but have <unk>.

To execute on and we believe our strong balance sheet provides us with the financial and operational flexibility to achieve our numerous value generating milestones across our programs and importantly, a potential regulatory approval for Acacia one 'twenty and giant on a property.

We look forward to our continued execution across our development and regulatory strategies and will update you on our progress throughout the remainder of this year.

Mahdi Goudarzi: And importantly, a potential regulatory approval for Taysha 120 and GYNEX on a raw basis. We look forward to our continued execution across our development and regulatory strategy, and we'll update you on our progress throughout the remainder of this year. I will now turn the call over to Suyash to provide a more detailed update on our R&D initiatives. Suyash, please go ahead.

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

Yeah.

Thanks, Alright.

We continue to advance our clinical and preclinical programs as well as strengthened our pipeline with complementary therapeutic approaches to address high unmet needs across monogenic diseases CNS.

Suyash: Thanks, Ari. We continue to advance our clinical and preclinical programs, as well as strengthen our pipeline with complementary therapeutic approaches to address high unmet needs across monogenic diseases of the CNS. As the end of the year approaches, we are highly anticipating multiple data readouts across several of our lead clinical programs. Let me start with Taysha 120, our most advanced clinical program for the treatment of giant axonal neuropathy, or GAM. In December, we expect to report clinical safety and MFM32 functional data from the high-dose cohort of 3.5 times 10 to the 14 total VG. These data will be generated by our partners and collaborators at the NINDS under the leadership of the PI for the study, Karsten Bonner.

At the end of the year approaches we are highly anticipating multiple data readouts across several of our lead clinical programs.

Let me start with Taishan, one 'twenty, our most advanced clinical program for the treatment of junk at cinema neuropathy or Gan.

In December we expect to report clinical safety MSM 32 functional data from the high dose cohort of three five times 10 to the 14 cultural Vg.

These data were generated by our partners and collaborators at the NIH, yes under the leadership of the payoffs of the study Kosten bornemann.

As a reminder, the collection rate to that make them touch to scale is a clinically validated.

Regulatory end point that assesses motor function.

To cancel the successful outcome will don't like based on the prospectively collected data on the natural history can there's a predictable decline in the image sensors to school of approximately eight points per year across all patients regardless of age.

Suyash: As a reminder, the clinician-rated MFM32 scale is a clinically validated and accepted regulatory endpoint that assesses motor function. To gauge what a successful outcome would look like based on the prospectively collected data on the natural history of GAN, there is a predictable decline in the MFM32 score of approximately 8 points per year across all patients regardless of age. A four-point change in the MFM32 scale is considered clinically meaningful.

A full point change an MFN since two scale is considered clinically meaningful.

To confirm modification of disease trajectory in comparison to the natural history study, we believe the high dose cohort should demonstrate continued slow disease progression durability of effect and safety comparable to that which was achieved with a 1.2 times 10 to 14 of the 1.8 12 14 total vg.

Suyash: To confirm modification of disease trajectory in comparison to the natural history study, we believe the high-dose cohort should demonstrate continued slowing of disease progression, durability of effect, and safety comparable to that which was achieved with the 1.2 x 1014 and the 1.8 x 1014 total VG doses. Regarding safety, recall that we have up to six years of clinical safety data demonstrating no drug-related serious adverse events. No signs of acute or subacute inflammation, no sudden sensory changes, and no persistent elevation of translaminates.

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Regarding safety recall that we have up to six years of clinical safety data demonstrates with no drug related serious adverse events no signs of acute sub acute inflammation no. Some sensory changes no persistent elevation of transaminase. This.

And also with regards to safety in preclinical studies using the Cowen wrote it takes you one 'twenty improved instead of technological or parents of the jokes root ganglia, which is a known computation of game that buoyed by supporting reduction in disease symptoms.

We anticipate publication of the clinical data and the parent feedstocks in the journal in the near future.

Suyash: And also, with regard to safety in preclinical studies using the GAN rodent, Keisha-120 improved the histopathological appearance of the dorsal root ganglia, which is a known complication of GAN, thereby supporting reduction in disease symptoms. We anticipate publication of the clinical data in the Peri-Future Scientific Journal in the near future. In September, we submitted scientific advice from a major ex-US regulatory agency and received a preliminary meeting date in January 2022. We anticipate submitting additional requests to multiple regulatory agencies by the end of this year.

In September we submitted a scientific advice from a major ex U S. Regulatory agency I received a preliminary meeting date to January 2022.

We anticipate submitting additional requests to multiple regulatory agencies by the end of this year.

How should we think about the approval pathway for Canada, the United States, We view three possible scenario with a potential to file for approval with the current data on hand, as the most likely scenario.

Simply the yesterday could request because it takes a few additional patients to demonstrate comparability of clinical effect between clinical and commercial grade material and.

Lastly, the FDA may request us to perform a new pivotal trial, which we view as the least likely option given the recently published guidance documents of gene therapies for Neurodegenerative diseases and extensive long term dataset that we have in hand.

Suyash: As we think about the approval pathway for Ghana and the United States, we view three possible scenarios with the potential to file for approval with the current data on hand as the most likely scenario. Alternatively, the FDA could request that we dose a few additional patients to demonstrate the comparability of clinical effects between clinical and commercial-grade materials. And lastly, the FDA may request us to perform a new pivotal trial, which we view as the least likely option given the recently published guidance documents on gene therapies for neurodegenerative diseases and the extensive long-term data set that we have in hand. In Europe, we believe we would be able to use the current data set to path conditional approvals.

In Europe, we believe we would be able to use the current data sets of pulp conditional approval.

We look forward to providing you updates pulling them all regulatory interactions in the meantime, we have finalized the plan commercial grade material and have initiated the comparable two protocol to support a BLA and MAA filings.

We continue to believe that early diagnosis and treatment can dramatically improve the lives of patients with cancer.

Last month, we announced the partnership with <unk>, a global leader in genetic testing to sponsor the inclusion of a genetic marker to Tesla Cam and the gtx routine hereditary neuropathy screening panel free of charge to individuals at risk for or suspected of having again.

Suyash: We look forward to providing you updates following our regulatory interaction. In the meantime, we have finalized the plan for commercial grade material and initiated a comparability protocol to support a BLA-MAA filing. We continue to believe that early diagnosis and treatment can dramatically improve the lives of patients with GAM. Last month, we announced a partnership with GeneDx, a global leader in genetic testing, to sponsor the inclusion of a genetic marker to test for GAN in the GeneDx Routine Hereditary Neuropathy Screening Panel, free of charge, for individuals at risk for or suspected of having GAN. Ultimately, this can help address current treatment barriers by raising disease awareness, making diagnostic tools more accessible, and facilitating early intervention for patients suffering from gout.

Ultimately this can help address current treating the borrowers by raising disease awareness, making diagnostic tools more accessible facilitating early intervention for patients suffering from Gal.

We are also excited to collaborate with the hereditary neuropathy Foundation and the Shocker Marie Tooth Association of centers of Excellence health care professionals and patient advocacy groups to increase access to genetic testing.

Collectively all colors to help all patients at risk of again have access to genetic testing and raise awareness of opportunities to participate in clinical trials for investigational treatments to facilitate earlier intervention for patients suffering from GERD.

Moving to our <unk> one program for the treatment of G. M. Two gangliosidosis, we plan to report preliminary clinical safety data and tech site enzyme activity in plasma and CSF in December.

Recall, the preclinical data demonstrated interests equaled delivery of tissue when no one was safe and well tolerated G M. Two knockouts in mice.

Suyash: We are also excited to collaborate with the Hereditary Neuropathy Foundation and the Charcot-Marie-Tooth Association Centers of Excellence, health care professionals, and patient advocacy groups to increase access to genetic testing. Collectively, our goal is to help all patients at risk for GAM have access to genetic testing and raise awareness of opportunities to participate in clinical trials for investigational treatments, and facilitate earlier intervention for patients suffering from GERD. Moving to our Taysha 101 program for the treatment of GM2 gangliosidosis, we plan to report preliminary clinical safety data and hexa enzyme activity in plasma and CSF in December.

Based on patient data from the natural history study demonstrating a correlation between clinical phenotype and hex a enzyme activity, we anticipate actually enzyme activity levels of at least 5% in plasma to be considered a disease modifying.

Screening and enrollment is progressing well and our Canadian study due.

Due to the severity of the disease and the unmet medical need we are currently assessing the need for a U S trial to support a regulatory filing I do continue evaluating the fastest path to approval with regulatory agencies.

As a reminder, it takes you one on one that's been granted orphan drug designation from the FDA and more recently from the European Commission for the treatment of G. M. Two ganglioside two doses.

Suyash: Recall that preclinical data demonstrated intrathecal delivery of Taysha 101 was safe and well tolerated in GM2 knockout mice. Based on patient data from the Natural History Study demonstrating a correlation between clinical phenotype and HexA enzyme activity, we anticipate HexA enzyme activity levels of at least 5% in plasma to be considered disease-modifying. Screening and enrollment are progressing well in our Canadian studies.

Takes you wanted one has also received a rare pediatric disease designation from the FDA.

For a sale of the seven program, we expect to report preliminary clinical safety data from the first patients in the clinical trial, who were dosed with a fifth generation construct.

The first patient in history to be dosed at one times 10 to the 15 total vg interest easily.

This isn't decided but this will be in December.

In preclinical toxicology studies safety and Tolerability and interesting for the administration of the first generation construct was demonstrated across all dose levels and time points.

Suyash: Due to the severity of the disease and the unmet medical need, we are currently assessing the need for a U.S. trial to support a regulatory filing as we continue evaluating the fastest path to approval with regulatory agencies. As a reminder, Taysha 101 has been granted both orphan drug designation from the FDA and, more recently, from the European Commission for the treatment of GM2 gangliosidose. Taysha 101 has also received a Rare Pediatric Disease designation from the FDA.

We anticipate a similar safety profile in the clinic.

We anticipate that's all colleagues and partners at Ut southwestern well definitely additional patient the first generation construct before the end of the year.

We are collaborating with Ut southwestern to finalize development of our next generation construct which should have improved potency.

Safety packaging efficiency and manufacturer ability over the first generation concert by year end and we plan to initiate a pivotal clinical study in 2022 using the next generation construct with reference to the human proof of concept clinical data generated from the first generation construct.

Suyash: For our CLN7 program, we expect to report preliminary clinical safety data from the first patients in the clinical trial who were dosed with a first-generation construct, including the first patient in history to be dosed at 1 times 10 to the 15 total VG intrathetally. This was in December; this will be in December.

Lastly, we anticipate having commercial grade GMP material for the next generation construct in 2022.

Suyash: In preclinical toxicology studies, safety and tolerability of intrathecal administration of the first-generation construct were demonstrated across all dose levels and time points, and we anticipate a similar safety profile in the clinic. We anticipate that our colleagues and partners at UT Southwestern will dose an additional patient with the first-generation construct before the end of the year. We are collaborating with UT Southwestern to finalize the development of the Next Generation Construct, which should have improved potency, safety, packaging efficiency, and manufacturability over the First Generation Construct by year end.

In August we held our first Investor Mini series highlights. It takes you a 118 for the treatment of CLO one disease.

Almost half Doctor Ungula shoots a global expert clinical researcher who specializes in lysosomal storage disorders from the University Medical Center home book at the door to review the current natural history data the seal on one disease and provide clinical insight into the use of natural history control data in clinical.

Called trials as well as clinical trial endpoints and design.

Doctor Steven Great reviewed encouraging preclinical data that takes you out one more night at clinically relevant doses demonstrates them. It takes you 118 was safe well tolerated following interests equal administration and CLR one knockout mice.

Suyash: And we plan to initiate a pivotal clinical study in 2022 using the Next Generation Construct with reference to the human proof of concept clinical data generated from the First Generation. Lastly, we anticipate having commercial-grade GMP material for the next generation construct in 2021.

In preclinical CLO one muscles takes you one when they treated mice demonstrated persistent super physiological levels of active P. P. T. One.

Improved survival rates of sustained preservation of motor function.

Suyash: In August, we held our first Investor mini-series highlighting Taysha 118 and the treatment of CLN1 disease. We were honored to have Dr. Angela Schultz, a global expert and clinical researcher who specializes in license memory storage disorders from the University Medical Center, Hamburg, Eckendorf, to review the current natural history data for CLN1 disease and provide clinical insight into the use of natural history control data in clinical trials, as well as clinical trial endpoints and design.

Associated adverse events, suggesting a wide therapeutic window for clinical dosing.

We also reviewed insights from the scientific Advisory board on CAG of the focus groups that helps inform our clinical study design therapeutic priorities on endpoint selection.

We continue to explore the fastest pathway to approval for all steel on one program.

We have submitted the Cta filing a plan to initiate a phase one two trial by year end.

Suyash: Dr. Stephen Gray reviewed encouraging preclinical data for Tayshia 118 at clinically relevant doses, demonstrating that Tayshia 118 was safe and well-tolerated following intrathecal administration. In preclinical CLN1 models, Taysha 118 treated mice demonstrated persistent supraphysiological levels of active TPT1.

We expect to report P. P. T. One biomarker data in the first half of 2020 to nurture the sudden increase in PBT, one activity from 1% to Forex It would be considered positive based on the 5% to 8% range seen in adult onset patients.

In September we hosted a rest investor day highlights and I'll take that one or two program.

Suyash: Improved survival rates and sustained preservation of motor function with no associated adverse events suggest a wide therapeutic window for this treatment. We also reviewed insights from the Scientific Advisory Board and Caregiver Focus Groups, who helped inform our clinical study design, therapeutic priorities, and endpoint selection. We continue to explore the fastest pathway to approval for our CLN1 program. We have submitted a CTA filing and plan to initiate a Phase 1-2 trial by year end.

Dr. Jeffrey Newell and international experts in genetic Neurodevelopmental disorders from Vanderbilt University Medical Center provides an overview of the natural history for Ret syndrome, and clinical consideration support clinical trial design, including outcome measures on biomarker selection.

Doctor Steven Great detailed requirements for regulated gene expression on a cell by cell basis to safely and effectively treat the disease.

Lastly, we'll tell novel M I wrap up form does it.

Which regulates the degree of trenching expression based on underlying genotype on a cell by cell basis, ensuring expression.

Suyash: We expect to report PPT1 biomarker data in the first half of 2022, noting that an increase in PPT1 activity from 0.1% to 5% would be considered positive based on the 5% to 8% range seen in adult-onset patients. In September, we hosted a REF Investor Day highlighting Arcatia 102. Dr. Jeffrey Newell, an international expert in genetic neurodevelopmental disorders from Vanderbilt University Medical Center, provided an overview of the natural history of Tourette syndrome and clinical considerations for clinical trial design, including outcome measures and biomarker selection.

Pete to at a level, that's improves the symptomatology of rats without causing do you onto its effects.

Importantly in preclinical animal models interest equal mix trends takes you wanted to it was not associated with early debt did not cause adverse behavioral side effects in the wild type mice, demonstrating appropriate downregulation of medically to protein expression.

Reviewed our clinical development strategy. The recent positive regulatory feedback supporting all R&D, enabling preclinical package in its current dosage selections.

