Taysha Gene Therapies Inc (TSHA) 2021 Q3 法說會逐字稿

Welcome to the Taysha Gene Therapies Third Quarter 2021 Financial Results and Corporate Update Conference Call. (Operator Instructions) As a reminder, this call is being recorded today, November 10, 2021.

I will now turn the call over to Dr. Kimberly Lee, Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.

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 RA Session II, Taysha's President, CEO and Founder; Dr. Suyash Prasad, Chief Medical Officer and Head of R&D; and Kamran Alam, Chief Financial Officer. After our formal remarks, we will conduct a question-and-answer session and instructions will follow at that time.

Earlier today Taysha issued a press release announcing financial results for the third quarter ended September 30, 2021. A copy of this press release is available on the company's website and through our SEC filings. Please note that on today's call we will be making forward-looking statements, including statements relating to the safety and efficacy and the therapeutic and commercial potential of our investigational product candidates. These statements may include the expected timing and results of clinical trials for our product candidates, our expectations regarding the data necessary to support regulatory approval of TSHA-120 and regulatory status and market opportunity for those programs as well as Taysha's manufacturing plans.

This call may also contain forward-looking statements relating to Taysha's growth and future operating results, discovering development and product candidates, strategic alliances and intellectual property, as well as matters that are not of historical facts or information. Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements.

These risks include uncertainties related to the timing and results of clinical trials and preclinical studies of our product candidates, our dependence upon strategic alliances and other third party relationships, our ability to obtain patent protection for our discoveries, limitation 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 a 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 obligations 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, RA Session II. RA?

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 GDX, the Hereditary Neuropathy Foundation and the Charcot-Marie-Tooth Association on increasing awareness for giant axonal neuropathy and hosting investor webinars featuring disease overviews from key opinion leaders as well as program highlights for CLN1 Rett and Angelman syndrome. 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.

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 Adviser, Dr. Steven 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 1EA15 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. 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. And we are excited to work with UT Southwestern and support Batten Hope to further advance this promising clinical stage program.

With the addition of the CLN7 program, we expect to have 5 clinical stage programs by the end of this year, including giant axonal neuropathy, GM2 gangliosidosis, CLN1 and Rett 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 TSHA-102 for GM2, TSHA-102 for Rett Syndrome and TSHA-105 for SLC13A5-related epilepsy.

Year-to-date we have had 9 regulatory interactions with multiple agencies across our portfolio and plan to submit additional request for end-of-phase meetings for giant axonal 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 TSHA-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.

In GAN, we have up to 6 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 8 years of robust longitudinal data from a natural history study being conducted at the NIH by Dr. Carsten Bonnemann. There has been consistency in the strength of data across multiple functional and biomarker endpoints, including the MFM32 scale, vision assessment and nerve biopsies. We look forward to reporting clinical safety and functional MFM32 data for TSHA-120 from the high dose cohort of 3.5E^14 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 confirmation of disease modification. For TSHA-101, the first bicistronic vector in the clinic in history, which is designed to express the subunits of Hex A enzyme in the endogenous 1:1 ratio. We remain on track to report preliminary clinical safety data and Hex A enzyme activity data in the plasma and CSF in December of this year.

Based on natural history, 2% to 4% Hex A enzyme activity in plasma normalizes survival and significantly improves clinical phenotype of GM2 gangliosidosis. We anticipate preliminary clinical safety data in Hex A enzyme activity in the plasma and CSF for TSHA-101 and GM2 gangliosidosis in December from the ongoing Canadian study. We believe a Hex A 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 intrathecally delivered TSHA-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. For our CLN7 program, we anticipate preliminary clinical data, including safety data, for the first patient in history to be dosed at 1EA15 total vg intrathecally 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 construct.

For CLN1 the program currently has an open IND and an additional CTA filing for TSHA-118 has been submitted. Preclinical data demonstrated that TSHA-118 was safe and well tolerated, following intrathecal administration in the CLN1 knockout mouse model.

In preclinical models, TSHA-118 treated mice demonstrated superphysiological levels of active PPT1 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 PPT1 enzyme activity data in the first half of 2022.

For TSHA-102 in Rett 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 in relevant disease mouse models. We plan to share this data at a later date.

Notably, preliminary data from a GLP toxicology study in nonhuman primates demonstrated no adverse findings at the highest dose tested, suggesting that the miRARE platform is successfully downregulating MECP2 expression to within normal physiological levels.

As I mentioned earlier, we will have 5 clinical programs by the end of this year. Many of those have been a major focus for investors given the near-term milestones. However, we wanted to highlight a few of these programs in our Investor miniseries 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 approaches. Leaders from patient advocacy organizations also discussed 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.

On the manufacturing front we have completed 5 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 3-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 directing structural steel and completing subfloor piping. We remain on track to complete the facility by 2023. Our translational and bio analytics labs will also be physically located near our manufacturing facility in Durham to ensure a 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. And importantly, a potential regulatory approval for TSHA-120 in giant axonal neuropathy. We look forward to our continued execution across our development and regulatory strategies, 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.

