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Taysha Gene Therapies, Inc. (TSHA 2.05%)
Q1 2021 Earnings Call
May 11, 2021, 8:00 a.m. ET


  • Prepared Remarks
  • Questions and Answers
  • Call Participants

Prepared Remarks:


Welcome to the Taysha Gene Therapies first-quarter 2021 financial results and corporate update conference call. [Operator instructions] As a reminder, this call is being recorded today, May 11, 2021. I will now turn the call over to Dr. Kimberly Lee, senior vice president of corporate communications and investor relations.

Please go ahead.

Kimberly Lee -- Senior Vice President of Corporate Communications and Investor Relations

Good morning and welcome to Taysha's first-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 first quarter ended March 31, 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 sub candidates. These statements may include the expected timing and results of clinical trials for our drug candidates and the regulatory status and market opportunity for those programs as well as Taysha's manufacturing plants.

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This call may also contain forward-looking statements relating to Taysha's growth and future operating results, discovery and development of drug candidates, strategic alliances and intellectual property as well as matters that are not 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 drug 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. For a list and description of the risks and uncertainties that we face, please see the reports we 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, May 11, 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 laws. With that, I'd now like to turn the call over to our president, CEO and founder, RA Session II.

RA Session II -- President, Chief Executive Officer, and Founder

Thank you, Kim. Good morning, and welcome everyone to our first-quarter corporate update and financial results conference call. As always, we hope you and your families continue to remain safe and healthy. Taysha has made great progress in the first quarter and continues to execute on its corporate initiatives.

I will elaborate on some of the key achievements made thus far this year and highlight the expected milestones for the remainder of 2021. Following this, I will turn the call over to Suyash and Kamran for updates on our pipeline development and financial results, respectively. Taysha has transformed into a pivotal stage gene therapy company with the recent acquisition of exclusive worldwide rights to a groundbreaking clinical program, TSHA-120, and AAV9 intrathecally dosed gene therapy invented by our chief scientific advisor, Dr. Steven Gray of UT Southwestern.

The NIH is conducting an ongoing clinical trial of TSHA-120 for the treatment of giant axonal neuropathy or GAN. Notably, the GAN program is the first intrathecally dosed AAV gene therapy study in history and as such, has had significant impact on the field. As the program has laid the foundation for our extensive pipeline, we believe this acquisition represents a clear strategic and value-accretive opportunity that will provide read through across our entire portfolio and inform the development of our gene therapy product candidates. We are thrilled to carry on the work done by Dr.

Gray's lab and the NIH. As Suyash will discuss in more detail, TSHA-120 has a comprehensive preclinical and clinical package that we believe may support an expedited approval pathway. The clinical data for TSHA-120 in patients with GAN are statistically significant, clinically relevant, dose-dependent and durable with a clear hop in disease progression at therapeutic doses. We are very encouraged that this represents significant value as the first potentially disease-modifying treatment for an estimated 2,400 patients living with GAN in the U.S.

and in Europe alone. As such, we intend to engage with major regulatory agencies as soon as possible and in parallel, we'll be accelerating the build-out of our commercial infrastructure to support patient identification, payer engagement and product distribution. We believe that TSHA-120, if approved, represents a near-term commercial opportunity for Taysha of more than $2 billion. Beyond further advancing our new clinical stage programs, we continue to achieve significant progress with our preclinical programs that we expect will provide the next wave of novel gene therapies.

We are extremely excited to announce the recent publication of new preclinical data for TSHA-102 in Rett syndrome in a highly regarded scientific journal Brain. For the first time, we have quantitative evidence of miRARE's ability to demonstrate genotype dependent regulation of MECP2 gene expression across different brain regions in both wild-type and knockout mouse models of Rett syndrome. Various challenges such as phenotypic variability, mosaicism, and targeting a dose-sensitive gene like MECP2 make development of a gene therapy difficult. miRARE offers a solution by allowing for the regulation of MECP2 gene expression on a cell by cell basis without causing overexpression-related toxicity.