Suyash: Dr. Stephen Gray detailed the requirements for regulated gene expression on a cell-by-cell basis to safely and effectively treat the disease, and that is exactly what our novel MI-RAD platform does. It regulates the degree of transgene expression based on underlying genotype on a cell-by-cell basis, ensuring that MeCP2 is expressed at a level that improves the symptomatology of rats without causing undue adverse effects.

We also discussed disease specific insights from our recent discussions with the advisory Board and can't get the focus groups. We provided recommendations on current clinical study design endpoints and the utility of the Ret syndrome natural history data.

Since the Investor day, we have recently obtained preclinical data showing improvement in survival.

Tree on most of the functions and irrelevant in mouse models of the disease.

Suyash: Importantly, in preclinical animal models, intrathecal MEK-tagged Taysha-102 was not associated with early death and did not cause adverse behavioral side effects in wild-type mice, demonstrating appropriate downregulation of MEK-B2 protein expression. We reviewed our clinical development strategy, the recent positive regulatory feedback supporting our IND-enabling preclinical package, and current dose selection. We also discussed disease-specific insights from our recent discussions with advisory board and caregiver focus groups who provided recommendations on current clinical study design, endpoints, and the utility of Rett syndrome and natural history data.

Notably preliminary data from a GOP toxicology study in nonhuman primates demonstrated no adverse findings at the highest dose tested suggesting that the MRM platform is successfully down regulating mcafee to expression within normal physiological level.

Yes.

We plan to submit an R&D CCA. It takes you at one or two this month followed by initiation of a phase one two trial by the end of this year.

We anticipate preliminary clinical data by the end of 2022.

Patient one or two has been granted rare pediatric disease designation and orphan drug designation from the FDA and more recently open drug designation from the European Commission.

Our most recent Investor day focused on Angelman syndrome, where we highlighted a two pronged approach to treat the significant neurodevelopmental disorder with no approved treatments.

Suyash: Since the investigation, we have recently obtained preclinical data showing improvement in survival and respiratory and motor functions in the relevant mouse models of the disease. Notably, preliminary data from a GLP toxicology study in non-human primates demonstrated no adverse findings at the highest dose tested, suggesting that the MRF platform is successfully down-regulating MeCP2 expression to within normal physiological levels.

Don't have been sales part of the U N C presented the U B E T. A gene replacement strategy I'm going to run Butler Obeche southwestern presented the veteran RNA mediated knockdown approach is arent on saddam's. Its total coffee you'd be three hygiene by talks Indiana since transcript responsible for solving some of the gene.

Suyash: We plan to submit an IND CTA for Taysha 102 this month, followed by initiation of a Phase 1-2 trial by the end of this year. We anticipate preliminary clinical data by the end of 2020. Taysha 102 has been granted a Rare Pediatric Disease designation, an Orphan Drug designation from the FDA, and more recently, an Orphan Drug designation from the European Commission. Our most recent research focused on Angelman Syndrome, where we highlighted our two-pronged approach to treat this significant neurodevelopmental disorder with no approved treatment.

Recent publication of promising preclinical data in the journal of clinical investigation insight further detailed.

A D mediated U B E. Three eight junior replacement approach recapitulate endogenous three to one I suppose ratios by replacing both the short and long isoforms of you'd be three eight in key regions of the brain leading to improvements in motor learning outcomes.

Outcomes seizure phenotypes in mouse models of Angelman syndrome.

These proof of concept preclinical data support further study of <unk> gene replacement therapy, as a potentially safe and.

If treatment for Angelman syndrome.

Suyash: Dr. Ben Philpott of UNC presented the UBE3A Gene Replacement Strategy, and Dr. Ryan Butler of UT Southwestern presented the Vectorized RNA-Mediated Knockdown Approach designed to silence the paternal copy of the UBE3A gene by targeting the antigen's transcript responsible for silencing the gene. Recent publication of promising preclinical data in the Journal of Clinical Investigation Insights further detailed how our AAV-mediated UBE3A gene replacement approach recapitulates endogenous three-to-one isoform ratios by replacing both the short and long isoforms of UBE3A in key regions of the brain, leading to improvements in motor learning, behavior outcomes, and procedure of penis types in mouse models of Angelman syndrome. These proof-of-concept preclinical data support further study of UBE3A gene replacement therapy as a potentially safe and effective treatment for Angelman syndrome.

Both strategies are highly encouraging and importantly allow us to target time Angelman syndrome population positioning patient that's a world leader in the discovery of treatments Angelman syndrome.

As you've heard this morning, we continue to progress our programs on both development and.

Breaking lately fronts and look forward to providing you updates along the way.

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

Cameron.

Thank you. This morning, I will discuss key aspects of our third quarter 2021 financial results 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 R&D expenses were $39 $5 million for the three months ended September 30 of 2021 compared to $11 $1 million for the three months ended September 32020.

The $28 $4 million increase was primarily attributable to an increase of $14 5 million of expenses incurred in research and development manufacturing and other raw material purchases, which included cgmp manufacturing batches produced by <unk> and Ut southwestern.

There was an increase in employee compensation expenses of $10 $7 million, which included $1 $9 million of noncash stock based compensation and $4 $9 million in third party research and development expenses, which include clinical trials Bureau activities, GOP toxicology studies and consulting for regulatory and clinical.

Kamran Alam: Both strategies are highly encouraging and, importantly, allow us to target the entire Angelman Syndrome population, positioning Taysha as a world leader in the discovery of treatments for Angelman Syndrome. As you've heard this morning, we continue to progress our programs on both development and regulatory fronts and look forward to providing you updates along the way. With that, I will turn the call over to Kamran to review our financial results.

<unk>.

This was partially offset by a decrease in licensing fees of $1 $7 million.

G&A expenses were $11 $2 million for the three months ended September 30 of 2021 compared to a 4.0 million for three months ended September 32020.

The increase of approximately $7 $2 million was primarily attributable to $4 $3 million of incremental compensation expense, which included $1 8 million of noncash stock based compensation.

There was an increase of $2 $9 million, mainly in professional fees related to legal insurance Investor Relations Communications accounting personnel recruiting market research and patient advocacy activities.

Net loss for the three months ended September 32021 was $51 $2 million or $1 35 per share as compared to a net loss of $15 million or $1 28 per share for the three months ended September 32020.

As of September 30 of 2021 piece, you had $188 $8 million in cash and cash equivalents.

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

Okay.

Okay.

Okay.

I wonder if I'll raise draw.

Dropped off for some reason this is my apologies.

Kamran Alam: Thank you, Suyash. This morning, I will discuss key aspects of our third quarter 2021 financial results. More details can be found in our Form 10-Q, which will be filed with the SEC.

Oh my apologies.

My apologies. Thank you I was talking on mute.

So I want to thank everybody for joining the call today.

We are pleased to share with you our success over the past several months looking ahead, we will continue our focus on advancing our pipeline expeditiously and executing on key anticipated upcoming milestones as a reminder, in December we anticipate data from our highest dose cohort from our phase one flash to taste at 120 <unk>.

Kamran Alam: This morning, I will discuss key aspects of our third quarter 2021 financial results. More details can be found in our Form 10-Q, which will be filed with the SEC shortly.

Kamran Alam: As indicated in our press release today, R&D expenses were $39.5 million for the three months ended September 30, 2021, compared to $11.1 million for the three months ended September 30, 2020. The $28.4 million increase was primarily attributable to an increase of $14.5 million of expenses incurred in research and development manufacturing and other raw material purchases, which included CGMT manufacturing batches produced by Catalan and UT Southwest. There was an increase in employee compensation expenses of $10.7 million, which included $1.9 million of non-cash stock-based compensation and $4.9 million in third-party research and development expenses, which include clinical trials, CRO activities, GLT toxicology studies, and consulting for regulatory and clinical studies.

And John it's Don on neuropathy, and preliminary phase one flashtube clinical safety data.

And heck a enzyme activity in the plasma and CSF for Acacia one O. One N G M. Two gangliosidosis.

Also in December we anticipate preliminary safety data.

For the first generation construct from our ceiling seven program lastly by year end, we expect to initiate a phase one flash to try it.

The all in one disease and Brett syndrome.

I would like to give special thanks to the continued support and dedication of our case employees Board of Directors Scientific Advisory Board collaborators and the patient advocates who remain our motivation every day to continue our mission to develop curative gene therapies and eradicate devastating monogenic CNS.

Disease.

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

Thank you we will now be conducting a question and answer session.

Kamran Alam: This was partially offset by a decrease in licensing fees of $1.7 million. G&A expenses were $11.2 million for the three-month-ended September 30, 2021, compared to $4.0 million for the three-month-ended September 30, 2020. The increase of approximately $7.2 million was primarily attributable to $4.3 million of incremental compensation expense, which included $1.8 million of non-cash stock-based compensation. Additionally, there was an increase of $2.9 million mainly in professional fees related to legal, insurance, investor relations, communications, accounting, personnel recruiting, market research, and patient advocacy activities.

You would like to ask a question. Please press star one on your telephone keypad.

Confirmation tone will indicate your line is in the question queue you.

You May press star two to remove your question from the queue for participants using speaker equipment. It may be necessary to pick up your handset before pressing the star keys, one moment. Please while we poll for your questions.

Our first questions come from the line of Joon Lee with true Securities. Please proceed with your questions.

Hi, Thanks for taking our questions and congrats on the impressive accomplishment in such a short period of time.

G. M. Two you seem to be implying that you may be able to submit for approval with existing data from the Canadian side and if so you know what your jurisdictions or do you think would be most amenable to this and can you give us some historic proxy where something like this has happened and I have a follow up.

Good morning June and things and thank you for the question, maybe I'll start and then I'll pass it over to Sue yes to provide his thoughts so.

Kamran Alam: The net loss for the three months ended September 30, 2021 was $51.2 million, or $1.35 per share, as compared to a net loss of $15 million, or $1.28 per share, for the three months ended September 30, 2020. As of September 30, 2021, Taysha had $188.8 million in cash and cash equivalents. And with that, I will hand the call back to RA.

The current G. M. Two study is a global study in a sense that the clinical trial is taking place in Canada, where patients are literally coming from all over the world.

From a from a registration in the U S perspective.

All you need to have is an open eye and be ultimately to file a BLA and then supporting data from a robust clinical trial and again based on the Fda's on guidance, where theres a robust natural history.

Mahdi Goudarzi: I wonder if I'll rise... So I want to thank everybody for joining the call today. We are pleased to have shared with you our success over the past several months. Looking ahead, we will continue our focus on advancing our pipeline expeditiously and executing on key anticipated upcoming milestones. As a reminder, in December, we anticipate data from our highest dose cohort from our Phase 1-2 patient 120 study in gynexonal neuromas, and Preliminary Phase 1-2 Clinical Safety Data, and Hex A Enzyme Activity in the Plasma and CSS, Cercasia 101, and GM2 gangliosidosis.

Good clinical a good robust clinical development plan a good.

Endpoint that supports registration this should not necessarily be an issue and so there's meaningful there's multiple meaningful are examples of this are across the rare disease spectrum.

I'll turn it over to Sue you have to provide a couple of examples of this but certainly we today feel based on the severity of the disease and the unmet medical need for the disease and how well the program is actually enrolling.

You know you may not necessarily to do a full clinical trial in.

In the U S and May just need to import one or two patients from the U S to be dosed. So I'll stop there turn it over to see us to provide his thoughts.

Mahdi Goudarzi: Also in December, we anticipate preliminary safety data for the first generation construct from our CLN7 program. Lastly, by year-end, we expect to initiate a Phase 1-2 trial in CLN1 disease and Rett syndrome. I would like to give special thanks to the continued support and dedication of our CACESIA employees, Board of Directors, Scientific Advisory Board, collaborators, and the patients and advocates who remain our motivation every day to continue our mission to develop curative gene therapies and eradicate devastating monogenic CNS diseases. I will now ask the operator to begin our Q&A session. Operator?

Yeah. Thanks, all right that's actually a question Judy Yeah, we're talking through regulatory strategy on an ongoing basis.

You know in the past.

Last four months.

Six months, we've had a nine regulatory meetings across.

Portfolio of programs and.

These are multiple meetings with the U S and several of the ex U S agency. So we're really getting a lot of real time information on the right approach.

Operator: Thank you. We will now be conducting a question and answer session. If you would like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue.

For pathway to approval is already has already said, we've been very pleased actually of how.

Able to identify patients for the Canadian Jan two study.

There's been some delays related to COVID-19, but essentially we've screened large numbers of patients that tell us the ash, there's a large number of Champ two patients out of that.

Operator: You may press star 2 to remove your question from the queue. For participants using speaker equipment, it may be

Operator: For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for your questions.

So while in Canada, we are talking about the fact, yes, perhaps we could just fall ex U S. Initially have the R&D iPhone and then fall principally with data from.

Joon So Lee: Our first questions come from the line of Joon Lee with Truist Securities. Please proceed with your questions. Hi, thanks for taking our questions and congratulations on the impressive accomplishments in such a short period of time. For the GM2, you seem to be implying that you may be able to submit for approval with existing data from the Canadian site. And if so, what jurisdiction do you think would be most amenable to this? And can you give us some precedents where something like this has happened?

Other countries as opposed to from the U S and that's always says it is a global study. So the likelihood is if theyre all U S patients, we could actually send them to come up with a dosing. So there's multiple options here in terms of specific examples when I put it on a couple of previously in particular of Biomarin, where iqos was much more on Europe initially.

<unk> followed by the U S lights out I think one springs to mind I don't really see I like to burn your program was one one.

Mahdi Goudarzi: Good morning, Joon, and thank you for the question. Maybe I'll start, and then I'll pass it over to Suyash to provide his thoughts. So, the current GM2 study is a global study in the sense that the clinical trial has taken place in Canada, where patients are literally coming from all over the world. From a registration in the U.S. perspective, all you need to have is an open IND, ultimately, to file a BLA, and then supporting data from a robust clinical trial.

The study stops.

Ex U S and then.

The filing happened in Europe prior to the U S. From my recollection of that is true, but there are several examples where this is this has happened.

Yeah, we continue to value options the likelihood we'll open in R&D in the U S with G. M. Two at some point soon as against the wall in Canada, We've decided to focus our time and energy and attention on continuing enrollment in gathering clinical data in Canada.

Mahdi Goudarzi: And again, based on the FDA's own guidance, where there is a robust natural history, a good, robust clinical development plan, and a good endpoint that supports registration, this should not necessarily be an issue. And so, there are multiple meaningful examples of this across the rare disease spectrum. I'll turn it over to Suyash to provide a couple of examples of this. But certainly, we today feel, based on the severity of the disease and the unmet medical need for the disease, and how well the program is actually enrolling, you may not necessarily need to do a full clinical trial in the U.S. and may just need to import one or two patients from the U.S. to be dosed. So, I'll stop there and turn it over to Suyash to provide his thoughts.

Great looking forward to the data in December.

Second question on the last question for take out 120 against what you have very strong data six eight years' worth of data.

You know are the materials used in the investigational study undergo the same GMP and QA process materials, you're producing.