Thanks, RA. We continue to advance our clinical and preclinical programs, as well as strengthen our pipeline with complimentary therapeutic approaches to address high unmet needs across monogenic diseases over to 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 TSHA-120, our most advanced clinical program for the treatment of giant axonal neuropathy, or GAN. In December, we expect to report clinical safety and MFM32 functional data from the high dose cohort of 3.5x10A14 total vg. These data are generated by our partners and collaborators at the NINDS under the leadership of the PI to the study Carsten Bonnemann. 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 4 point change in MFM32 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 slowing of disease progression, durability of effect and safety comparable to that which was achieved with the 1.2x10A14 and the 1.8x10A14 total vg doses.

Regarding safety, recall that we have up to 6 years of clinical safety data demonstrating no drug-related serious adverse events, no signs of acute or subacute inflammation, no sudden sensory changes or no persistent elevation of transaminitis.

And also with regards to safety in preclinical studies using the GAN rodent, TSHA-120 improved 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 a peer-reviewed scientific journal in the near future.

In September we submitted a scientific advice from a major ex U.S. 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. As we think about the approval pathway for GAN in the United States, we view with 3 possible scenarios. With a potential to file for approval with the current data on hand as a most likely scenario. Alternatively, the FDA could request that we dose 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 clinical 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 dataset that we have in hand.

In Europe, we believe we would be able to use the current dataset to pass conditional approval. We look forward to providing you updates following our regulator interactions. In the meantime, we have finalized the plan of commercial-grade material and have initiated the 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 GAN. 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 to 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 GAN. We are also excited to collaborate with the Hereditary Neuropathy Foundation and the Charcot-Marie-Tooth Association Centers of Excellence, healthcare professionals and the patient advocacy groups to increase access to genetic testing. Collectively, our goal is to help all patients at risk for GAN have access to genetic testing and raise awareness of opportunities to participate in clinical trials for investigational treatments to facilitate early intervention for patients suffering from GAN.

Moving to our TSHA-101 program for the treatment of GM2 gangliosidosis, we plan to report preliminary clinical safety data and Hex A enzyme activity in plasma and CSF in December. Recall that preclinical data demonstrated intrathecal delivery of TSHA-101 was safe and well-tolerated in GM2 knockouts mice. Based on patient data from the natural history study, demonstrating a correlation between clinical phenotype and Hex A enzyme activity, we anticipate Hex A enzyme activity levels of at least 5% in plasma to be considered disease-modifying.

Screening and enrollment are progression well in our Canadian study. 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 you continue evaluating the fastest path to approval with regulatory agencies. As a reminder, TSHA-101 has been granted both an orphan drug designation from the FDA and more recently from the European Commission for the treatment of GM2 gangliosidosis. TSHA-101 has also received Rare Pediatric Disease designation from the FDA.

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 1x10A15 total vg intrathecally. This is in December. This will be in December. A preclinical toxicology of studies safety and tolerability of intrathecal administration of the first-generation construct was demonstrated across all dose levels and time points. And we anticipate a similar safety profile in the clinic. We anticipate that's our colleagues and partners at UT Southwestern will dose additional patient with the first-generation construct before the end of the year.

We are collaborating with UT Southwestern to finalize development of the next-generation construct which should have improved potency, safety, packaging efficiency and manufacturability over the first-generation construct 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. Lastly, we anticipate having commercial-grade GMP material for the next-generation construct in 2022.

In August we held our first investor miniseries highlighting TSHA-118 for the treatment of CLN1 disease. We were honored to have Dr. Angela Schultz, a global expert and clinical researcher who specializes in lysosomal storage disorders from the University Medical Center Hamburg-Eppendorf to review the current natural history data at the 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. Dr. Steven Gray reviewed encouraging preclinical data for TSHA-118 at clinically relevant doses, demonstrating that TSHA-118 was safe and well-tolerated following intrathecal administration in CLN1 knockout mice.

In preclinical CLN1 models TSHA-118-treated mice demonstrated persistent super-physiological levels of active PPT1, improved survival rates and sustained preservation of motor function with no associated adverse events, suggesting a wide therapeutic window for clinical dosing.

We also reviewed insights from the Scientific Advisory Board and caregiver focus groups who helps inform on 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 the CTA filing and plan to initiate a Phase I/II trial by year. We expect reports of PPT1, the biomarker data, in the first half of 2022, noting that an increase in PPT1 activity from "1% to 5%" would be considered positive based on the 5% to 8% range seen in adult-onset patients.

In September we hosted a Rett Investor Day, highlighting our TSHA-102 program. Dr. Jeffrey Neul, an international expert in genetic neurodevelopmental disorders from Vanderbilt University Medical Center provided an overview of the natural history for Rett syndrome and clinical [consideration to support] clinical trial design, including outcome measures and biomarker selection.

Dr. Steven Gray detailed the requirements for regulated gene expression on the cell-by-cell basis to safely and effectively treat the disease. And that is exactly what our novel miRARE platform does. It regulates the degree of transgene expression based on underlying genotype on a cell-by-cell basis, ensuring expression of MECP2 at the level that improves the symptomatology of rats without causing undue adverse effects. Importantly, in preclinical animal models, intrathecal myc-tagged TSHA-102 was not associated with early death and did not cause adverse behavioral side effects in wild-type mice, demonstrating appropriate downregulation of MECP2 protein expression.