Importantly, treatment with TSHA-102 in four, five old knockout mice with Rett syndrome resulted in a statistically significant survival extension by 56%, which is a very impressive result as these mice had meaningful accumulated disease. In our view, the benefits in these adolescent knockout mice should be a more translatable model of the disorder in humans. We believe these data validate our novel approach to treating Ret, help derisk the clinical program and support the advancement of TSHA-102 into Phase 1/2 clinical trial by end of the year. We remain on track to file an IND or CTA in the second half of this year.

You will hear from Suyash shortly as he will review the robust data in greater detail. Our chief scientific advisor, Dr. Steven Gray initiated his work on miRARE and TSHA-102 in 2007. We are very pleased that his team's efforts are being realized and recognized.

Amongst other compelling preclinical data packages, we are particularly excited about TSHA-113, which has demonstrated successful AAV mediated gene knockdown, resulting in reduced tau expression in mouse models of human tauopathy. These data may have significant implication for certain neurodegenerative diseases, including Alzheimer's disease. We are also pleased with preclinical results for TSHA-105 and SLC13A5 deficiency that demonstrate a reduction in plasma citrate levels, normalized EEG activity and reduced number of seizures and seizure susceptibility in SLC13A5 knockout mice. In SLC6A1 haploinsufficiency, TSHA-103 improved nesting and EEG activity in the SLC6A1 knockout mouse model and reduced spike train activity in both the SLC6A1 knockout and heterozygous mouse models.

In Lafora disease, TSHA-111-LAFORIN and TSHA-111-MALIN have achieved effective knockdown of GYS1 expression in insoluble glycogen and decreased Lafora body formation in the appropriate Lafora disease mouse model. In APBD TSHA-112 has generated significant reduction in GYS1 protein, abnormal glycogen accumulation and polyglucosan body formation in the APBD knockout mouse model. In Angelman disease, TSHA-106 increased UBE3A expression through shRNA-mediated knockdown of UBE3A-ATS, an in vitro cell line. We believe that this promising results demonstrated by our preclinical candidate validate our scientific approach and underscore our ability to drive a sustainable development engine for innovative gene therapy with the potential to impact meaningful patient population.

We are working diligently to advance our other preclinical programs in IND/CTA enabling study and to date have already advanced six programs into IND/CTA enabling studies with an IND or CTA planned for at least one of these programs by the end of 2021. We look forward to providing further updates on our key programs at our R&D event which will take place over two days on June 28 and 29. To support our programs, we have developed several key partnerships. Notably, we have established collaborations with Yale University, Cleveland Clinic and the UT Southwestern gene therapy program to support the creation of a novel next-generation mini-gene platform that is designed to overcome key challenges in gene therapy.

These mini-gene payloads for AAV gene therapies will be targeted for the treatment of genetic epilepsies, neurodevelopmental disorders and other CNS diseases. We are excited to leverage each partner's unique capabilities to expand the boundaries of AAV vector engineering and potentially open the door to treating genetic CNS diseases that have been traditionally precluded from treatment with gene therapies. Foundational to our success is our team, which remains focused on advancing the development of our portfolio of innovative gene therapy candidates. We intend to continue this momentum by further growing our experienced team.

Since becoming a public company, we have expanded our team more than 10-fold and have now surpassed 120 employees. We expect to grow the team to approximately 150 employees by year-end. As noted, we are complementing the efforts of our internal team with our collaborators at UT Southwestern. With the collective expertise and dedication of these teams, our seasoned board of directors and independent internationally renowned scientific advisory board, we believe we are uniquely positioned to expedite the development of our gene therapy candidate and our technology platform.

I will now turn the call over to Suyash to provide a more detailed update on our R&D initiatives. Suyash, please go ahead.

Suyash Prasad -- Chief Medical Officer and Head of R&D

Thanks, RA. As RA mentioned, Taysha has a robust portfolio of 26 gene therapy product candidates for monogenic diseases of the CNS. Our candidates target broad therapeutic categories of immense unmet medical need, including neurodegenerative diseases, neurodevelopmental disorders and genetic epilepsies. We have recently added TSHA-120 for the treatment of giant axonal neuropathy or GAN to our pipeline, making it our most advanced program.