In your GMP facilities and if there are different you know what would you need to do to satisfy the FDA requirements.

That they are equivalent and be able to.

Commercialize our submits for approval politics listing data. Thank you.

Suyash: We're talking through regulatory strategy on an ongoing basis. In the past four to six months, we've had nine regulatory meetings across our portfolio of programs. These are multiple meetings with the U.S. and several other ex-U.S. agencies, so we're really gathering a lot of real-time information on the right approach for the pathway to approval. As R.A. has already said, we've been very pleased, actually, at how we've been able to identify patients for the Canadian GM2 study. This has been...

Thanks for the question Great question by the way so essentially one of the things that we decided to do early on when we brought in the program was to make was to make sure that we can secure a like for like manufacturing platform.

To support comparability from the clinical stage material and the commercial grade material. So in order to do that what we've decided to do was to manufacture.

Suyash: Some delays that are related to COVID, but essentially, we've screened large numbers of patients that tell us that actually there are a large number of GM2 patients out there. Because things are going so well in Canada, we are talking about the fact that, yeah, perhaps we could just file ex-US initially, have the R&D open, and then file principally with data from other countries as opposed to from the US. And as RS says, it is a global study.

The commercial grade material, which will ultimately support a validation run and go into the BLA and support the BLA filing and commercialization, we what we decided to do is to partner with the same P. D. M O partner that manufactured the original clinical grade material producing it in a like for like process literally like for <unk>.

Just scaled up so it's the same cell line at the same purification filtration literally a a scene.

Suyash: So the likelihood is, if there are US patients, we could actually send them to Canada for dosing. So there are multiple options here. In terms of specific examples, I mean, I've worked on a couple previously, in particular at BioMarin, where our focus was much more on Europe initially, followed by the US later. I think one springs to mind. I think the CLN2 Brand Europe program was one where the study started in the ex-US, and then the filing happened in Europe prior to the US.

Exane process update it for some of the recent development.

For GMP manufacturing for gene therapy that the FDA likes to see so nothing that's out of the normal so we feel.

Strongly that our current dataset and our current comparability panel should support a like for like a product ultimately supporting a sameness argument I'll stop there. So yes do you have anything to add.

You know I think the NCL I'm really.

Suyash: From my recollection, that's true. But there are several examples where this has happened. So yeah, we continue to evaluate options. The likelihood is we'll open an IND in the US for GM2 at some point, but things are going so well in Canada, we decided to focus our time, energy, and attention on continuing enrollment and gathering clinical data in Canada.

We spent a lot of time and energy are very early on ensuring that we are able to characterize.

Product.

In terms of contaminants in terms of fill empty capsid ratios and we bring about learnings we bring those learnings through two to account program as well.

And there's a very real meaningful example, where actually two weeks ago that.

Joon So Lee: Great. I'm looking forward to the data in December. And a second question, and the last question. For Taysha 120 and GANS, would you have...

The team over at the C D and my partner Who's manufacturing the drug for the manufacturing the drug clinically and will also manifest shrunken through into the commercialized process, such a fresh portraits, Chief Technology Officer, Mischka head of regulatory and a team of about 10.

unknown: [inaudible]

Mahdi Goudarzi: GMP facilities. And if they're different, you know, what would you need to do to satisfy the FDA?

Mahdi Goudarzi: Thank you. Thanks, Joon, for the question. A great question, by the way.

Mahdi Goudarzi: So, essentially, one of the things that we decided to do early on when we brought in the program was to make sure that we could secure a like-for-like manufacturing platform to support comparability between the clinical stage material and the commercial grade material. So, in order to do that, what we decided to do was to manufacture the commercial grade material, which will ultimately support a validation run and go into the BLA and support the BLA filing and commercialization. What we decided to do was to partner with the same CDMO partner that manufactured the original clinical grade material, producing it in a like-for-like process, literally like-for-like, just scaled up. So it's the same cell line.

People spent a full week.

Let's say going through all the details.

We control the processes and ensuring that things will absolutely as pristine as possible. So we feel very confident that the the clinical material. The materials used in the clinical studies is going to be absolutely equivalents to what we're going to be using going forward and the gown program commercially. So yes, great question June, but we're very comfortable with the approach.

Yeah.

The only thing that I would add.

Yeah. The only thing that I would add is that we plan to have the commercial grade material available to support a BLA filing in the second half of next year.

Got it well looking forward to all the data in December.

Thank you.

Mahdi Goudarzi: It's the same purification, filtration, literally the same process updated for some of the recent developments for GMP manufacturing, for gene therapy that the FDA likes to see. So, nothing that's out of the normal. So, we feel strongly that our current data set and our current comparability panel should support a like-for-like product, ultimately supporting a sameness argument. I'll stop there.

Thanks, Jim.

Thank you our next questions come from the line of Gil Blum with Needham <unk> Company. Please proceed with your questions.

Good morning, and thank you for taking our questions. This is a bit of a follow up on on the previous discussion.

It actually makes good conceptual sense that considering you guys are using or production methods commercially used.

To make your a benign.

That would be translatable across your platform, but theres still variance and are you using different teams in each program.

Suyash: CS, do you have anything to add? You know, I think the only thing I liked really, um... We spent a lot of time and energy very early on ensuring that we were able to characterize product in terms of Hammanance in terms of full anti-captured ratios, and we bring that learning, we bring those learnings through to our GAN program as well. And there's a very real meaningful example where actually it was two weeks ago that the team was over at the CDMO partner who's manufacturing the drug for, the manufacturer of the drug clinically, and will also manufacture the drug through the commercialized process.

Do you guys expect the FDA will be looking for a bridging study of any time I mean this is the cross programs now right. So you could have it for Gan sealant and seven because I haven't heard him to it it seems that you.

Yeah, you make really long head ways with the initial studies and.

We're looking to kind of transfer quickly into commercial products. Thank you.

Hey, good morning, Gil Thanks for the question, maybe I'll start and then I'll allow us to yes to chime in on some of our recent discussions with regulators about kind of the this platform approach what I would say, it's again, it's somewhat of an outlier and what I mean by that is this was a program that essentially when we brought it in house had five to six years.

Suyash: So Fred Porter, our Chief Technology Officer, Mitch Gerhert, our Head of Regulatory, and a team of about 10 people spent a full week at the facility going through all the details and looking through all the processes and ensuring that things were absolutely as pristine as possible. So we feel very confident that the clinical material, the material used in the clinical studies, is going to be absolutely equivalent to what we're going to be using going forward in the GAN program commercially.

Robust data basically 55 years collectively worth of safety and efficacy data with really robust product produced by a high quality kind of commercial process and so what we wanted to do to make sure that we have the fastest pathway.

<unk> approval was basically not change anything and this is the reason why we decided to exclusively focused on the manufacturing partner that manufactured.

Suyash: So yes, great question June, but we're very comfortable with the approach here. The only thing that I would add... The only thing that I would add is that we plan to have the commercial grade material available to support a BLA filing in the second half of next year. Got it.

The original clinical grade material to support our commercial grade material, which will ultimately go into the BLA. So Gan is somewhat off buyer side now for the rest of the portfolio I think you're absolutely right. Our approach has always been this is a platform and not necessarily individual products and some.

Joon So Lee: Got it. Well, I'm looking forward to all the data in December. Thanks, Cliff.

Gil Blum: Thank you. Our next questions come from the line of Gil Blum with Needham and Company. Good morning, and thank you for taking our questions. It's a bit of a follow-up to the previous discussion. So it actually makes good conceptual sense that, considering you guys are using a production method commercially used to make your AAV9, that it would be translatable across your platform. But there are still variants, you know; you're using different genes in each program. Do you guys expect the FDA will be looking for a bridging study of any kind? This is across programs now, right?

Casey, there's absolutely a product of product variability, but essentially it's the same upstream process. The same downstream downstream process. The same cell line the St purification the thing Bioreactors. So there's this notion around platform value and essentially there's a consistency around our regulatory.

With each one of our programs I'll stop there and I'll, let sue yeah, just kind of talk about some of our recent regulatory interaction is fortunate that we've had nine regulatory accident interactions with with.

Multiple regulatory authorities, both in the U S and ex U S. Because it really gives us this deep understanding of how to augment our strategy or if our strategy is actually working and we're pretty confident around this platform. So see us maybe you want to chime in and provide some context.

Gil Blum: You could have it for GAN, you could have it for CLN7, you could have it for GM2. It seems that you're making really great progress with the initial studies and are looking to kind of transfer quickly into commercial products. Hey, good morning, Gil.

Yeah. Thanks, Thanks, all right and yes, thanks for the question Gil.

Mahdi Goudarzi: Thanks for the question. Maybe I'll start and then I'll allow Suyash to chime in on some of our recent discussions with regulators about this platform approach. What I would say is GAN is somewhat of an outlier.

And I think alright quite rise again, this a little bit of an outlier because gun, Washington, all hands in the earlier part of the clinical trials.

Mahdi Goudarzi: And what I mean by that is, this was a program that, when we brought it in-house, had five to six years of robust data, basically 55 years' worth of safety and efficacy data, with really robust products produced by a high quality kind of commercial process. And so what we wanted to do to make sure that we had the fastest pathway to approval was basically not change anything. And this is the reason why we decided to exclusively focus on the manufacturing partner that manufactured the original clinical grade material to support our commercial grade material, which will ultimately go into the BLA. So GAN is somewhat on its side.

It came into our hands and so we're having to adapt.

Somewhat which is very.

Very appropriate and as I say the team visited the C. D. M. I a couple of weeks ago, we feel very comfortable with that to add some color to the regulatory discussions.

You know we we have this just three topics really the come up in every regulatory interaction there relate to CMC and once again I'll mention Fred Poitra, Our Chief Technology Officer, who doesn't really.

Wonderful Japanese regulatory interactions on the street always to keep coming up.

Mahdi Goudarzi: Now, for the rest of the portfolio, I think you're absolutely right. Our approach has always been this is a platform and not necessarily individual products. In some cases, there is absolutely product-to-product variability. But essentially, it's the same upstream process, the same downstream process, the same cell line, the same purification, the same bioreactors. So there's this notion around platform value.

CMT characterization, how you're characterizing the quality the purity the pristine list of the products. The second topic is.

Its potency assays, how are you planning potency assays and what stage are you and how is that progressing and the third topic is bridging studies and what type of bridging studies do we need to do so we have a very specific approach to all those three topics first talks about them very nicely in the meetings and we actually have the regulation.

Mahdi Goudarzi: And essentially, there's a consistency around our regulatory discussions with each one of our programs. I'll stop there and let Suyash kind of talk about some of our recent regulatory interactions. It's fortunate that we've had nine regulatory action interactions with multiple regulatory authorities, both in the U.S. and ex-U.S., because it really gives us this deep understanding of how to augment our strategy or if our strategy is actually working, and we're pretty competent around this platform. So, Suyash, maybe you want to chime in and provide some context. Yeah, thanks.

Lest Friday.

On one of our one of our programs and B.

On the topic of bridging studies came out and our approach was very well accepted by the regulator that they said look just this all sounds fine just watch it up when you filed the Cta and what you propose is absolutely appropriate and once again you know.

We know that the CMC matters, you have to do the right thing as early as possible and we try as hard as we can we're successful for the vast majority of our programs. Once again kind of has it become an outlier, but the vast majority of our programs getting getting commercial grade material ready definitely by the time of the pivotal.

Suyash: Thanks, RA. And yeah, thanks for the question, Gil. And I think RA's quite right. GAN is a little bit of an outlier because GAN wasn't in our hands in the earlier part of the clinical trials. And it came into our hands, and so we're having to adapt somewhat, which is very appropriate. And as I say, the team visited the CDMO a couple of weeks ago. We feel very comfortable with that

When you study for the most part before we saw any clinical study at all and ideally in the actual R&D, enabling preclinical.

Preclinical studies, that's really when we want to have us all exploration to make sure we have a commercial grade product.

Suyash: To add some color to the regulatory discussions, You know, there are three topics really that come up in every regulatory interaction that relate to CMC. And once again, I'll mention Fred Porter, our Chief Technology Officer, who does a really wonderful job with these regulatory interactions.

Time point it just hasn't just makes the whole regulatory process go much smoother from a CMC perspective.

Thank you for a very complete answer.

On this question.

Maybe a quick scientific question.

Suyash: And the three topics that keep coming up are CMC characterization; how are you characterizing the quality, the purity, the pristineness of the product? The second topic is potency assays, how are you planning potency assays and at what stage are you, and how is that progressing? And the third topic is bridging studies, and what type of bridging studies do we need to do?

For two program is there any differences between let's say measured in CSF and serum.

Seeing a high level and one no different than the other or.

Better than the other thank you.

So Gil it's.

Great question, and maybe I'll start and then I'll turn it over to Sue Yes, you know I think based off of the natural history and the natural history for G. M. Two gangliosidosis, it's actually pretty well characterized the disease has been known for for over 100 years and when you look at the hex enzyme activity level and the infantile form of that.

Suyash: So we have a very specific approach to all those three topics. Fred talks about them very nicely in the meetings, and we actually had a regulatory meeting last Friday on one of our programs, and the topic of bridging studies came up, and our approach was very well accepted by the regulator. They said, look, this all sounds fine; just write it up when you file the CTA, and what you propose is absolutely appropriate.

Disease and this is essentially the most severe form of the disease. These patients are essential knockouts, they have 0.1% enzyme activity and that correlates to an early death of around three win just taken a patient from 0.1% and this is enzyme activity in the plasma and let me be specific.

And just taking a patient from 0.1%, 2.5% or half a percent you actually extend survival out to the mid teens that goes from an infantile onset patient to a juvenile onset patients that typically two to come to the D than they are in their mid teens, just getting a patient to two to four.

Suyash: Once again, you know, we know that for CMC matters, we have to do the right thing as early as possible, and we try as hard as we can, and we're successful in the vast majority of our programs. Once again, Gann is a bit of an outlier, but the vast majority of our programs, getting commercial-grade material ready definitely by the time of the pivotal part of any study, for the most part before we start any clinical study at all, and ideally in the actual IND-enabling preclinical studies. That's really what we want to have.

4% you know go from a infantile onset patient to an adult onset patient and it normalizes lifespan, just at 2% to 4% and this again is in the plasma and so the plasma is it measures. The Peck state are are probably the most well known.

Gil Blum: That's our aspiration to make sure we have a commercial-grade product at that early time point. This just makes the whole regulatory process go much smoother from a CMC perspective. Thank you for a very complete answer to this question. Maybe a quick scientific question.

Correlate to disease progression and that's the reason why we wanted to make sure that we benchmark.

To that but certainly you'll have different levels of xa activity in plasma versus CSF I'll, let sue you just go into that a little bit more in depth.

Gil Blum: For the M2 program, are there any differences between HEXA measured in CSF and serum? Is seeing a high level in one different than the other or better than the other? So Gil, it's a great question. And maybe I'll start with it and then I'll turn it over to Suyash.

Yeah, Thanks, Alright, and Gil so really perceptive question, because I think it's important to understand.