We reviewed our clinical development strategy, the recent positive regulatory feedback supporting our IND-enabling preclinical package and current dose selections. 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 the Rett syndrome and natural history data. Since the Investor Day we have recently obtained preclinical data showing improvement in survival and respiratory and motor functions in 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 miRARE platform is successfully down-regulating MECP2 expression to within normal physiological levels. We plan to submit an IND CTA for TSHA-102 this month followed by initiation of a phase I/II trial by the end of this year. We anticipate preliminary clinical data by the end of 2022.

TSHA-102 has been granted rare pediatric disease designation and orphan drug designation from the FDA. And more recently orphan drug designation from the European Commission. Our most recent Investor Day focused on Angelman syndrome, where we highlighted our 2-pronged approach to treat this significant neurodevelopmental disorder with no approved treatments.

Dr. Ben Philpot of the UNC presented the UBE3A gene replacement strategy. And Dr. Ryan Butler of UT Southwestern presented the vectorized RNA-mediated knockdown approach designed to unsilence the paternal copy of the UBE3A by targeting the unsent transcript responsible for silencing the gene. Recent publication of promising preclinical data in the Journal of Clinical Investigation Insight further detailed how AAV mediated UBE3A gene replacement approach recapitulates endogenous 3:1 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 seizure phenotypes in mouse models with Angelman syndrome.

These proof-of-concept preclinical data supports further study of UBE3A gene replacement therapy as a potentially safe and effective treatment for Angelman syndrome. Both strategies are highly encouraging, and importantly allows 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 all financial results. Kamran?

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 shortly. As indicated in our press release today, R&D worth $39.5 million for the 3 months ended September 30, 2021, compared to $11.1 million for the 3 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 cGMP manufacturing batches produced by Catalent 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 includes clinical trial CRO activities, GLP toxicology studies, and consulting for regulatory and clinical studies. This was partially offset by a decrease in licensing fees of $1.7 million.

G&A expenses were $11.2 million for the 3 months ended September 30, 2021, compared to $4 million for the 3 months 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 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 3 months ended September 30, 2021 was $51.2 million or $1.35 per share, as compared to a net loss of $15.0 million, or $1.28 per share, for the 3 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.

I wonder if RA has dropped off for some reason. This is…

My -- hey, Suyash.

My apologies…

My apology. Thank you. I was talking on mute. 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 I/II TSHA-120 study in giant axonal neuropathy. And preliminary Phase I/II clinical safety data and Hex A enzyme activity in the plasma and CSF for TSHA-101 in GM2 gangliosidosis. 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 I/II trial in CLN1 disease and Rett syndrome.

I would like to give special things to the continuous support and dedication of our Taysha employees, Board of Directors, Scientific Advisory Board, collaborators, and the patients and advocates who remain our motivation every day to continue our mission to develop curative gene therapies and eradicate devastating monogenic CNS disease.

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

(Operator Instructions) Our first question has come from the line of Joon Lee with Truist Securities.

Congrats 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 historic proxy where something like this have happened? And I have a follow-up.

Joon, 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 a sense that the clinical trial was taking 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.

And again, based on the FDA's own guidance where there's a robust natural history, 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 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 to do a full clinical trial in the U.S. and may just need to import 1 or 2 patients from the us to be dosed. So I'll stop there, turn it over to Suyash to provide his thoughts.

Yes. And yes, we're talking through regulatory strategy on an ongoing basis. In the past 4 months, 4 to 6 months, we've had 9 regulatory meetings across our portfolio of programs. And these are multiple meetings with the U.S. and several of the ex U.S. agency.

So we're really gouging a lot of real-time information on the right approach for pathway to approval. As RA has already said, we've been very pleased actually of how we've been able to identify patients for the Canadian GM2 study. There's been some delays related to COVID, but essentially we've screened large numbers of patients that tell us there actually is a large number of GM2 patients out there, because things are going so well in Canada we are talking about the fact, yes, perhaps we could just file ex U.S. initially, have the R&D open and then file principally with data from other countries as opposed to from the U.S. And as RS says, it is a global study.

So the likely it is if there are U.S. patients, we could actually send them to Canada for dosing. So there's multiple options here. In terms of specific examples, I mean, I've worked on a couple previously in particular BioMarin where our focus was much more on Europe initially followed by the U.S. later. I think 1 springs to mind, I think that the CLN Brineura program was one where the study started in the ex U.S. and then the filing happened in Europe prior to the U.S. From my recollection that's true.

But there are several examples where this has happened. So yes, we continued to evaluate options. The (inaudible) will open an IND in the U.S. for GM2 at some point, but things are going so well in Canada, we've decided to focus our time and energy and attention on continuing enrollment and gathering clinical data in Canada.

Great. I'm looking forward to the data in December. And a second question and a last question. For TSHA-120 in GAN which you have very strong data, 6, 8 years' worth of data. Are the materials used in the investigational study undergo the same GMP and QA process as materials you are producing in your GMP facilities. And if they are different, what would you need to do to satisfy the FDA requirement that they are equivalent and be able to commercialize or submit for approval with existing data?