We believe the preclinical and clinical data generated to date hold significant promise for GAN patients. Preclinical studies have demonstrated strong proof-of-concept data for both the construct and the delivery modality. TSHA-120 performed well in preclinical studies demonstrating improved motor function and nerve pathology and long-term safety across several animal models. Preclinical data also demonstrated that TSHA-120 showed a significant improvement in the pathological appearance of the dorsal root ganglion, a key component of disease progression.

DRG inflammation is a topic that has been the focus of much discussion within gene therapy circles in recent months. This is because it has been observed as a histopathological finding in some nonhuman primate gene therapy studies although the NHPs exhibited no functional compromise. Interestingly, in Down and in the majority of diseases in our neurodegenerative franchise, the DRG have a significantly abnormal histological appearance and function as a consequence of underlying disease pathophysiology. Thus, it was not surprising that when treated with TSHA-120, we saw considerable improvements in the pathological appearance of the DRG in the GAN knockout mice.

We are fortunate that in addition to robust preclinical results, those consequence natural history that provides us with patient data to identify optimal markers and endpoints for a clinical trial. To date, there are data in 45 GAN patients that demonstrate an average eight point decline per year in the MFM32 scores that are consistent across patients of all ages. Recall that the four point decline per year in the MFM32 is considered clinically meaningful. Notably and in line with recently published FDA guidance, regulatory agencies appreciate the availability of a well-controlled and high-quality prospective natural history study as a comparator in clinical trials for rare diseases.

In addition, we believe this natural history study provides us with a head start in identifying patients. Based on the positive preclinical results, an IND was opened, and TSHA-120 is being further evaluated in an ongoing clinical trial. The primary endpoint is to assess safety, with secondary endpoints measuring efficacy using pathologic, physiologic, functional and clinical markers. To date, 14 patients have been administered intrathecal TSHA-120 and six patients have at least three years worth of long-term follow up data.

TSHA-120 has shown a dose-response relationship with the rest of disease progression at the second highest dose level, 1.8 times 10 to the 14 total vg at one-year post-treatment, affecting a statistically significant eight point improvement on the MFM32 score in comparison to the predicted natural history trajectory. These results are very promising as a four point change in the MFM32 scores considered clinically meaningful. Six of these patients treated at therapeutic dose levels have shown sustained dose-dependent improvements in MFM32 scores for more than three years. Long-term results demonstrated that treatment with TSHA-120 at multiple dose levels was well tolerated with no severe drug-related adverse events.

We look forward to reporting additional data later this year, including results from the highest dose cohort 3.5 times 10 to the 14 total vg. The FDA has already granted TSHA-120 orphan drug and rare pediatric disease designations, and we will continue to work closely with the regulatory authorities in the U.S. In the near term, we expect to have discussions with the FDA and engage with other major regulatory agencies by year-end to discuss the pathway to approval for TSHA-120. I would also like to highlight some of the promising preclinical data coming from our earlier-stage candidates that demonstrate the incredible breadth, depth and velocity of our development engine.

It is important to note that there are no approved disease-modifying therapies for any of the programs in our portfolio. With such compelling data to date for our pipeline, we are very encouraged as our gene therapy candidates could offer significant value to meaningful patient populations. We are very excited to show new preclinical data for TSHA-102 in Rett syndrome, that was recently published in Brain. As RA discussed earlier, historically, it has been a challenge to find the right approach to safely regulate MECP2 expression in this disease.

The complexities are highlighted by phenotypic variability, mosaicism and the need to regulate MECP2 such that it does not cause over expression related toxicity. Today's data give us confidence that we can achieve appropriate MECP2 expression in all cells in a genotype-dependent manner with no signs of toxicity. With the built-in regulatory element, miRARE, TSHA-102 provided a statistically significant survival extension in knockout Rett mice by 56%, while the unregulated mini MECP2 gene transfer failed to significantly extend knockout survival at either dose tested. Additionally, the unregulated full-length MECP2 construct did not demonstrate a significant extension in survival and was associated with unacceptable toxicity profile in wild-type mice.