Expectations of what we're going to see from from a site perspective, alright quite right. There was a lot learned about Tay Sachs Soundoff JMP ganglia Pseudocyst that's been done historically because as was described in the lifestyle hundreds by William tell you put yourself in a mall logistic. The enzyme was identified in 19 and 16 alike and there's been many many screening.

Mahdi Goudarzi: You know, based on the natural history, the natural history for GM2 gangliosidosis is actually pretty well characterized because the disease has been known for over 100 years. And when you look at the hexenzyme activity level in the infantile form of the disease, which is essentially the most severe form of the disease, these patients are essential knockouts. They have 0.1% enzyme activity.

So we have a really good understanding of hexane levels in the plasma having said that we wanted to not only look at plasma levels. We also when COVID-19 CSF levels because to us intuitively, if we're trying to transfuse brain cells. We should also see an elevation of heck site in the CSF and we believe that.

Mahdi Goudarzi: And that correlates to an early death of around three. When just taking a patient from 0.1%, and this is enzyme activity in the plasma, let me be specific. And just taking a patient from 0.1% to 0.5% or half a percent, you actually extend survival out to the mid teens. That goes from an infantile onset patient to a juvenile onset patient that typically succumbs to disease in their mid teens.

That will actually reflect what's happening Brian a little more in the plasma activity. So that's why we're plentitude bugs and we'll be sharing data on both.

Towards the end of the year now always quite correct tool. So that once we hit 5% levels of enzyme in the serum.

In terms of the clinical phenotype, those all adult patients with Gen. Two gangliosidosis they have some cognitive deficits and movement disorder, but they haven't generally normal lifespan. So if we change the heck site level from less than 1% for NIM vitol to over 5%.

Mahdi Goudarzi: Just getting a patient to two to 4%, you now go from an infantile onset patient to an adult onset patient, and it normalizes lifespan just at two to 4%. And this, again, is in the plasma. And so the plasma measures of hexA are probably the most well-known correlates to disease progression, and that's the reason why we wanted to make sure that we benchmarked against that. But certainly, you'll have different levels of hexA activity in plasma versus CSF. I'll let Suyash go into that a little bit more in depth.

We anticipate that that will dramatically modified the clinical phenotypes that softball.

It centers on what levels, we want to see in the CSF, we're assuming 5% as well, but actually it may be less maybe a little bit less because my guess is the CSF levels of Xa may actually be a little lower on the plasma levels yet.

From a customer that spec side, but as I say, we will be presenting both.

<unk> talked.

Suyash: Yeah, thanks, RA. And Gil, this is a really perceptive question because I think it's important to understand expectations of what we're going to see from a HEXA perspective. RA is quite right. There's a lot known about Tay-Sachs and standoff, GM2 ganglifidosis, that's known historically. The disease was described in the late 1800s by William Tay, a British ophthalmologist.

My Xa levels and.

CSF levels Opex I would call. The S is working very nicely when we presented that data towards the end of the year.

Alright. Thank.

Thank you for taking our questions and congrats on all the progress.

Thanks, Joe.

Thank you our next questions come from the line of Laura Chico with Wedbush Securities. Please proceed with your question.

Hey, good morning, guys. Thanks, very much for taking the questions I just have two small ones. So first on the $1 20 program could you just discuss a little bit more about the timing. After the January meeting I guess I'm, just trying to better understand when we might have a little bit more clarity on the U S regulatory path for 120, I apologize if I missed that and then.

Suyash: The enzyme was identified in 1969, and there have been many, many screening programs. So we have a really good understanding of HEXA levels in the plasma. Having said that, we wanted to not only look at plasma levels; we also wanted to look at CSF levels because, intuitively, if we're trying to transduce brain cells, we should also see an elevation of hexafate in the CSF, and we believe that that will actually reflect what's happening in the brain a little more than plasma activity.

Kind of related to that really your commentary it sounds like the base case, we should have in our estimates is really assuming ex U S. Regions proceed the U S and I just wanted to make sure that that is the kind of working base case assumption right now last one just on one 'twenty already I think you mentioned second half would be released a commercial grade material for 120 I just wanted to.

Suyash: So that's why we're planning to do both, and we'll be sharing data on both towards the end of the year. Now, Ari's quite correct also that once we hit 5% levels of enzyme in the serum, in terms of the clinical phenotype, those are adult patients with GM2 gangliosidosis. They have some cognitive deficits and movement disorder, but they have a generally normal lifespan.

To understand are there any remaining headwinds or issues that could perhaps impact timing there. Thank you guys.

No. It's a good it's a great question and thank you Laura maybe I'll tackle your first the first question and then I'll turn it over to see us to talk about our regulatory strategy, so around manufacturer ability and in manufacturing of the commercial grade material for Donegal amid a rapidly right now we actually don't foresee any headwind.

Gil Blum: So if we change the HEXA level from less than 0.1% for an infantile to over 5%, then we anticipate that that will dramatically modify the clinical phenotype. So that's our bar. In terms of what levels we might see in the CSF, we're assuming 5% as well, but it may actually be less. It may be a little bit less because my guess is that the CSF levels of Hex A may actually be a little lower than the plasma levels of Hex A.

That would actually limit the limit the availability of that product in the second half of the year. We're actually fortunate we actually did a small scale right of that internally of that product and it's actually one of our best producing programs until we're pretty fortunate to have that data in hand, that's at a small scale, but.

Gil Blum: But as I say, we'll be presenting both... Plasma Hex A-Levels, and... We have got the assets working very nicely. We will be presenting that data towards the end of the year. All right. Thank you for taking our questions and congratulations on all the progress.

But certainly when we look across our portfolio and having the luxury to be able to have such a large portfolio to reference it too. It's actually one of our best producing programs. So we're pretty excited about that being that this is going to be our first commercial.

Operator: Thank you. Our next questions come

Laura Chico: The next questions come from the line of Laura Chico with Wedbush Securities. Please proceed with your questions.

First commercial campaign, so we actually don't perceive any headwinds on that so you know we would reiterate that guidance of having a commercial grade material available in the second half of 2022.

Laura Chico: Hey, good morning, guys. Thanks very much for taking the questions.

Laura Chico: I have two small ones. First, on the 120 program, could you just discuss a little bit more about the timing after the January meeting? I guess I'm just trying to better understand when we might have a little bit more clarity on the U.S. regulatory path for 120.

When you start to think about you know timing from an approvable any perspective I think the strategy is it still that the thing you know I I think this program essentially checks all the boxes that were laid out and the in the draft guidance that the FDA issued in January of this year, we have.

Laura Chico: And then, kind of related to the earlier commentary, it sounds like the base case we should have in our estimates is really assuming ex-US regions perceive the US, and I just wanted to make sure that that is the kind of working base case assumption right now. Last one, just on 120RA, I think you mentioned the second half would be the release of commercial grade material for 120. I just wanted to understand, are there any remaining headwinds or issues that could perhaps impact timing there? No, it's a great question.

Six years of longitudinal individual patient data we have dose response, we have collected 55 years of patient safety and efficacy multiple endpoints, we have not only functional endpoints MFN thirty-two functional endpoints around visual acuity, but we also have biopsy.

The data and a number of and a number of other endpoints that were collected that we'll be talking about in the publication that comes out here in the near term. So the way that we're looking at this is essentially.

It's three scenarios in the U S. We think two of those are high probability the burst is gonna be our going in strategy essentially pointing to the fda's on guidance and this is really around using analytical comparability to support the BLA filing essentially confirming the like for like material from the clinical grade <unk>.

Mahdi Goudarzi: No, it's a great question and thank you, Laura. Maybe I'll tackle the first few questions and then I'll turn it over to C.S.

Mahdi Goudarzi: to talk about our regulatory strategy. So around manufacturability and manufacturing of the commercial-grade material for diagnostic neuropathy, right now, we actually don't foresee any headwinds that would actually limit the availability of that product in the second half of the year. We're actually fortunate; we did a small-scale run of that internally, of that product, and it's actually one of our best-producing programs. And so we're pretty fortunate to have that data in hand, that's at a small scale, but certainly, when we look across our portfolio and have the luxury to be able to have such a large portfolio to reference it to, it's actually one of our best-producing programs. So we're pretty excited about that, being that this is going to be our first commercial campaign. So we actually don't foresee any headwinds for that.

<unk> commercial grade material again, we're not changing anything we're literally not changing anything so there's really nothing that we could really point to other than scale and and so that would support a end of year BLA in the 2020 to.

BLA.

They could come back and say, we'd like for you to dose a few more patients. We're fortunate to have those patients identified that are currently in the natural history study. We now have a robot natural history study, we reported on approximately a 40 plus patients. There's now over 50 patients in the natural history study that are currently being run at the NIH by our collaborator Dr. Carr.

The bottom it and so for us to be able to rollover patients from that study to treat two to three more patients. If we need it to perform some sort of clinical comparability would be something that we would be able to do relatively quickly and so we think the difference between doing an analytical comparability that would support a BLA filing at the end of 2022.

Mahdi Goudarzi: So we would reiterate that guidance of having commercial-grade material available in the second half of 2022. But when you start to think about timing from an approvability perspective, I think the strategy is still the same. I think this program essentially checks all the boxes that were laid out in the draft guidance that the FDA issued in January of this year. We have We have six years of longitudinal individual patient data. We have dose response.

We're needing to do some clinical comparability that would be just about a six month difference so that would probably push a BLA filing to probably mid 2023.

Europe is all by itself right and so Europe. The conditional approval pathway is wide open based on the guidance that the EMA has issued around conditional approval Keystone once when he checks all the boxes and that's going to be are going in discussion early in the new year, when we'd be with our ex U S regulators really around what.

Mahdi Goudarzi: We have a collective 55 years of patient safety and efficacy, multiple endpoints. We have not only functional endpoints, MFM 32, functional endpoints around visual acuity, but we also have biopsy data and a number of other endpoints that were collected that we'll be talking about in the publication that comes out here in the near term.

Is the conditional approval innovative medicines paas way that are available to us and currently that the data will support our pause there maybe C. S. You want to just comment on you know our regulatory strategy and just the timing to get those responses back.

Mahdi Goudarzi: So the way that we're looking at this is essentially... You know, there are three scenarios in the U.S. We think two of those are high probability. The first is going to be our approach, essentially pointing to the FDA's own guidance. And this is really around using analytical comparability to support the BLA filing, essentially confirming the likes for like material from the clinical grade material and commercial grade material. Again, we're not changing anything. We're literally not changing anything.

Yeah, I will do just give a bit of color Laura to the gist.

Some of the operational aspects of what we're trying to on the Gan program.

We'll go to our great takes puckish again.

That's we've already.

You mentioned this great natural history study.

Spun states huh.

Cliffs stabilization of disease.

Medium low medium high doses in the high dose yet to come.

Long term safety durability.

Mahdi Goudarzi: So there's really nothing that we could really point to other than scale. And so that would support an end of year BLA, end of 2022 BLA, they could come back and say, we'd like for you to dose a few more patients. We're fortunate to have those patients identified that are currently in the natural history study. We now have a robust natural history study.

And efficacy and so we're really feeling confident and good about our discussions with regulators one of the practical challenges frankly is that.

The regulators just very very busy and thought you were looking forward to having all 10th regulation meeting this month, but the regulator agency question actually contacted US and said Hey look we're really so we're really busy.

We're going to have to push you out to January.

Mahdi Goudarzi: We reported on approximately 40 plus patients. There are now over 50 patients in the natural history study that is currently being run at the NIH by our collaborator, Dr. Carson Bonneman. And so for us to be able to roll over patients from that study to treat two to three more patients, if we needed to perform some sort of clinical comparability, that would be something that we would be able to do relatively quickly. And so we think the difference between doing an analytical comparability that would support a BLA filing at the end of 2022 or needing to do some clinical comparability would be just about a six month difference. So that would probably push a BLA filing to probably mid 2023. Europe is all by itself, right?

So this is on a different program, but it just is that that very rarely happens and so it just gives us a sense.

How busy the agencies are at the moment.

Generally with a whole bunch of Covid stuff. So so we're putting our requests for meetings, but not actually getting the meeting for 345 months.

You know that down the Pike. So it is it is there.

A little bit of an operational challenge that frankly, but I'll just say first messing around them in January we anticipate the subsequent meetings shortly thereafter.

The likelihood is for we May also separate out really policy for the timing CMC discussions with clinical data discussions and I think that's probably how we're planning the cadence with some of the agencies, especially those that have more folks in CMC and this was already touched on before CMC.

Mahdi Goudarzi: And so, in Europe, the conditional approval pathway is wide open based on the guidance that the EMA has issued around conditional approval. Patient 120 checks all the boxes, and that's going to be our going topic early in the new year when we meet with XUS regulators really around what is the conditional approval innovative medicines pathway that is available to us and currently that the data will support. I'll pause there.

It's something that we want to make sure we explain all process all situations very well so what we're planning for a separate one on Tuesday agencies and CMC discussions on the clinical discussions and the final point I'll make and.

Alright, and I were talking about this at some length over the past few days.

Suyash: Maybe CS, you want to just comment on, you know, our regulatory strategy and just the timing to get those responses back. Yeah, I will do and just give a bit of color, Laura, on some of the operational aspects of what we're trying to do with the GAN program. You know, we've got a great data package for GAN. As we've already mentioned, this is a great natural history study.

Again, we've got this great efficacy data and we talk about the efficacy data at Legg.

We can clear disease stabilization of dose response, one of the things we don't focus on so much is the safety data because that's actually what the regulators focus on more than anything when it comes up closer to a BLA filing and I just want to emphasize the fact that we've got years and years worth of safety.

Suyash: There's response data, Clear Stabilization of Disease at Medium Low and Medium High Doses and the High Dose Yet to Come, Long-term Safety and Durability Editors-in-Chief, CCCC, NPR, CCCC, NPR, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, CCCC, In fact, we were looking forward to having our 10th regulatory meeting this month, but the regulatory agency in question actually contacted us and said, hey, look, we're really, so we're really busy. We're gonna have to push you out to January. So this was on a different program, but you know, that very rarely happens.

These data in this program is very nice for me as a head.

The head of R&D going into regulatory discussions with the duration of safety data, usually I'll have you know six months or year.

Regulate to always turns around and says hey, you need to studying this for another year before you can file, but we have patients who are dosed.

In 2015, so there are patients with up to six or seven years worth of clinical safety data and we show there.

It's minimal.

Minimal issues around inflammation, there's no liver issues, there's nice evidence of thrombotic microangiopathy.

Suyash: And so it just gives a sense of, how busy the agencies are at the moment. Generally with a whole bunch of COVID stuff. So we're putting in requests for meetings, but not actually getting the meeting for three, four, five months. There's a little bit of an operational challenge there, frankly, but as I say, we've got our first meeting lined up in January, we anticipate the subsequent meetings shortly thereafter. The likelihood is for, we may also separate out, really partly for the timing, CMC discussions with clinical data discussions, and I think that's probably how we'll plan the cadence with some of the agencies, especially those that have more of a focus on CMC, and as we've already touched on before, CMC is something that we want to make sure we explain our process, our situation very well, so we're planning to separate for one or two of the agencies the CMC discussions and the clinical discussions.

There's no evidence of any and you're running a law. So in Colombia, you change in the brain. So.