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 sure that we can secure a like-for-like manufacturing platform to support comparability from the clinical stage material and the commercial-grade materials. So in order to do that, what we've 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 is 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. It's the same purification filtration, literally a same process updated 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 data set and our comparability panel should support a like-for-like product, ultimately supporting a sameness argument. I'll stop there. Suyash, do you have anything to add?

I think the only thing I'll add rarely, we spent a lot of time and energy very early on ensuring that we are able to characterize product in terms of contaminants, in terms of, well, anticapsid ratios. And we bring that learnings, we bring those learnings through to our GAN program as well. And there is a real meaningful example where actually 2 weeks ago that the team were over at the CDMO partner who's manufacturing the drug for -- the manufacturer of the drug clinically and will also manufacture drug through into the commercialized process. So Fred Porter, our Chief Technology Officer; Mishima Gerhart, our Head of Regulatory, and that team -- a team of about 10 people spent a full week at a 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. So yes, great question Joon, but we're very comfortable with the approach here.

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.

Our next question has come from the line of Gil Blum with Needham & Company.

Just a bit of a follow up on the previous discussion. So it actually makes the conceptual sense that no, considering you guys are using a production method commercially used to make your AAV9s, that it would be a translatable across your platform. But there are variants. You're using different genes in each program. Do you guys expect the FDA will be looking for a bridging study of any kind? I mean, this is across programs now, right? So you could have it for GAN, you could have it for CLN7, you could have it for GM2. It seems that, yes, you make really long headways with the initial studies and are looking to kind of transfer quickly into commercial products.

Maybe I'll start and then I'll allow Suyash to chime in on some of our recent discussions with regulators about kind of this platform approach. What I would say is GAN is somewhat of an outlier. And what I mean by that is this was a program that essentially when we brought it in-house had 5 to 6 years of 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 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 off by its 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. In some cases there's 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 bio-reactors. So there is this notion around platform value.

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 9 regulatory actions -- 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 confident around this platform. So Suyash maybe you want to chime in and provide some context.

Yes. And I think RA is quiet right, the GAN is a little bit of an outlier because GAN wasn't in our hands in the earlier parts 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.

To add some color to the regulatory discussions, we have just 3 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 in these regulatory interactions. And the 3 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. So we have a very specific approach to all those 3 topics. Fred talks about them very nicely in the meetings. And we actually had a regulation 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, just this all sounds fine, just write it up when you filed the CTA. And what you propose is absolutely appropriate. And once again, 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 for the vast majority of our programs, once again it comes a bit as an outlier, but the vast major 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. That's our aspiration to make sure we have a commercial-grade product at that early time point (inaudible) makes the whole regulatory process going much smoother from a CMC perspective.

Maybe a quick scientific question for the GM2 program is there any differences between Hex A measured in CSF and serum? Are you seeing a high level in 1 different than the other or better than the other?

So Gil, it's a great question, and maybe I'll start and then I'll turn it over to Suyash. I think based off of the natural history, the natural history for GM2 gangliosidosis is actually pretty well characterized. The disease has been known for over 100 years. And when you look at the Hex A enzyme activity level in the infantile form of the 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 3. When just taking a patient from 0.1%, and this is enzyme activity in the plasma, they may be specific. And just taking a patient from 0.1% to 0.5% or 0.5%, you actually extend survival out to the mid-teens. That goes from an infantile onset patient to a juvenile onset patient that typically succumb to disease in their mid-teens.

Just getting a patient to 2% to 4%, you now go from an infantile-onset patient to an adult-onset patient and it normalizes lifespan, just that 2% to 4%. And this again is in the plasma. And so the plasma measures of Hex A are probably the most well-known correlates 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 Hex A activity in plasma versus CSF. I'll let Suyash go into that a little bit more in depth.

Yes. 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 Hex A perspective. RA is quite right. There was a lot known about TSHA (inaudible) GM2 gangliosidosis that's been done historically. Disease was described in the late 1800s by [William Tay] a British ophthalmologist, the enzyme was identified in 1969, and there's been many, many screening programs.

So we have a really good understanding of Hex A in the plasma. Having said that, we wanted to not only look at plasma levels we also want to look at CSF levels because to us, intuitively, if we're trying to transduce brain cells, we should also see an elevation of Hex A in the CSF. And we believe that that will actually reflect what's happening in the brain a little more than the plasma activity. 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 RA is quite correct also that once we hit 5% levels of enzyme in the serum, in terms of clinical phenotype, those are adult patients with GM2 gangliosidosis, they have some cognitive deficits and movement disorder, but they have a generally normal lifespan. So if we change the Hex A 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 actually it may be less, it may be a little bit less because my guess at the CSF levels of Hex A may actually be a little lower than the plasma levels of Hex A. But as I say, we'll be presenting both plasma Hex A levels and CSF levels of Hex A. We've got the assets working very nicely. We're going to be presenting that data towards the end of the year.

Congrats on all the progress.