We believe that the 56% improvement in survival in TSHA-102 treated knockout mice is extremely impressive, as these adolescent mice have accumulated significant disease. Of note, since Rett patients do not demonstrate symptoms until about one year of age, and therefore, will not be treated until after this point, we believe these data are likely to be highly translatable to the clinical setting. In addition to survival, behavioral side effects were explored, TSHA-102 treated wild-type mice have a significantly lower, meaning better mean aggregate behavioral score than those treated with unregulated of full length MECP2 and unregulated mini-MECP2. Importantly, miRARE-mediated genotype-dependent gene regulation was shown by analyzing tissue sections from wild-type and knockout mouse treated with AAV9 vectors given intrathecally.

TSHA-102 demonstrated reduced levels of MECP2 in different regions of the brain, suggesting that miRARE inhibited mean expression in a genotype dependent manner. This demonstrates that TSHA-102 achieved MECP2 expression levels within normal physiological parameters. In summary, these positive data demonstrated miRARE's ability to exhibit genotype dependent regulation of MECP2 gene expression across different brain regions in both wild-type and knockout mouse models of Rett syndrome without overexpression toxicities. We are very encouraged by these results and look forward to filing an IND or CTA in the second half of this year, followed by initiation of a Phase 1/2 trial by year-end.

TSHA-102 has the potential to address a significant unmet need for an estimated 25,000 patients with Rett syndrome across the United States and in Europe. Now, I'd like to highlight some of our other preclinical programs that we have recently released data. TSHA-104, which is currently an IND/CTA enabled studies for the treatment of SURF1-associated Leigh syndrome, has demonstrated increased COX1 activity in brain and muscle and restored elevation of blood lactate on exhaustive exercise in a dose-dependent manner in SURF1 knockout mice. Dr.

Qinglan Ling of UT Southwestern will be presenting these compelling data this Thursday at ASGCT. We remain on track to file an IND or CTA in the second half of this year. TSHA-105, our gene therapy candidate, which is currently in IND/CTA enabling studies for the treatment of SLC13A5 deficiency caused a significant sustained decrease of plasma citrate levels up to three months post injection compared to aged-matched wild-type controls. TSHA-105 normalized EEG brain activity reduced the number of seizures and reduced seizure susceptibility compared to vehicle-treated controls.

Dr. Rachel Bailey will be presenting these positive data this Thursday at ASGCT. TSHA-103 is a gene therapy candidate that is in IND/CTA enabling studies for the treatment of SLC6A1 haploinsuffiency. In the SLC6A1 knockout mouse model, TSHA-103 improved nesting and EEG activity.

In addition, in SLC6A1 knockout and heterozygous mouse models, TSHA-103 reduced spike train activity, which is a recording of abnormal neuronal activity associated with seizures. We believe the estimated prevalence is 17,000 patients in the U.S. and in EU. TSHA-111-LAFORIN and TSHA-111-MALIN are gene therapy candidates in IND/CTA enabling studies for the treatment of both subtypes of Lafora disease achieved effective knockdown of GYS1 expression in the Lafora disease LAFORIN and MALIN mouse models, respectively.

Both product candidates decreased Lafora body formation within the brain in their respective mouse models. TSHA-112 has been tested in IND/CTA enabling studies for the treatment of adult polyglucosan body disease or APBD. In preclinical studies, miRNA knockdown of GYS1-induced significant reductions in GYS1 mRNA, GYS1 protein, abnormal glycogen accumulation and polyglucosan bodies throughout the brain and an APBD knockout mouse model. For GM2 AB variant in preclinical studies, TSHA-119 caused a significant dose-dependent reduction of GM2 accumulation at 20 weeks in mice that were dosed intrathecally at postnatal day 1 or at six weeks of age.