No drug related serious adverse events. It really we really have a very nice bucket of safety data, which I think will be very.

Over the longer term, which I think will be very much appreciated by the regulators because that's even though.

The safety message of AAV gene therapy of <unk>.

Then you know discussed at some length recently, so I just want to emphasize that in addition to the wonderful efficacy data. We have for this program. We have some really nice long term safety data, which I think will stand us in good stead to these regulatory discussions. So we look forward to telling about how those go.

Early in the new year.

Okay.

Thank you.

To remind everyone to please ask one question.

Thank you so much.

Our next questions come from the line of Salvia Richter with Goldman Sachs. Please proceed with your question.

Suyash: And the final point I'll make, and you know, Ari and I were talking about this at some length over the past few days, you know, for GAN, we've got this great efficacy data, and we talked about the efficacy data at length, which shows clear disease stabilization and dose response. One of the things we don't focus on so much is safety data because that's actually what the regulators focus on more than anything when it comes to BLA filing, and I just want to emphasize the fact that we have got years and years of safety data in this program.

Hey, good morning, guys and thanks for taking our question that says what's the background.

Dean.

I would just to hear from us and one would be you touched upon our different properties expected between the first and the next generation construct for the ceilings seven program and maybe if you could just remind us on the molecular level our structural differences between the two and then quickly on the second question just you know.

Touching on places like Hertz Pro data, that's closer I'll give a new hot several data readouts descent.

December and then into next year, and then you know what venue or.

I'll just close off on that those can take thank you.

Hey, Elizabeth Good morning, and thank you for the question. So I'll take your first question and I'll allow us to you to provide some insight to the second question on the first question around the key differences between the first generation construct in the second generation construct of the next generation construct Brasil and seven we haven't yet disclosed what those key molecular.

Suyash: It's very nice for me as a head of R&D going into regulatory discussions with that duration of safety data. Usually, I have, you know, six months or a year, and the regulator always turns around and says, "hey, you need to study this for another year before you can file." So there are patients with up to 6 or 7 years of clinical safety data, and we show minimal issues around inflammation, there's no liver issues, there's no evidence of thrombotic microangiopathy, and there's no evidence of any neuronal loss or inflammatory change in the brain at all.

Differences are we do plan to disclose that upon construct a design finalization, which will happen here in the next few weeks. What we know is based on some of the changes that we've made previously across our portfolio. There are changes that we can make to the construct and the sequence as well as the itr.

Suyash: No Drug Related Serious Adverse Events, it really, we really have a very nice bucket of safety data, which I think will be very, over the longer term, which I think will be very much appreciated by the regulators, because as you know, The safety methods of AV gene therapy have been, you know, discussed at some length recently, so I just wanted to emphasize that in addition to the wonderful efficacy data we have for this program, we have some really nice long-term safety data, which I think will stand us in good stead for these regulatory discussions, and we look forward to telling you about how those go early in the new year.

That will actually make the gene therapy vector more state make it more potent improve on the manufacturer ability and allow it to actually package more efficiently in order to increase yields once we start to get into large scale large scale manufacturing. So just based on our history and some of the changes that.

We previously made from construct that we're coming out of our collaborators at Ut southwestern we're gonna be applying that those same changes to this program, we feel pretty strongly that we would be able to still referenced a clinical proof of concept data. That's currently being generated from the proof of concept trial.

Operator: Thank you. We would just like to remind everyone to please ask one question.

Operator: Our next questions come from the line of Salveen Richter with Bowman Sachs. Please proceed with your questions.

So that our partners at UT southwestern are currently running they've dosed two patients one patient has been dosed at five each of the 14 total Vg and are equally second patient had been dosed at 1% to the 15 inert equally a total total BG and the third patient is to be dosed in in December and so what I.

Salveen Jaswal Richter: Hey, good morning, guys. And thanks for taking our questions. This is Elizabeth from Salveen. So just two from us, and one would be you touched upon the different properties expected between the first and the next generation construct for the CLN7 program. And maybe if you could just remind us of the specific molecular level or structural differences between the two.

What I'll say is once that construct design is completed which should happen here in the next few weeks and work for them, we're pretty confident of that we'll be happy to share. Some of the changes that we've made are in order to improve multiple multiple aspects of of the gene therapy here.

Salveen Jaswal Richter: And then quickly on the second question, just, you know, touching on Taysha's approach to data disclosure, given you have several data readouts towards December and then into next year, and then, you know, what venue or potential disclosure format those could take. Thank you.

As far as your second question around data disclosure I'm really it is our approach it is confirming our guidance today around the availability of data for our high dose cohort, which is 3.5 b to the 14th total B G.

Mahdi Goudarzi: Disclosure Format those could take. Thank you. Hey, Elizabeth, good morning.

For Janus wanted to rapidly by the end of this year hefei enzyme activity in the plasma and CSF.

Mahdi Goudarzi: Thank you for the question. So I'll take your first question, and I'll allow CES to provide some insight into the second question. On the first question around the key differences between the first generation construct and the second generation construct and the next generation construct for CLN7, we haven't yet disclosed what those key molecular differences are. We do plan to disclose that upon construct design finalization, which will happen here in the next few weeks.

For our G. M. Two program by the end of this year and preliminary clinical data from the seal and seven program by the end of this year as we move into as we move into 2022 you're absolutely right.

Our portfolio is kind of playing out exactly we're fortunate the portfolio was playing out how we would like it to in a sense, where youll kind of have this constant drumbeat of data readouts and updates as the as the program start to mature. So what we proactively said there'll be an update for GM to mostly.

Mahdi Goudarzi: Based on some of the changes that we've made previously across our portfolio, there are changes that we can make to the construct and the sequence as well as the ITRs that will actually make the gene therapy vector safer, make it more potent, improve its manufacturability, and allow it to actually package more efficiently in order to increase yield once we start to get into large-scale manufacturing. So just based on our history and some of the changes that we've previously made from constructs that were coming out of our collaborators at UT Southwestern, we're going to be applying those same changes to this program.

Likely in the middle of next year there'll be an update for our ceiling, one program, which will be P. P. T. One enzyme activity.

In the CSF and in the plasma as well as clinical safety that'll happen in the first half of next year there'll be an update again on our steel and seven program around a functional assessments as well as clinical safety.

That'll happen in the first half of next year and then they'll also be a constant update around regulatory feedback is that come then with that we hope will ultimately support a rapid path to approval for giant's own them to rapidly and adds that come in as well as progress on our manufacturing across all fronts. So.

Mahdi Goudarzi: We feel pretty strongly that we would still be able to reference the clinical proof of concept data that's currently being generated from the proof of concept trial that our partners at UT Southwestern are currently running. They've dosed two patients. One patient's been dosed at 5E to the 14, total BG, inter-thecally. The second patient has been dosed at 1E to the 15, total BG.

So I think you'll actually see this constant drumbeat.

High quality clinical data, both efficacy and safety, starting and you know starting in December of this year and just going out to the foreseeable future. Lastly, we plan to have as you know our ret syndrome are first glimpses of ret syndrome data available to us.

Mahdi Goudarzi: And the third patient is to be dosed in December. And so, what I'll say is once that construct design is completed, which should happen here in the next few weeks, and we're pretty confident of that, we'll be happy to share some of the changes that we've made in order to improve multiple aspects of the gene therapy here. As far as your second question around data disclosure, really, our approach is confirming our guidance today around the availability of data for our high-dose cohort, which is 3.5e to the 14 total BG, for gynecological neuropathy by the end of this year, hexaenzyme activity in the plasma and CSF for our GM2 program by the end of this year, and preliminary clinical data from the CLN7 program by the As we move into 2022, you're absolutely right.

And at the end of next year, and and I think most people understand.

The value creation that that program is going to generate not only because of the large patient population, but also the fact that we are.

That we are essentially.

Controlling the expression of Mac P to.

<unk> typically on a cell by cell basis, and vivo and not using any type of exogenous support or anything else. This is all self contained within the construct basically hijacking. The endogenous feedback loop of of the body and so again that is it's going to be high quality data. We were excited about some.

The preliminary G O P talks.

Data that we've gotten in our in Hp's studies as well as some new pharmacology data and so we will continue to provide updates on that as well as we get into the new year and providing updates on enrollment. So that's kind of how you could think about data readouts we will.

Mahdi Goudarzi: The portfolio is kind of playing out exactly as we would like it to, in a sense where you'll kind of have this constant drumbeat of data readouts and updates as the programs start to mature. So, as we proactively said, there'll be an update for GM2 most likely in the middle of next year. There'll be an update for our CLN1 program, which will be PPT1 enzyme activity in the CSF and in the plasma as well as clinical safety. That'll happen in the first half of next year. There'll be an update again on our CLN7 program around functional assessments as well as clinical safety. That will happen in the first half of next year.

Be presenting data at some of the larger conferences, but as soon as those are are those.

Those presentations are accepted.

We will be updating the street and and I would also tell you that we plan on publishing a number of a number of papers and high quality journal, starting with John its own in neuropathy, where are our collaborators are putting the final touches on their definitive a research paper and hopefully that'll be accepted.

Here and published a relatively soon.

Yes.

Thank you. Our next question comes from the line of Michael <unk> with Morgan Stanley. Please proceed with your questions.

Mahdi Goudarzi: And then there'll also be a constant update around regulatory feedback as that comes in that we hope will ultimately support a rapid path to approval for giant cellular neuropathy, and as that comes in, as well as progress on our manufacturing across all fronts. So I think you'll actually see this constant drumbeat of high-quality clinical data, both efficacy and safety, starting in December of this year and just going out for the foreseeable future.

Hey, guys. Thanks for taking the question maybe a question on 120 and again.

Sure around the upcoming data in December for the highest dose maybe you can just talk about how you're thinking about that.

The dose going forward you know for example, if you see in the highest dose sort of continued stability.

What does that mean for you in terms of the optimal dose. Thanks.

Mahdi Goudarzi: Lastly, we plan to have our Rett syndrome, our first glimpses of Rett syndrome data, available to us at the end of next year. And I think most people understand the value creation that that program is going to generate, not only because of the large patient population but also the fact that we are, essentially, controlling the expression of MeCP2 genotypically on a cell-by-cell basis, in vivo, and not using any type of exogenous support or anything else. This is all self-contained within the construct, basically hijacking the endogenous feedback loop of the body.

Hey, good morning, Mike and Great question, I'll turn it over to Sue Yes, Yes, you want to take that question.

Sure.

Yeah, so as we've already as you're already aware, we've got a nice dose response across the three dose groups that we've shared previously so the $3 five equals a threep will probably 13 total vg.

Low dose, which was the more of a safety dose.

But TUI 14, the medium low dose and the one point a T 14.

Medium high touch really showed disease stabilization. So the ongoing decline of eight points per year with M. S. M 32 was wholesale with both of those doses.

Mahdi Goudarzi: And so, again, that is just going to be high-quality data. We were excited about some of the preliminary GOP talks where those presentations were accepted. We'll be updating the street. And I would also tell you that we plan on publishing a number of papers in high-quality journals, starting with John Exon and Neuropathy, where our collaborators are putting the final touches on their definitive research paper. And hopefully, that'll be accepted here and published relatively soon. Thank you. Our next question comes from the line of Mike Bowles with Morgan Stanley. Please proceed with your order.

My guess is that the high dose is going to show at least.

Degree of improvements.

That's really a dose stabilization, which is clinically meaningful as we know a full point changing them become 32 seems to be a clinically meaningful change to the fact that we prove disease by eight points per year, which translates to 16 points of the two years 24 points of the three years.

Is really very meaningful for these patients and families and if we identify patients earlier.

Mike Bowles: Hey guys, thanks for taking the question. Maybe a question on 120 and GAN and around the upcoming data in December for the highest dose, maybe you can just talk about how you're thinking about the dose going forward. You know, for example, if you see in the highest dose sort of continued stability, Gil. What does that mean for you in terms of the optimal dose thing?

And we treat them when they are in such a high level of functioning that's going to be a.

Probably the most meaningful thing we can do for these patients and families and as you've already heard on the.

On a cold this morning, and we shouldn't press release, three or four weeks ago on our partnership with gene Dx AR, where we now have the mutation for Gan.

Mike Bowles: Hey, good morning, Mike. And a great question. I'll turn it over to Suyash. Suyash, do you want to take that question?

Gamma mutation now on many of these registry in Europe pretty screening panels and the costs are covered so actually presented that the shock of my tooth Association meeting.

Suyash: Sure. Yeah, so as you're already aware, we've got a nice dose response across the three dose groups that we've shared previously. So the 3.5E13 total VG was the low dose, which was the more the safety dose, the 1.2E14, the medium low dose, and the 1.8E14. Thus, the ongoing decline of 8 points per year on the MFM32 was halted with both those doses. My guess is that the high dose is going to show at least that degree of improvement, that degree of dose stabilization, which is clinically meaningful.

Meeting last weekend and talks about the screening approach and there's a lot of excitement a lot of interest from patients who have a different forms of so when you walk the seasons have been diagnosed with shocking right to them.

Taught to wanting to get screened in case, they have begun mutation of wood that will be eligible for gene therapy construct so identify patients earlier is going to be more critical things in dose.

In terms of what it means if we have generally equivalent.

Suyash: As we know, a 4-point change in the MFM32 is deemed to be a clinically meaningful change. So the fact that we improved the disease by 8 points per year, which translates to 16 points over 2 years and 24 points over 3 years, is really very meaningful for these patients and families. And if we identify patients earlier, and we treat them earlier when they're at a higher level of functioning, that's probably the most meaningful thing we can do for these patients and their families.

Levels are generally equivalent degrees of disease stabilization from getting from the medium low hold up to the high dose you know there's an argument that we should go in with the high dose is the the dose we should fall for an approval. This in all kinds of it maybe we go for the medium high touch the woman with Daiichi 14 total would be.

Some of it will depend on safety profile and what I will say is on the medium low in the medium high dose the safety profile is very very encouraging.

Suyash: As you already heard on the call this morning, and we should have pressed this three or four weeks ago on our partnership with GeneDx, where we now have the mutation for GAN. The GAN mutation is now on many of these hereditary neuropathy screening panels, and the costs are covered. So, I actually presented at the Charcot-Marie-Tooth Association meeting last weekend and talked about this screening approach, and there was a lot of excitement, and a lot of interest from patients who have different forms of axonal neuropathy that have been diagnosed with Charcot-Marie-Tooth.

We sold some additional safety concerns the hardest would maybe dropped down a day so far of the one point I T 14 days.

That's going to be the case actually be standing out from the medium low medium high to the high you're actually doubling the amount of drug which for gene therapy is not a huge jump in and does so the actual dose we filed for approval with I think will become a bit clearer once we.

Suyash: Type 2 wanting to get screened in case they have a gang mutation and would therefore be eligible for gene therapy constructs. So identifying patients earlier is going to be more critical, I think, than dose. In terms of what it means, if we have generally equivalent levels or generally equivalent degrees of disease stabilization from going from the medium-low all the way up to the high dose, there's an argument that we should go in with the high dose of the dose we should file for approval.

I'm sure the high dose data and will become clearer.