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

I just have 2 small ones. So 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. Apologies if I missed that. 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 U.S. regions perceive 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 120, RA. I think you mentioned second half would be 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. Maybe I'll tackle your first question, and then I'll turn it over to Suyash to talk about our regulatory strategy. So around manufacturability and manufacturing of the commercial-grade material for giant axonal 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 actually 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 having 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 -- our first commercial campaign.

So we actually don't foresee any headwinds on that. So we would reiterate that guidance of having commercial-grade material available in the second half of 2022. 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 6 years of longitudinal individual patient data. We have dose response. We have collective 55 years of patient safety and efficacy, multiple endpoints. We have not only functional endpoints, MFM32, 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. So the way that we're looking at this is essentially it's 3 scenarios in the U.S.

We think 2 of those are high probability. The first, it's going to be our going-in strategy, essentially pointing to the FDA's own 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 material and 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 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. We reported on approximately 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. Carsten Bonnemann. And so for us to be able to roll over patients from that study to treat 2 to 3 more patients if we needed 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 or needing to do some clinical comparability, that would be just about a 6-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 conditional approval, TSHA-120 checks all the boxes.

And that's going to be our going-in discussion early in the new year when we meet with ex U.S. regulators really around what is the conditional approval, innovative medicines pathway that are available to us and currently that the data will support. I'll pause there. Maybe Suyash you want to just comment on our regulatory strategy and just the timing to get those responses back.

Yes, I will do. And just to give a bit of color, Laura, to the -- just some of the operational aspects of what we're trying to do on the GAN program. We've got a great data package for GAN. As we've already mentioned this (inaudible) study, dose response data, clear stabilization of disease at medium-low, medium-high doses and the high dose yet to come, long-term safety, durability 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 regulator is just very, very busy. In fact, we're 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 going to have to push you out to January." So this is on a different program.

But it just -- that very rarely happens. 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 a request for meetings, but not actually getting the meeting for 3, 4, 5 months down the pike. So 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're anticipating 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 folks in 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 1 or 2 of the agencies of CMC discussions and the clinical discussions.

And the final point I'll make, and RA and I we're talking about this at some length over the past few days. For GAN, we've got this great efficacy data, and we talk about the efficacy data at length. We show clear disease stabilization and 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 BLA filing. And I just want to emphasize the fact that we have got years and years' worth of safety data in this program.

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 6 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. But we have patients who are dosed in 2015. So there are patients with up to 6 or 7 years' worth of clinical safety data. And we show is minimal, minimal issues around inflammation. There's no liver issues. There's no evidence of thrombotic microangiopathy. There's no evidence of any neuronal loss or inflammatory change in the brain at all, 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 AAV gene therapy have been 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 step for these regulatory discussions. And we look forward to telling you about how those go early in the new year.

(Operator Instructions) Our next question is coming from the line of Salveen Richter with Goldman Sachs.

This is Elizabeth on for Salveen. So just 2 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 on the specific molecular level or structural differences between the 2? And then quickly on the second question, just touching on Taysha's approach to data disclosure, given you have several data readouts towards December and then into next year and then what venue or potential disclosure format those could take.

So I'll take your first question, and I'll allow Suyash to provide some insight to the second question. On the first question around the key differences between the first-generation construct and the second-generation construct or 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. 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 ITRs that will actually make the gene therapy vector more safe, make it more potent, improve on the 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 previously made from constructs that were coming out of our collaborators at UT Southwestern, we're going to be applying that -- those same changes to this program. We feel pretty strongly that we would be able to still 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 dosed 2 patients.

One patient has been dosed at 5 each of the 14 total vg intrathecally. Second patient has been dosed at 1E^15 intrathecally total vg. 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 is -- our approach is confirming our guidance today around the availability of data for our high dose cohort, which is 3.5EA14 total vg for giant axonal neuropathy by the end of this year, Hex A enzyme 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 end of this year.

As we move into 2022, you're absolutely right. The portfolio is kind of playing out exactly -- we're fortunate the portfolio is playing out how 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 what 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 will 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.

And then there'll also be a constant update around regulatory feedback as that comes in with -- that we hope will ultimately support a rapid path to approval for giant axonal neuropathy. And as that come 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 to the foreseeable future.

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 -- 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.

And so again, that is just going to be high quality data. We were excited about some of the preliminary GLP tox data that we've gotten in our NHP studies as well as some new pharmacology data. And so we'll 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 be presenting data at some of the larger conferences.

But as soon as those are -- those presentations are 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 giant axonal neuropathy where our collaborators are putting the final touches on their definitive research paper. And hopefully that will be accepted here and published relatively soon.

Our next question comes from the line of Mike Ulz with Morgan Stanley.

Maybe a question on 120 and GAN 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. 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?

And great question. I'll turn it over to Suyash. Suyash, do you want to take that question?

Sure. Yes. So as we've already -- as you're already aware, we've got nice dose response across the 3 dose groups that we've shared previously. So the 3.5EA13 total vg with a low dose, which was the [model] safety dose; the 1.2EA14, the medium-low dose; and the 1.8EA14, the medium-high dose really showed disease stabilization.