When we talk to regulators and unless you heard earlier, we're planning those discussions I'm. The first one will be January and then put them in.

Yeah, we'll have this discussion with other agencies, but my guess is it's going to be falling on the high dose or the medium higher does that would be my guess.

Thank you. Our next question comes from the line of Kevin Decatur with Oppenheimer. Please proceed with your question.

Suyash: There's an argument that maybe we should go for the medium-high dose, the 1.8014 total BG. Some of it will depend on the safety profile, and what I will say is that on the medium-low and the medium-high dose, the safety profile is very, very encouraging. If we saw some additional safety concerns, the high dose would maybe drop down a dose or file the 1.8014 dose, but I don't anticipate that's going to be the case, actually, because going up from the medium-low, sorry, medium-high to the high, you're actually doubling the amount of drug, which for gene therapy is not a huge jump in dose.

Hey, guys. Thanks for taking my questions I mean, just maybe two quick ones on Jim too you. Appreciate the updated perspective on how you're thinking about regulatory path I guess with that in mind how.

How many patients should we expect to see an update on in December.

To kind of appreciate it kind of.

Where you are from building our patient data safety base, and then as I think about duration of follow up.

You know from a clinical perspective, but I guess for this discussion from a regulatory perspective.

What duration.

Hmm.

A follow up hex enzyme expression do you think you'll you'll need to be able to gather to have robust discussions with regulators.

Hey, Kevin Good morning, and thanks, and thanks for the question maybe I'll take your first question and so yes. If you don't mind you can take Kevin and second question on the first question, what what I'll say is we haven't disclosed the number of patients that will be in that update what I will say is that a C. S and his team is.

Suyash: So the actual dose we file for approval with will become a bit clearer once we share the high dose data and will become clearer when we talk to regulators, and as you heard earlier, we're planning those discussions. The first one will be in January, and then early in the new year, we'll have those discussions with other agencies. But my guess is it's either going to be filing on the high dose or the medium-high dose. That would be my guess.

Well as our patient advocacy groups as well as our Med Affairs group collectively have done a fantastic job with identifying patients globally.

Unknown Executive: Thank you. Our next question comes from the line of Kevin DeGeter with Oppenheimer. Please proceed with your question. Hey guys, thanks.

And this is a true global study and so we're quite excited about that and this is ultimately what what changed our mindset really around what the fastest pathway to approval could potentially look like essentially because we were getting patient from from literally all over the world and identifying patients.

Unknown Executive: Hey guys, thanks for taking my questions. I mean, just maybe two quick ones on GM2.

Unknown Executive: You appreciate the updated perspective on how you're thinking about the regulatory path, I guess, with that in mind. How many patients should we expect to see an update on in December to kind of appreciate kind of where you are from building a patient data safety base? And then as I think about the duration of follow-up. You know, from a clinical perspective, but I guess for this discussion, from a regulatory perspective, you know, what duration of follow-up do you have for hexenzyme expression? Do you think you'll need to be able to meet to have robust discussions with regulators? Thanks. Hey Kevin,

From all over the world and so.

What I'll say is that we are on track to have that data it'll be on multiple patients I will say that and what I'll also say, it's three years and a team from a screening perspective I have now have now identified and have assessed.

Over double digits worth of patient I'll, I'll say that again that really gives us a lot of competence that theres a lot more patients out there that maybe the the epidemiology is really let on and this is typically the case from a rare disease perspective, when there is a therapeutic alternative patients patients tend to find you.

Mahdi Goudarzi: Good morning, and thanks for the question. Maybe I'll take your first question. And Suyash, if you don't mind, you can take Kevin's second question.

And so yes, and again the patient advocacy group in and and our multiple teams have done a fantastic job getting out there finding the kols, having the discussion making sure people know that this study is up and running and make sure people know that they have an ability if they're not in the territory.

Mahdi Goudarzi: On the first question, what I'll say is we haven't disclosed the number of patients that will be in that update. But what I will say is that Suyash and his team, as well as our patient advocacy group, as well as our MedAffairs group collectively, have done a fantastic job of identifying patients globally. And this is a true global study, and so we're quite excited about that.

To actually traveled to the territory to be treated and so I'll stop there. So yes, maybe you want to address Kevin's question around just picks a enzyme activity and duration of effect.

Mahdi Goudarzi: And this ultimately changed our mindset really around what the fastest pathway to approval could potentially look like, essentially because we were getting patients from literally all over the world and identifying patients from all over the world. And so, what I'll say is that we are on track to have that data. It'll be on multiple patients. I will say that. And what I'll also say is Suyash and his team, from a screening perspective, have now identified and assessed over double digits worth of patients.

Yeah. This is a really good question Kevin and.

I think the way to think about it is it takes a step back and just just.

Anticipate the cadence of what might happen. So it wasn't a gift with the drug.

Interest equally it travels to the brain.

Ah the cabinets in the brain, so Neil wrong, but denied pulps out starts producing the Boston strong like.

<unk> Alpha sub unit because they combine.

And stopped breaking down gene to gang beside now you can look at Maxwell transgene expression, probably three to four weeks after dosing and then you should get national production of events.

Mahdi Goudarzi: Again, this really gives us a lot of confidence that there are a lot more patients out there that maybe the epidemiology has really let on. And this is typically the case from a rare disease perspective. When there's a therapeutic alternative, patients tend to find you. And Suyash and, again, the patient advocacy group and our multiple teams have done a fantastic job getting out there, finding the KLLs, having the discussions, making sure people know that this study is up and running, and making sure people know that they have an ability, if they're not in the territory, to actually travel to the territory to be treated. And so I'll stop there. Suyash, maybe you want to address Kevin's question around just hexane enzyme activity and duration of effect? Yeah, this is a really good question, Kevin.

Events on <unk> shortly thereafter so.

Oh Gosh. This is the one month time point, we take the CSF somewhat one months, we'd take one to three months, we tell you when that six months and then we'll take it when the 12 months for the first year My guess is that the.

Heck city level and the CSF will go up as a woman time points, but probably will not reach maximum levels. While the three month time point my expectation is it will reach maximum levels in parallel with that.

With regard to the earlier discussion we had you would also see an elevation of xa levels in the plasma which is.

While we have more experience, but it's probably less relevant for a treatment the transducers brain cells.

My guess is that you're going to see.

Suyash: I think the way to think about it is, take a step back and just... Participate in the cadence of what might happen. So we're going to give the drugs. Interstitially, it travels through the brain. The capsule enters the brain cell, the neuron, the DNA pops out, starts producing the vicistronic, Hex Alpha Subunit, and Beta Subunit, they combine and start breaking down GM2

Elevated levels at the six month time point in D. C S and persistently elevated levels at the 12 month time point and the CFO.

Thank you guys see any diminution in activity over time and the reason for this is that.

Is that once you've trumps used to bring so it should keep it should stay trumps to Houston still be producing.

Transgene in perpetuity.

There's some kind of inflammatory or I mean, the logical or disease taught insult, which should others thing will be the case really.

Suyash: Now you're going to get maximal transgene expression probably three to four weeks after dosing, and then you should get maximal production of the enzyme Hex A shortly thereafter. Our guess is that at the one-month time point, and we take a CSF sample at one month, we take one at three months, we take one at six months, and then we take one at 12 months for the first year. My guess is that the HEX-A level in the CSF will go up at the one-month time point but probably will not reach maximum levels.

My My guess is that the enzyme levels once the brainiest transduce the enzyme levels and the SaaS will stay high persistently.

Now are.

And we've seen this to some degree in the mouse models, where we see across a range of all programs where content CSF levels from mice. Unfortunately.

All things all the time, but what we can do is look at plasma observations on that at the time and we see them raised persistently in a chronic mouse studies over time. So my guess is we're going to see elevated losses depends on consistently now how much ensign what persistence what your ability is required by the regulators.

You know my guess is that.

If they see a nice increase I think that probably going to want to see.

Suyash: By the three-month time point, my expectation is that it will reach maximal levels. In parallel with that, and with regard to the earlier discussion we had, you will also see an elevation of HEX-A levels in the plasma, which is... where we have more experience, but it's probably less relevant for a treatment that transduces brain. My guess is that you're going to see persistently elevated levels at the six-month time point in the CSF and persistently elevated levels at the 12-month time point in the CSF.

Yeah. It will probably go in if we're seeing.

Good clinical benefit of the six month time point and persistent levels of enzyme in the states. One of the time point, we might consider filing on that data, but a reality the regulators do usually once a year.

And so my guess is it will probably make a case that six months, if we're seeing good clinical effect and persistent enzyme levels.

But in reality, the irregular cause will pushback about once a year, but that's my guess in hopkinsville playback of the longer term.

Yeah.

Thank you our next questions come from the line of <unk> Zhang with BTG. Please proceed with your question.

Suyash: And I don't think you're going to see any diminution in activity over time. And the reason for this is that once you've transduced a brain cell, it should stay transduced and still be producing. Transgene in perpetuity unless there's some kind of inflammatory or immunological or disease-type insult which I don't think will be the case really so my guess is that the enzyme levels once the brain is transduced, the enzyme levels in the CS will stay high persistently.

Hi, good morning, Thanks, very much for taking the question. This is a follow up question on the Seo and Sem program I'm. Just wanted to confirm have you had any discussion with the FDA to confirm that it will be possible to move into pivotal study was the second generation construct and given that there seems to be quite a lot of components or you're going to change from them.

Generation one to generation two how do you feel comfortable that some courthouses will allow you to find the optimal doses and feel comfortable still with the safety going into pivotal study. Thank you.

Okay.

For the question, maybe I'll start and end so yes, please chime in if.

If you if you'd like to so what I would say there are multiple aspects that we know that we can change and maintain.

Suyash: Now, and we've seen this to some degree in the mouse models, where we see across a range of our programs, we can't take CSF levels from mice, unfortunately, of enzyme over time. But what we can do is look at plasma levels of enzyme over time, and we see them raised persistently in our chronic mouse studies over time. So my guess is we're going to see elevated levels of enzyme persistence. Now, how much enzyme and what persistence, and what durability is required by the regulators? You know, my guess is that if they see a nice increase, I think they're probably going to want to see... You know, we'll probably go in if we see an increase.

A certain level of functionality of the ceiling seven construct because we've done it before essentially taking programs from.

From our collaborators from Academia, and then making the subtle changes, making any subtle changes in moving that program forward into IND, enabling studies and ultimately forward into the clinic, while using the data that's been generated proof of concept data that's been generated as as a basis to support our clinical development.

We've actually done this multiple times across our portfolio.

And and these changes that we have made before will be consistent with some of the aspects that we look.

Suyash: If there is good clinical benefit at the six-month time point and persistent levels of enzyme at the six-month time point, we might consider filing on that data. But in reality, the regulators usually want a year. And so my guess is it will probably make a case at six months if we're seeing good clinical effects and persistent enzyme levels. But in reality, the regulators will push back and will want a year. But that's my guess on how things will play out over the long term.

To change on the field and seven programs. So we think there's there this notion of massive massive movements from one contract to the next it it is not necessarily there right. What we do know is and there's multiple FDA guidance documents on on how to do this.

What you can do in order to reference data that's been generated essentially by another construct or or similar product.

Suyash: Thank you. Our next questions come from the line of Eun Zang with VTIG. Please proceed with your, Hello, good morning.

So there so there's clear precedent that's been set by multiple agencies around the world both moving from animal proof of concept data into R&D, enabling studies and ultimately into the clinic and also in the clinical setting. We we've most recently seen that with one of unit cures gene therapy programs.

Eun Kyung Yang: Thanks very much for taking the question. This is a follow-up question on the CLN7 program. Just wanted to confirm, have you had any discussions with the FDA to confirm that it will be possible to move into a pivotal study with the second-generation counts drug? And given that there seems to be quite a lot of components you're going to change from generation one to generation two, how do you feel comfortable that some quick assays will allow you to find the optimal doses and feel comfortable still with the safety going into a pivotal study? Thanks for the question. Maybe I'll start, and so, yes, please chime in if you'd like to.

I believe it was in hemophilia. So so so this is a there has been precedent on on this and to your second question, we Havent yet approached the F. D. A with discussions around this program essentially we've had nine discussions across our portfolio.

And and multiple discussions planned for the new year, and we plan to discuss this program in the new year with the F. D. A around the protocol for comparability I'll stop there. So yes, maybe you want to comment.

Mahdi Goudarzi: So what I would say is there are multiple aspects that we know that we can change and maintain a certain level of functionality of the CLN7 construct because we've done it before, essentially taking programs from our collaborators, from academia, and then making these subtle changes, making these subtle changes and moving that program forward into IND-enabling studies and ultimately forward into the clinic, while using the data that's been generated, the proof-of-concept data that' We've actually done this multiple times across our portfolio, and these changes that we have made before will be consistent with some of the aspects that we look to change on the CLN7 program. So we think this notion of massive movements from one construct to the next is not necessarily there.

Sure.

Thank you.

You know I think the you know.

We've spent some considerable time talking about modifications to the construction.

The phrase modification, but just the relatively minor changes that we think will have some.

Reasonable.

In park.

And we won't go into the details of the changes with it with where we are.

We're proposing but suffice it to say, it's optimizing the construct while we think there's going to be.

To a degree of benefit from an efficacy perspective benefit from a safety perspective on the benefit for manufacture ability perspective.

Mahdi Goudarzi: What we do know is, and there are multiple FDA guidance documents on how to do this, what you can do in order to reference data that's been generated essentially by another construct or similar product. So, there's clear precedent that's been set by multiple agencies around the world, both moving from animal proof of concept data into IND-enabling studies and ultimately into the clinic and also in the clinical setting. We've most recently seen this with one of Unicure's gene therapy programs, and I believe it was in hemophilia.

But we're very very mindful that we don't want to change it. So much so that becomes a whole new package will very well what we can change it will be call. It change to allow us to reference the first generation construct from a similarity perspective with minimal bridging work it's likely.

We're going to need to do some bridging work in the animal but its lots to be a very simple study, perhaps a combined mouse model short duration.

Mahdi Goudarzi: So, this is a, there has been precedent for this. And to your second question, we haven't yet approached the FDA with discussions around this program. Essentially, we've had nine discussions across our portfolio and multiple discussions planned for the new year. And we plan to discuss this program in the new year with the FDA around the protocol for comparability. I'll stop there. Suyesh, maybe you want to comment?

Pharmacology toxicology study, but it's once again with.

Planning to make minimal minimal changes.

In line with our ability to reference the earlier first generation constraints.

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

Hi, This is Nancy on for young Thanks for taking our question I was just curious how is the progress on ratio of empty capsid during the 89 protection and what the current ratios emptied a package capsid.

Suyash: Sure, and I think that, you know, we've spent some considerable time talking about modifications to the construct. And I use the phrase modification because they're relatively minor changes that we think will have some reasonable impact. And we won't go into the details of the changes that we are proposing, but suffice it to say it's optimized in the construct where we think there's going to be... To a degree, a benefit from an efficacy perspective, a benefit from a safety perspective, and a benefit from a manufacturability perspective.

And what the range is between your different indications. Thank you.

Alright. Thank you for the question what I'll say is an end and because we have such an extensive portfolio. We we won't go into each each one of our programs what I'll say for or current standard is to strive for 90%.

On a full capsid and that's kind of consistent that's consistently our strategy across our portfolio and sometimes we do better than that in and what I can say for our G. M. Two program, we've actually we've actually gone above that.

Suyash: But we're very, very mindful that we don't want to change it so much that it becomes a whole new package. We are very aware of what we can change and what we can't change to allow us to reference the first generation construct from a similarity perspective, with minimal bridging work. It's likely we're going to need to do some bridging work in the animal, but it's likely to be a very simple study, perhaps a combined mouse model, short duration pharmacology, and toxicology study. But it's, you know, once again we're planning to make minimal changes, in line with our ability to reference the earlier first generation construct.

That that empty to full ratio that pool ratio of 90%. So that's kind of what our current standard is obviously every program is different and.

And so some are better producers than others, but what I will say.

We try to maintain some level of consistency in our manufacturing platform also ultimately to support this whole notion of platform effect in and what I would say is we will always sacrifice yield for a high quality of material and so that's probably one of the more important are important aspects of menu.

Operator: Thank you. Our next questions come from the line of...

Eun Kyung Yang: This has come from the line of Eun Yang with Jeffries. Please proceed with your... Hi, this is Nancy on behalf of Youm. Thanks for taking our question. I was just curious how the progress on the ratio of empty capsids during AAV9 production has been and what the current ratio of empty to packaged capsids is, and mostly on what the range of this is between your different indications. Thank you.

Back to your ability to us to make sure that we're getting good high quality full capsid and the patients ultimately to many to minimize any real safety concerns, which can be a concern that we've you know which is something that we've seen are within the field. So yes do you want to do you want to comment.

Mahdi Goudarzi: Hi, thank you for the question. What I'll say is, and because we have such an extensive portfolio, we won't go into each one of our programs. What I'll say for our current standard is to strive for 90% full taxes. And that's kind of consistent; that's consistently our strategy across our portfolio. And sometimes we do better than that. And what I can say for our GM2 program is that we've actually gone above that, that empty to full ratio, that full ratio of 90%. So that's kind of what our current standard is. Obviously, every program is different.

I will I will comment you know this is a really excellent question and.

I think always weaving in some of what the importance here is that and it's really about the sidewalks factor you know what does the presence if I can pick up since may not know I've been a thumps unbeliever for many years and I think the field is moving in this direction that we have to remove as much empty couch this possible.

Although the amount of fractures find this hard to do without sacrificing yields.

Tremendously and so there's sometimes a reluctance to try and remove the empty capsid, but from my perspective looking at the patient.

Mahdi Goudarzi: And so some are better producers than others. But what I will say is that we try to maintain some level of consistency in our manufacturing platform to ultimately support this whole notion of the platform effect. And what I would say is we will always sacrifice yield for high-quality material. And so that's probably one of the more important aspects of manufacturability to us, to make sure that we're getting good, high-quality, full capsids into patients ultimately to minimize any real safety concerns, which can be a concern that we, you know, which is something that we've seen within the field. So yes, do you want to comment?

Can you just kind of unnecessary viral load, which then feeds into some of the safety issues that we've seen and people are concerned about.

And the AAV gene therapy space.

All right I've been talking about this at length and I'm always quite right. So our intent is to have at least 90% full we do better than that.

Definitely back from that for some of our programs, which I'm very pleased about is the physician overseeing the safety of these patients.

And we I really appreciate the fact that our anr and full alignment that we will sacrifice yield in order to make sure we get pristine appeal.

Suyash: I will comment, this is a really excellent question. I think R.A.'s weaving in some of what the importance here is, and it's really about the so-what factor, you know. What does the presence of empty capsules mean? Now, I've been a firm, firm believer for many years, and I think the field is moving in this direction, that we have to remove as many empty capsules as possible. A lot of manufacturers find this hard to do without sacrificing yields.

Hardly purified product was a little empty capsules as possible. So I think it's a really important question. We you know we work closely with spread our chief Technology officer to try and make sure that we have very high quality products and we've got good characterization screens early on.

But our intent is to inject patients with a less than 10% empty greater than 90% full.

Suyash: Very significantly, and so there's sometimes a reluctance to try and remove the anti-capsid, but from my perspective looking at the patient, Anticaps just adds unnecessary viral load, which then feeds into some of the safety issues that we've seen and people are concerned about in the AAV gene therapy space.

Products.

Thank you. Our next question comes from the line of Kristen <unk> with Cantor Fitzgerald. Please proceed with your question.

Hi, good morning, everybody. Thanks for taking the questions just wanted to ask as you look at the clinical trial and do you anticipate running next year, how youre thinking about the cadence in terms of trial enrollment and given all of these different indications have different prevalent.

Suyash: Nara and I have been talking about this at length, and Nara is quite right. Our intent is to have at least 90% full. We do better than that, significantly better than that for some of our programs, which I'm very pleased about as the physician overseeing the safety of these patients. I really appreciate the fact that Ari and I are in full alignment, that we will sacrifice yield in order to make sure we get a pristine, pure..., highly purified product with as little empty capsule as possible.

Hey, Chris and good morning, and thank you for the question I'll turn it over to see us to answer that question.

Yeah. Thank you Christian Great question, you know, it's a little different from program to program a few common themes I would say.

First of all.

Talk a lot about our platform approach.

I T delivery HEK 293, but the platform approach actually works in many other ways one of which is frankly that the vast majority of clinicians we deal with.

Suyash: So I think it's a really important question. We work closely with Fred, our Chief Technology Officer, to try and make sure that we have very high quality products and we've got good characterization screens early on. But our intent, yes, is to inject patients with less than 10% empty and greater than 90% full products. Thank you. Our next question comes from the line of Kristen Kluska.

<unk> pediatric metabolic or neurology experts.

G M two shale and one ceiling southern rat.

It's generally a little tough to similar physicians.

Kristen Kluska: Hi, good morning everybody. Thanks for taking the questions. I just wanted to ask, as you look at the clinical trials you anticipate running next year, how you're thinking about the cadence in terms of trial enrollment, given all of

So we.

A lot of the touch points in terms of.

Finding investigators are all similar so I think that's one thing that helps us in terms of recruitment.

Kristen Kluska: Hey, Kristen, good morning. And thank you for the question. I'll turn it over to CS to answer that question. Yeah, thank you, Kristen.

I think the other thing that helps us as well.

Other diseases, where there are.

More the ultra rare population, so we're thinking that.

Suyash: Great question. You know, it's a little different from program to program. There are a few common themes, I would say. First of all, we talk a lot about our platform approach, AV-9 IT Delivery, HEK-293, but the platform approach actually works in many other ways. One of these is, frankly, that the vast majority of clinicians we deal with are pediatric, metabolic, or neurology experts. GM2, CLN1, CLN7, Rett.

The diseases with the house.

A thousand patients prevalent for example, we plan to have one or two sites in the U S and one or two songs ex U S. And then transport patients from from around the world to those sites.

We're focusing heavily on that.

You know the ability to transport patients from other countries to the U S. So it's kind of a Delta York and that's worked very well for our G. M. Two program. We only have one sites for a G. M. T program currently in Canada.

Suyash: It's generally looked after by similar physicians. And so are we. A lot of the touch points in terms of finding investigators are similar, so I think that's one thing that helps us in terms of recruitment. I think the other thing that helps us is we're for diseases where there is, More the ultra-rare population. So we're thinking, you know, the diseases would have, you know... We plan to have one or two sites in the U.S. and one or two sites outside the U.S. and then transport patients from around the world to those sites. So we're focusing heavily on that.

For a list of patients and in patients that have been enrolled and screened for the study to come from all over the world.

It's a little different for diseases that are less raw, so a disease like rats, why you're thinking 25000 patients in the U S and Europe recruitment and enrollment is a little different.

It's it's a little easier because patient there's more patients and they they they're they generally tend to congregate in centers of excellence, where clinicians will have 30, 40 50 patients with ret syndrome on the books, we have one woman key opinion leader one investigates when considering cross 200 pay.

Suyash: The ability to transport patients from other countries to the US or to Canada or to Europe, and that's worked very well for our GM2 program. We only have one site for our GM2 program currently in Canada, but our list of patients and patients that have been enrolled and screened for the study come from all over the world. It's a little different for diseases that are less rare, so a disease like RET where you think about 25,000 patients in the US and Europe, recruitment and enrollment are a little different.

With Ret syndrome.

So if we use individual's a clinical trial site, where hitachi and roll the whole study potentially on that site.

But we're gonna have we don't manage to a single source different routes of course, but it would probably be three or four sites, but I don't anticipate that being problems with enrolling some of the larger patient populations.

Suyash: It's a little easier because there are more patients, and they generally tend to congregate in centers of excellence where clinicians will have 30, 40, 50 patients with Rett syndrome on their books. We have one key opinion leader, one investigator we're considering who has 200 patients with Rett syndrome. And so if we use that individual as a clinical trial site, we could actually enroll the whole study potential of that site. But we're going to have... We're not going to just do a single site for this representative, of course, but there will probably be three or four sites.

And.

In principle, there's three real approach is to.

Two finding patients for these studies are not really led by two colleagues at Tatius, Emily Mcguinness, who tends to patient advocacy and kind of my competitors, who heads up our medical affairs and we.

We engaged with patient advocacy groups and detail and in a very sincere wholehearted white to.

To help educate them pay.

Patients and families. What it means type policy gene therapy trial in that way, we find patients who are interested in taking part.

Suyash: But I don't anticipate there being problems with enrolling some of the larger patient populations. In principle, there are three real approaches to finding patients for these studies, and they're really led by two colleagues at Taysha. So Emily McGinnis, who heads up patient advocacy, and Tomoya Pozo, who heads up medical affairs.

We work with key opinion leaders the experts in the fields, we have them attempt advisory boards, we talk to them.

And that's another route of finding patients and then the third approach is with on the ground medical science lays on activity.

Suyash: And we engage with patient advocacy groups in detail and in a very sincere, wholehearted way to help educate patients and families what it means to take part in a gene therapy trial. And that way, we find patients who are interested in taking part. We work with key opinion leaders, the experts in the fields.

With.

Team's knocking on the doors of Christians to define patient journey support. So those are really the three philosophical approaches we used to find patients.

I say a track record thus far for G. M. T. We found many many patients that are screened many have not been eligible and will spend will share more details on that when we update you.

Suyash: We have them attend advisory boards, we talk to them, and that's another way of finding patients. And then the third approach is with on-the-ground medical science liaison activities, with our teams knocking on the doors of clinicians to find patients who are on the support. So those are really the three philosophical approaches we use to find patients. As I say, our track record thus far for GM2, we've found many, many patients that we've screened.

Fuel with the data from the clinical trial, but that's so that's our approach and it seems to have been very successful for G. M too and so I would anticipate the same approach across the rest of our programs.

Thank you. Our next question comes from the line of Rajiv Prasad with William Blair. Please proceed with your question.

Okay.

Thanks for taking the question just curious to know.

On the the G.

<unk> Dx deal just how many patients do you anticipate.

Suyash: Many have not been eligible, and we'll share more details on that when we update you all with the data from the clinical trial. But that's our approach, and it seems to have been very successful for GM2, and so we anticipate the same approach across the rest of our programs.

Finding with a with kind of a.

Genetic marker and do you have any kind of initial.

Thoughts there and then some.

On the G M two program.

You know it seems like 5% as the benchmark year for biomarker, but is there any initial clinical.

Hmm.

Mahdi Goudarzi: Thank you. Our next question comes from the line of Raju Prasad with William Blair. Please proceed with your question.

Measured that we could see moving moving to kind of show that there's a clinical benefit that's being.

No change bye bye this AR increase.

Mahdi Goudarzi: Thanks for taking the question. I was just curious to know...

And Christian enzyme activity. Thanks.

Hey, Roger Good morning, Thanks for the question, maybe I'll take both questions and then for the second question. So yes happy to provide some color as well so for the first questions were around our collaboration with GE Dx not only was it a collaboration to include Jonathan neuropathy now on their standard neuropathy panel, but it's also.

Mahdi Goudarzi: On the GDX-VL, just how many patients do you anticipate finding with this kind of a...

Mahdi Goudarzi: Iyengar, and do you have any kind of initial thoughts... Thoughts there and then. Second, on the GM-2 program, you know, it seems like 5% is the benchmark here for biomarkers, but are there any initial clinical measures that we could see?

The collaboration that includes both the charcuterie tooth foundation as well as the hereditary neuropathy Foundation and this was extremely important because both of those patient advocacy groups fund and partner with centers of excellence both here in the U S.

Mahdi Goudarzi: Transcribed by https://otter.ai Hey, Raj. Good morning. Thanks for the questions. Maybe I'll take both questions and then, for the second question, I'd be happy to provide some color as well.

In Europe, and particularly for the charcuterie tooth.

Mahdi Goudarzi: So, for the first question about our collaboration with GeneDx, not only was it a collaboration to include Jynaxon Neuropathy now on their standard neuropathy panel, but it's also a collaboration that involves both the Charcote-Marie-Tooth Foundation and the Hereditary Neuropathy Foundation. And this is extremely important because both of those patient advocacy groups fund and partner with centers of excellence, both here in the U.S. and in Europe And particularly for the Charcote-Marie-Tooth Association, a number of patients that are clinically diagnosed with Charcote-Marie-Tooth have not undergone genetic screening.

Association a number of the patients that are clinically diagnosed with sharp with Marie to have not undergoing genetic screening and based on this again robust natural history data that our partners at the.

The NIH and Carson bought them and had been leading over the last eight years. It was identified that this late onset phenotype of giant iguana neuropathy was essentially a commonly misdiagnosed the charcuterie.

A sharp group Marie tooth and more particularly charcuterie to type two we also understand that the later onset form of the disease.

Is is extremely severe and kind of.

Mahdi Goudarzi: And based on this, again, robust natural history data that our partners at the NIH and Carson Bonneman have been leading over the last eight years, it was identified that this late-onset phenotype of Jynaxon Neuropathy was essentially commonly misdiagnosed as Charcote-Marie-Tooth and more particularly Charcote-Marie-Tooth type 2. We also understand that this later-onset form, [inaudible] And essentially, it's kind of one of these quality of life, significant kind of a significant impediment to quality of life, but they tend to live a normal lifespan or, at the very least, into their fifth decade of life.

Debilitating, but it's not life limiting in the sense that the early onset form of the diseases, where patients are essentially diagnosed at age three and either in their early teens or I'm sorry in their late teens or early twenty's. They they succumb to the disease are typically in the in the later onset form of the disease. These patients are dying.

I diagnose some some time after their fifth birthday.

Have issues around walking have issues around muscle strength and essentially it it's kind of one of these quality of life are significant it kind of a significant impediment to quality of life, but they tend to live a normal lifespan or the barely used into their fifth decade.

A decade of life. So what we understand is that there's just based off of the epidemiology, there's a large pool of prevalent patients and that later onset population that hasn't necessarily undergone a genetic tests because essentially when a person who are diagnosed with sharp with Marie tooth and particularly the type two form there.