So 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. As we know, a 4-point change in MFM32 is deemed to be a clinically meaningful change. So the fact that we improved disease by 8 points per year, which translates to 16 points over 2 years, 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 going to be probably the most meaningful thing we can do for these patients and families. And as you already heard on the call this morning, and we issued press these 3 or 4 weeks ago on our partnership with GeneDx where we now have the mutation for GAN, the GAN mutation now on many of these (inaudible) screening panels and the costs are covered.

So actually presented at the Charcot-Marie-Tooth Association meeting last weekend and talked about this screening approach. And there's a lot of excitement, a lot of interest from patients who have different forms of axonal neuropathy who have been diagnosed with Charcot-Marie-Tooth type 2 wanting to get screened in case they have the GAN mutation and would therefore be eligible for gene therapy construct.

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, going from the medium-low or up to the high dose, there's an argument that we should go in with the high dose as the dose we should file for an approval. There's an argument that may we go for the medium-high dose, the 1.8EA14 total vg.

Some of it will depend on safety profile. And what I will say is 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 (inaudible). But I don't anticipate that's going to be the case actually. It's 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.

So the actual dose we file for an approval with I think 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.

Our next question comes from the line of Kevin DeGeeter with Oppenheimer.

Just maybe 2 quick ones on GM2. Appreciate the updated perspective on how you're thinking about 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 duration of follow-up from a clinical perspective, but I guess, for this discussion from a regulatory perspective, what duration of follow-up on Hex enzyme expression do you think you'll need to be able to gather to have robust discussions with regulators?

Maybe I'll take your first question, and Suyash, if you don't mind, you can take Kevin's second question. On the first question, 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 Suyash and his team as well as our patient advocacy group as well as our med affairs group collectively have done a fantastic job with identifying patients globally. And this is a true global study.

And so we're quite excited about that. And this is ultimately what 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 will be on multiple patients.

We'll say that. And what I'll also say is Suyash and his team from a screening perspective have now identified and have assessed over double digits worth of patients. I'll say that. Again, this really gives us a lot of confidence that there's 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 KOLs, having the discussions, 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 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 Hex A enzyme activity and duration of effect.

Yes. This is a really good question, Kevin. And I think the way to think about it is take a step back and just anticipate the cadence of what might happen. So we're going to give the drug intrathecally. It travels to the brain. The capsid enter the brain cell, the neuron, the DNA pops out, starts producing the [bystronic] Hex alpha subunit, beta subunit, they combine and start breaking down GM2 ganglioside.

Now you're going to get maximal transgene expression probably 3 to 4 weeks after dosing, and then you should get maximum production of enzyme Hex A shortly thereafter. So our guess is that at the 1-month time point we take a CSF 1 month, we take 1 at 3 months, we take on at 6 months, and then we take 1 at 12 months for the first year.

My guess is that the Hex A in the CSF will go up at the 1-month time point, but probably will not reach maximum levels. By the 3-month time point, my expectation is it will reach maximum levels. In parallel with that -- with regard to the earlier discussion we had, you will also see an elevation of Hex A levels in plasma, which is where we have more experience, but it's probably less relevant for a treatment that transduces brain cells.

My guess is that you're going to see persistently elevated levels at the 6-month time point in the CSF and persistently elevated levels at the 12-month time point in the CSF. And I don't think you're going to see any diminution in activity over time. And the reason for this is that is that once you've transduced a brain style, it should keep -- 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 should -- 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 CSF will stay high persistently. 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 fortunately 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 entire persistently. Now how much enzyme and what persistence, what durability is required by the regulators. My guess is that if they see a nice increase, I think they're probably going to want to see -- we'll probably go in. If we're seeing good clinical benefit at the 6-month time point and persistent levels of enzyme at a 6-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 -- we'll probably make a case at 6 months if we're seeing good clinical effect on persisting enzyme levels. But in reality, the regulators will push back in once a year. But that's my guess on how things will play back over the longer term.

Our next question come from the line of on Yun Zhong with BTIG.

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 pivotal study with the second-generation construct? And given that there seems to be quite a lot of components that you're going to change from generation 1 to generation 2, 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 pivotal study?

Maybe I'll start, and Suyash please chime in if you'd like to. So what I would say, 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, proof-of-concept data that's been generated as a basis to support clinical development.

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 there's this notion of massive movements from one construct to the next is not necessarily there, right? What we do know is -- and there's 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 a 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 uniQure's gene therapy programs. I believe it was in hemophilia. So this is a -- there has been precedent on this.

And to your second question, we haven't yet approached the FDA with discussions around this program. Essentially, we've had 9 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. Suyash, maybe you want to comment?

Sure. And I think -- I think that 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 to the details of the changes that we are proposing. But suffice it to say, it's optimizing 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.

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 a very simple study, perhaps a combined mouse model, short duration pharmacology, toxicology study. But it's -- once again, we're planning to make minimal, minimal changes in line with our ability to reference the earlier first generation construct.

Our next questions come from the line of Eun Yang with Jefferies.

This is Nancy on for Eun. I was just curious, how is the progress on ratio of anticapsids during the AAV9 production and what the current ratio of anti to packaged capsid is. And mostly on what the range of this is between your different indications?

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 capsids. And that's consistently our strategy across our portfolio. And sometimes we do better than that. And what I can say for our GM2 program, we've actually gone above that to full ratio, that full ratio of 90%. So that's kind of what our current standard is. Obviously every program is different. And so some are better producers than others. But what I will say is we try to maintain some level of consistency in our manufacturing platform, ultimately, to support this whole notion of 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 -- which is something that we've seen within the field. Suyash, do you want to comment?

I will comment. Yes, this is a really excellent question. And I think RA is weaving in some of what the importance here is, and it's really the so-what factor. What does the presence of anticapsid 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 much anticapsid as possible. A lot of manufacturers find this hard to do without sacrificing yields tremendously.

And so there's sometimes a reluctance to try and remove the anticapsid. But from my perspective, looking at the patient, anticapsid 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. And RA and I have been talking about this at length. And RA 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 a physician overseeing the safety of these patients. And we -- I really appreciate the fact that RA and I are in full alignment, that we will sacrifice yield in order to make sure we get pristine, pure, highly purified product, as little anticapsid as possible.

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% anti, greater than 90% for our products.

Our next question comes from the line of Kristen Kluska with Cantor Fitzgerald.

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 these different indications have different prevalences?

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

Yes. Great question. It's a little different from program to program. There are few common themes, I would say. First of all, we talk a lot about our platform approach, AAV9 IT delivery, HEK293, but the platform approach actually works in many other ways, one of which is, frankly, that the vast majority of clinicians we deal with are pediatric, metabolic or neurology experts, GM2, CLN1, CLN7, Rett, is generally looked after similar physicians.

And so 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 the diseases where there are more the ultrarare population. So we're thinking the diseases that have 1,000 patients prevalent, for example, we plan to have 1 or 2 sites in the U.S. and 1 or 2 sites ex U.S. and then transport patients from around the world to those sites.

So we're focusing heavily on that, the ability to transport patients from other countries to the U.S. or to Canada or to Europe. And that's worked very well for our GM2 program. We only have 1 site for our GM2 program currently in Canada -- a 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 Rett where you're thinking 25,000 patients in the U.S. and Europe, recruitment and enrollment is a little different. It's a little easier because patients -- there's more patients.

And they're generally sent to congregated centers of excellence where clinicians will have 30, 40, 50 patients with Rett syndrome on that book. We have one key opinion leader, one investigator (inaudible) 200 patients with Rett syndrome. And so if we use that individual as a clinical trial site, we could actually enroll the whole study potentially on that site.

But we're going to have -- we're not going to do a single site for Rett of course, but it will probably be 3 or 4 sites. But I don't anticipate there being problems with enrolling some of the larger patient populations. And in principle there's 3 real approaches to finding patients for these studies. And they're really led by 2 colleagues at Taysha. So Emily McGinnis who handled patient advocacy and (inaudible) who heads up medical affairs.

And we engaged 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 of 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. We have them attend 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 liaison activity with our teams knocking on the doors of clinicians to find patient (inaudible) support. Those are really the 3 philosophical approaches we used to find patients. As I say, our track record thus far for GMT, we've found many, many patients that we've screened. Many have not been eligible. And we'll spend -- 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.

Our next question comes from the line of Raju Prasad with William Blair.

Just curious to know on the GeneDx deal, just how many patients do you anticipate finding with kind of a genetic marker? And do you have any kind of initial thoughts there? And then second, on the GM2 program, it seems like 5% is the benchmark here for biomarker, but is there any initial clinical measures that we could see moving to kind of show that there's a clinical benefit that's being changed by this increase in enzyme activity?

Maybe I'll take both questions and then for the second question, Suyash, happy to provide some color as well. So for the first question around our collaboration with GeneDx. Not only was it a collaboration to include giant axonal neuropathy now on their standard neuropathy panel, but it's also a collaboration that includes both the Charcot-Marie-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. and in Europe. And particularly for the Charcot-Marie-Tooth Association, a number of the patients that are clinically diagnosed with Charcot-Marie-Tooth have not undergone genetic screening.

And based on this, again, robust natural history data that our partners at the NIH and Carsten Bonnemann have been leading over the last 8 years, it was identified that this late onset phenotype of giant axonal neuropathy was essentially commonly misdiagnosed as Charcot-Marie-Tooth and more particularly Charcot-Marie-Tooth type 2.

We also understand that this later onset form of the disease is extremely severe and kind of debilitating, but it's not life-limiting in the sense that the early onset form of the disease is where patients are essentially diagnosed at age 3 and either in their early teens or -- I'm sorry, in their late teens or early 20s they succumb to the disease. Typically, in the later onset form of the disease, these patients are diagnosed sometime after their fifth birthday. Have issues around walking, have issues around muscle strength.

And essentially, it's kind of one of these quality of life -- kind of the significant impediment to quality of life, but they tend to live a normal life span or at the very least into their fifth decade of life. So what we understand is that there is -- just based off of the epidemiology, there is a large pool of prevalent patients in that later onset population that hasn't necessarily undergone a genetic test because essentially when a person is diagnosed with Charcot-Marie-Tooth and particularly the type 2 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 having talked to both the CMTA foundation as well as the hereditary neuropathy foundation, they both agree that a large section of these patients are typically misdiagnosed 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 giant axonal neuropathy mutation.