Mahdi Goudarzi: So what we understand is that, based on the epidemiology, there's a large pool of prevalent patients in that later onset population that haven't necessarily undergone a genetic test because, essentially, when a person is diagnosed with shark boot, Marie tooth, and particularly the type two form, there is no genetic screening for because there's a number of genetic mutations that would cause this kind of umbrella diagnosis. So we actually think that there's a large group of patients, and after having, you know, talked to both the CMTA foundation and the hereditary hereditary neuropathy foundation, they both agree that a large section of these patients are typically misdiagnosed.

No genetic screening for it because there's a number of.

Genetic mutations that were called caused they've kind of umbrella diagnosis. So we actually think that there's a large group of patients and after having you know talk to both.

The C M T a foundation as well as the hereditary hereditary neuropathy foundation. They both agreed that a large section of these patients are typically misdiagnose and most likely there is a genetic underpinning of which we know a large portion up to 6% if not more are going to be.

Mahdi Goudarzi: And most likely, there is a genetic underpinning of which we know a large portion, up to 6%, if not more, are going to be gynecological neuropathy mutations. So we think there's a large number of patients both in the US and Europe out there. And so we're doing the work right now to kind of identify these ahead of any type of regulatory approval and eventual commercial launch.

Are gonna be Jonathan or neuropathy mutations. So we think there's a large number of patients both in the U S and Europe out there and and so we're doing the work right now to kind of identify these ahead of any type of regulatory approval and eventual commercial launch so.

Mahdi Goudarzi: So I'm answering your question, but not answering your question; I won't give you a specific number. But what I will say, it's a large number of patients. And we would probably say we'd put that number, you know, above 1000 patients out there that we hope to, you know, are able to identify a large number of those. Raj, do you mind just reminding me of yours?

I'm answering your question, but not answer your question I won't give you a specific number but what I will say, it's a large number of patients and we would probably say we'd put that number you know above a thousand patients out there that are out there that we hope to you know are able to identify a large number of those.

Raj do you mind, just reminding me of your second question.

Mahdi Goudarzi: It reminded me of your second question.

Mahdi Goudarzi: Yeah, I, you know, obviously, it seems as though natural history would say 5% is kind of the biomarker threshold for GM2. Just curious to know.

Yeah.

Obviously, it seems as though natural history would say, 5% is kind of the the.

Biomarker thresholds for G. M. Two I'm just curious to know.

Mahdi Goudarzi: So, you know, the timeline for when that may translate over into maybe early clinical measure benefit. Absolutely. Great question. So, yes, do you mind taking that? Sure, yeah.

The timeline for when that may translate over into maybe early clinical measure of benefit.

Absolutely Great question. So I guess do you mind taking that.

Sure Yeah, I shall I'll, just make one comment on the Gan Charcot Marie tooth.

Mahdi Goudarzi: Actually, I'll just make one comment on the GAM Shark and Marrow Tooth discussion because I actually spoke at the Shark and Marrow Tooth Association meeting last weekend and sat on a panel and got to meet many, you know, patients and families, and it was clear, you know, to Aray's point that the many individuals with Shark and Marrow Tooth, we only have a clinical diagnosis that, you know, there are many adults there So there's a large pool of patients, I think, who will really take advantage of this GDX partnership that we've created.

Discussion because I actually spoke to the shelf camera Tooth Association meeting last weekend.

And second Pamela and got to meet many and.

Patients and families and it was it was clear it's all right point that the many individuals the shocking right tooth.

I only have a clinical diagnosis.

There are no. Many adults who were diagnosed with the disease and haven't got a chance to mutation analysis of genetic testing. So there's a large pool of patients I think who really.

Take advantage of this this gene Dx partnership that we've created and our expectation is that our.

Mahdi Goudarzi: And our expectation is that... A significant number of patients will be found there, and that, you know, just based on the subjective discussions I had last weekend, I think that seems very real and meaningful. With regard to GM2, that's a good question.

A significant number of patients will be found but yeah. Just based on the subject of discussions I had last weekend and I think that the same story really meaningful.

With regard to G M too. It's a good question I talk to the cadence of highlights, but enzyme levels to modify and improve over time.

Suyash: I talked through the cadence of how I expect enzyme levels to modify and improve over time. I think with the clinical improvements, it's going to take longer to see clinical improvements, and it may be more stabilization of disease progression than improvement. And the reason I say this is that GM2 is a very rapidly progressive destructive disease, and what happens pathophysiologically is that you get the accumulation of GM2 ganglioside in the lysosomes of the cells.

With the clinical improvements.

I think I'm gonna take longer to see clinical improvements and it may be more stabilization of disease progression and improvement and the reason I say this is that.

G N. Two is a very rapidly progressing destructive disease.

What happens pathophysiological is that you get the accumulation of shame to ganglioside into license aimed at the south unless I'm slow they rupture the knee category.

Suyash: The lysosomes swell, they rupture, they leak out their acidic enzymatic contents and actually cause damage to the neurons. This is initially an inflammatory process, but then it results in fibrosis and death of the neuron, and once you've lost a neuron, you don't get it back.

I must say complex I'm actually cause damage in neurons initially an inflammatory process, but then it results in fibrosis definitely neuron.

And once you've lost in your when you don't get it back so I think.

Suyash: If a patient is significantly affected and they've lost a lot of neurons, you're going to be able to produce the enzyme HEXA, stop additional damage, and you may get some resolution of some of the inflammation that's going on in the neurons, but if you've lost neurons, you won't see any improvement there. If we treat the child earlier in life, and this is why it would be important at some point in the future to have a newborn screening for this disease and then treatment before the child has had a chance to deteriorate too much and before the neural loss has had the chance to take hold, that will be when you start to see the best clinical improvement.

If a patient is significantly affected.

A lot of new rooms.

And to be able to produce the enzyme heck say stopped additional damage and you may get some resolution of some of the inflammation the scaling of the neurons, but she lost neurons, you're not going to see improvement that if.

If we.

Treat earlier in life and this is why it would be important at some point in the future to have newborn screening for this disease and the treatment before the chocolates hubs.

Adjusted deteriorate too much and before the neuron losses have a chance to take hold that will be when you start to see.

The best clinical improvements.

Suyash: Specifically, in terms of what we're collecting and what I expect to see, we're looking at measures of we're looking at a whole host of measures. We're looking at hypotonia, hypotonia dysphagia, lack of head control, the Vineland looking at adaptive behaviors, the Bayley-3 scale looking at general development. We're looking at seizures, we're looking at EEGs, we're performing We're looking at quality of life scales and clinical global impression scales.

Specifically in terms of what we're collecting and would I expect to see when looked one message that we're looking at a whole host of measure. So we're looking at Hypotonia Hypotonia Dysphagia Luckett head control.

The vineland adaptive behavior as the baby three scale, we're looking at a general development. We're looking at seizures loosen E cheese with performing a communication assessment scale or sort of a reported communication ability.

Scale, we're looking at quality lifestyles and clinical global impression scales. My guess is that by the three month old patched for the six month time point, you should see some stabilization of disease and maybe some improvement probably the earliest indicator we will just be a general global clinical impression. So the CGI I scale will likely be a what.

Suyash: My guess is that by the three-month, or perhaps by the six-month time point, you should see some stabilization of disease and maybe some improvement. Probably the earliest indicator will just be a general global clinical impression. So the CGI eye scale will likely be what we hope will show some improvement. And then potentially some improvement in hypotonia, see some improvements there. See some loss, some...

We heightened show some improvements and then potentially some improvement in Hypotonia see some improvements that see some loss of some some.

Suyash: Some reacquisition of milestones, which will be measured by the Bayley-3, and I'd also hope to see some diminution in seizure activity. But I'm guessing you're going to have to wait at least three months after dosing, probably six months after dosing to see that. And I think you'll see a greater improvement in the younger patients than you will in the older patients.

Some.

Some re.

Additional milestones, which will be measured by the baby three and I would also hope to see some diminution in CS right. So, we'll see but I'm guessing you're going to have to wait at least three months after dosing probably six months after dosing to see that and I think youll see a greater improvement in the younger patients than you will in the older patients.

Suyash: I can see you as well.

Suyash: Thank you. Our next questions come from the line of Silvan Tuerkcan with JMP Securities. Please proceed with your question. Yeah, good morning.

Yeah.

Thank you our next questions come from the line of silver on Turkey with JMP Securities. Please proceed with your question.

Yeah, Good morning, and thanks for taking my question, maybe you can just give us a big picture of you about your ability to manage all of these programs as the pipeline expand so rapidly, especially next year with five six Ah trials and regulatory discussions of infotainment potential finding it.

Silvan Tuerkcan: We will manage all of these programs as the pipeline expands so rapidly, especially next year with 5-6 trials and regulatory discussions and potential filing. What about your cash and manpower? and all of that. Hey, Silvan.

The end of year, what about your cash and manpower.

To maintain all of that and.

Do you expect there will be maybe some attritional deeper prioritization or potentially some partnerships.

Mahdi Goudarzi: So, thanks for the question. So what I would probably say, you know, when you start to think about the company scaling to what we hope is eventually going to be a fully integrated gene therapy company that supports, you know, not only early discovery but also commercialization, this is exactly what we were hoping to build out as we, you know, kind of put the blueprint of the company together, and the company, and, quite frankly, the company is executing. You know, so I think the ability has just been shown. The proof is in the pudding, in a sense.

Thoughts there would be great. Thank you.

Okay. So then so thanks for the question so what I would probably say you know when you start to think about the companys scaling to what we hope is eventually going to be a fully integrated gene therapy company that supports not only early discovery, but also commercialization. This is exactly what we were hoping to build out as we you know.

Kind of put the the blueprint of the company together in the company and you know quite frankly the company is executing you know so I think the ability as they have been shown to proof that the proof is in the pudding innocent five concurrent GMP runs.

<unk> completed this year non regulatory interactions this year good activity on the BD front, albeit a lot of those programs are coming from our chief scientific adviser Doctor Stephen Gray, but they all kind of support the central thesis around.

Mahdi Goudarzi: Five concurrent GMP runs completed this year, non-regulatory interactions this year, good activity on the BD front, albeit a lot of those programs are coming from our chief scientific advisor, Dr. Stephen Gray, but they all kind of support the central thesis around intersecal delivery, AAV9, HET293, suspension manufacturing. We finished the year last year with one clinical stage program. We'll finish this year with five clinical stage programs. You know, we plan to have three data readouts that we're on track and reiterating our guidance to hit those. And we have multiple programs in IND enabling studies.

Inner thecal delivery, a benign had 293 suspension manufacturing monogenic CNS disease. So you can kind of see there's a a a a certain platform that we're creating that essentially.

<unk> allows us to kind of quickly pivot from one program to the next as you think about scaling the company was founded.

Early last year, and we quickly progressed to a public company in September of last year. We just recently had our one year anniversary as a public company. We finished the year last year with one clinical stage program will finish this year with five clinical stage programs. You know we plan to have three data.

<unk> that we are on track and reader reiterating our guidance to hit those and we have multiple programs in IND, enabling studies and so what I would say is the team has performed beautifully we finished the year with we finished last year. So 2020.

Mahdi Goudarzi: And so what I would say is the team has performed beautifully. We finished the year with, we finished last year, so 2020, with 38 employees, as a foundational year, kind of a building year for Taysha. So 2021 really kind of laid the foundation. A lot of work happened to get us to the point where as we move into 2022, there'll be this constant drumbeat of data, right?

With 38 employees, we'll finish this year with close to 200 employees and that ability to scale has really allowed us to be able to execute on really some ambitious plans.

As we get into 2022 we've kind of laid out a couple of the the data Readouts that are you know will be supportive.

Supportive of continued value creation ceiling, one enzyme activity data ret syndrome, you know Ah clinical safety and efficacy data at the end of next year, but also just kind of ongoing cadence of updates from our current clinical programs. This year I would think of it.

Ah is a foundational year kind of a building year for tasted. So 2021 really kind of laid the foundation a lot of work happen to get us to the point to where as we move into 2022 there'll be this constant drumbeat of data right. So we'll provide updates on you know ongoing up.

Mahdi Goudarzi: So we'll provide updates on, you know, ongoing updates on our current programs, angina, pulmonary neuropathy, NCLN1, NGM2, gangliosidosis, NCLN7, you know, and plus the newer programs that'll be moving into the clinic next year. So for us, we've shown the ability to scale, we've shown the ability to execute this year, and we'll continue to do that. On the cash front, you know, I think what we've reported provides us with the opportunity to keep our guidance of having cash into the second half of 2023 without the need to raise additional capital.

Rates on our current programs and giant its own on a Robert the NCL and won a N. G M. Two gangliosidosis NCL and seven and plus the newer programs that'll be moving into the clinic next year. So for US we've shown the ability to scale, we've shown the ability to execute this year and will continue.

You too to do that on the cash front you know I think what we've reported provides us to consider.

Keep our guidance of having cash into the second half of 2023 without the need to raise additional capital. This also gets us past some definitive regulatory readouts and our giant zone in a rapidly program plus multiple high quality value.

Mahdi Goudarzi: This also gets us past some definitive regulatory readouts in our gynecomastia neuropathy program, plus multiple high-quality value inflection points from a clinical data perspective. So I think just across, you know, kind of all aspects of the business, I'm extremely proud of the work that the TASIA employees have undertook this year, as well as our collaborators over at UT Southwestern. They're phenomenal partners to work with. But also, you know, our collaborators on gynecomastia neuropathy at the NIH have been just phenomenal partners to work with.

Inflection points from a clinical data perspective, so I think just across you know kind of all aspects of the business and I'm extremely proud of the work that the taste of employees have undertook this year as well as our collaborators over at Ut southwestern they're phenomenal partners to work with but also.

Our collaborators are dinosaur no neuropathy at the NIH has been just phenomenal partners to work with them. So you know what I see moving forward is for us to continue executing like we have but really I think you've got to see 2021 as a foundational building year for the company and you'll start to see kind of this.

Mahdi Goudarzi: And so, you know, what I see moving forward is for us to continue executing like we have. But really, I think you've got to see 2021 as a foundational building year for the company. And you'll start to see kind of this slow growth from here because we've kind of laid the foundation to support what we hope to achieve moving into 2022.

Slow growth from here, because we've kind of laid the foundation to support what we hope to achieve moving into 2022.

Operator: Thank you. There are no further questions. I will now turn the call back over to Mr. Session for his closing remarks.

Thank you there are no further questions I will now turn the call back over to Mr session for his closing remarks.

Mahdi Goudarzi: So we really appreciate everybody joining the call this morning. Again, we look forward to building on the momentum that we've had in the first part of this year and continuing to keep you guys posted on the progress for the portfolio during the remainder of the year and into 2022. Thank you so much, and you guys have a wonderful day.

So we really appreciate everybody joining the call. This morning again, we look forward to building on the momentum that we've had in the first part of this year and will continue to keep you guys posted.

On the progress for the portfolio from the portfolio for the remainder of the year and into 2020 two.

Thank you so much and you guys have a wonderful day.

Operator: Ladies and gentlemen, this concludes today's presentation.

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

Operator: Thank you once again for your participation. You may now disconnect.