So we think there's a large number of patients, both in the U.S. 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. 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 put that number above 1,000 patients out there that are out there that we hope to, are able to identify a large number of those. Raj, do you mind just reminding me of your second question?

Yes. Obviously it seems as though natural history would say 5% is kind of the biomarker threshold for GM2. Just curious to know the time line for when that may translate over into maybe early clinical measure benefit?

No, absolutely. Great question. Suyash, do you mind taking that?

Sure. Yes. Actually I'll just make one comment on the GAN Charcot-Marie-Tooth discussion because I actually spoke to the Charcot-Marie-Tooth Association meeting last weekend and sat on a panel and got to meet many patients and families. And it was clear, to RA's point, that the many individuals with Charcot-Marie-Tooth only have a clinical diagnosis.

There is many adults there who were diagnosed with the disease and haven't actually had the mutation analysis or genetic testing. So there's a large pool of patients, I think, who will really take advantage of this GeneDx partnership that we've created. And our expectation is that a significant number of patients that we have -- just based on the subjective discussions I had last weekend, I think that seemed very real and meaningful.

With regard to GM2, it's a good question. I talked through the cadence of how I expect enzyme levels to modify and improve over time. I think with the clinical improvements, I think 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 disruptive disease. And what happens pathophysiologically is that you get the accumulation of GM2 ganglioside and the lysosome to the cells.

The lysosomes swell, they rupture, they leak out their acidic enzymatic content and actually cause damage to neurons, initially an inflammatory process but then it results in fibrosis and definitely neuron. And once you've lost a neuron, you don't get it back.

So I think if a patient is significantly affected and have lost a lot of neurons, you're going to be able to produce the enzyme Hex A, stop additional damage, and you may get some resolution of some of the inflammation that's going on in the neurons, but if you're lost neurons, you're not going to see improvement there.

If we treat earlier in life, and this is why it will be important at some point in the future to have newborn screening for this disease and then treatment before the child has had a chance to 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. 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 look at hypertonia, hypotonia, dysphagia, lack of head control, the Vineland Adaptive Behaviors, the Bayley-III scale, looking at general development.

We're looking at seizures, we're looking at EEGs. We're performing a communication assessment scale, the ORCA, the Observer-Reported Communication Ability scale. We're looking at quality of life scales and Clinical Global Impression scales. My guess is that by the 3-month or perhaps by the 6-month time, 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 scale will likely be -- we hope would show some improvements. And then potentially some improvement in hypotonia, see some improvements there, see some loss, some reacquisition of milestones, which will be measured by the Bayley-III. 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 3 months after dosing, probably 6 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.

Our next questions come from the line of Silvan Tuerkcan with JMP Securities.

Maybe you can just give us a big picture view about your ability to manage all of these programs as the pipeline expand so rapidly, especially next year with 5, 6 trials and regulatory discussions and potential filing at the end of year. What about your cash and manpower to maintain all of that? And do you expect there will be maybe some attrition or deprioritization or potentially some partnerships? Your thoughts there would be great.

So what I would probably say, 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 not only early discovery, but also commercialization. This is exactly what we were hoping to build out as we kind of put the blueprint of the company together.

And the company -- and quite frankly, the company is executing. So I think the ability has just been shown, the proof is in the pudding, in a sense, 5 concurrent GMP runs completed this year, nonregulatory interactions this year, good activity on the BD front, albeit a lot of those programs are coming from our Chief Scientific Adviser, Dr. Steven Gray, but they all kind of support the central thesis around intrathecal delivery, AAV9, HEK293 suspension manufacturing, the monogenic CNS disease.

So you can kind of see there's a certain platform that we're creating that essentially 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 1-year anniversary as a public company. We finished the year last year with 1 clinical-stage program.

We'll finish this year with 5 clinical-stage programs. We plan to have 3 data readouts that we're on track in 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, with 38 employees. We'll finish this year with close to 200 employees. And that ability to scale has really allowed us able to execute on really some ambitious plan.

As we get into 2022, we've kind of laid out a couple of the data readouts that will be supportive of continued value creation, CLN1 enzyme activity data, Rett syndrome, clinical safety and efficacy data at the end of next year, but also this kind of ongoing cadence of updates from our current clinical programs. This year I would think of it 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 to where, as we move into 2022 there'll be this constant drumbeat of data, right? So we'll provide updates on, ongoing updates on our current programs in giant axonal neuropathy, in CLN1, in GM2 gangliosidosis, in CLN7 and plus the newer programs that will 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, I think what we've reported provides us to 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 in our giant axonal neuropathy program, plus multiple high-quality value inflection points from a clinical data perspective.

So I think just across kind of all aspects of the business, I'm extremely proud of the work that the Taysha 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 on giant axonal neuropathy at the NIG have been just phenomenal partners to work with. And so 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.

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

So we really appreciate everybody joining in 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 2022. Thank you so much, and you guys have a wonderful day.

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