Long-term follow-up study which include bi-monthly behavioral, as well as biochemical and histological analyses are currently ongoing. TSHA-106 is being developed for the treatment of Angelman syndrome. In vitro testing in the neuroblast cell line demonstrated consistent knockdown of UBE3A-ATS and the subsequent increase in UBE3A expression across 26 distinct shRNA candidates. Selection of a development candidate is expected by midyear, followed by interim expression and safety data from confirmatory nonhuman primate studies by the year-end.

TSHA-113, an AAV-mediated gene knockdown construct has shown particular promise. TSHA-113's AAV9 capsid packages microRNA shuffles are designed to target tau mRNA for all six isoforms found in the human and/or mouse brain. Treatment with TSHA-113 has shown a significant reduction in tau mRNA and protein levels while demonstrating widespread expression in neurons and glia. This is potentially significant implications for patients with neurodegenerative disorders characterized by deposition of abnormal tau protein in the brain, including Alzheimer's disease, MAPT-associated frontotemporal dementia and progressive supranuclear palsy.

As you can see collectively, these preclinical data highlights our next wave of novel gene therapies but with a potential to impact patient populations affected by significant diseases in a meaningful way. With that, we intend to file an IND/CTA for one of the following programs by the end of 2021: SLC13A5 deficiency, Lafora disease, APBD or GM2 AB variants. We also remain on track to file an IND/CTA for TSHA-102 in Rett syndrome and TSHA-104 in SURF1-Associated Leigh Syndrome and an IND for TSHA-101 in GM2 gangliosidosis in the U.S. during the second half of this year.

We expect to initiate the Phase 1/2 trial for TSHA-118, which is an already open IND. We are excited to have six near-term Phase 1/2 trial initiations planned throughout our top portfolio. We are making incredible progress advancing our product candidates into clinical development, and we look forward to providing additional updates at our R&D Day that will span two days in June. We will continue to advance our pipeline by leveraging our next-generation platform technologies.

As part of this initiative, we have recently established collaborations with Dr. Dennis Lal of the Genomics Institute, Cleveland Clinic, and Dr. Yong-Hui Jiang at Yale University to further push the boundaries of AAV vector engineering by developing next-generation mini-gene payloads. This has the potential to overcome current limitations of packaging capacity, which is a critical barrier to treating genetic diseases not addressable by conventional AAV gene therapy technologies.

This may enable us to effectively treat a wider range of devastating CNS diseases. UT Southwestern will produce viral vector constructs that incorporate the mini-gene payloads and evaluate the constructs in both in vitro and in vivo studies. Through collective efforts of Taysha and our partners, we will continue to strive for innovations in our platform technologies that will enable us to treat a broad range of CNS diseases with novel gene therapies. With that, I'll turn the call over to Kamran to review our financial results.

Kamran Alam -- Chief Financial Officer

Thank you, Suyash. This morning, I will discuss key aspects of our first-quarter 2021 financial results. More details could be found in our Form 10-Q, which will be filed with the SEC shortly. As indicated in our press release today, R&D expenses were $23.9 million for the first quarter ended March 31, 2021, compared to $5.5 million for the first quarter ended March 31, 2020.

The increase was primarily related to the company's development program as a result of increased manufacturing-related spend, clinical and preclinical activity and headcount. G&A expenses were $8.2 million for the first quarter ended March 31, 2021, compared to $0.07 million for the first quarter ended March 31, 2020. The increase was primarily due to an increase in personnel costs resulting from increased headcount, professional services fees and other corporate-related expenses. Net loss for the first quarter ended March 31, 2021, was $32 million or $0.87 per share as compared to a net loss of $5.4 million or $0.50 per share for the first quarter ended March 31, 2020.

As of March 31, 2021, Taysha had $228.7 million in cash and cash equivalents. We continue to expect that our working capital will be sufficient to fund our operations into 2023, inclusive of the development, regulatory and operational milestones RA and Suyash actually have outlined today. And with that, I will hand the call back to RA.

RA Session II -- President, Chief Executive Officer, and Founder

Thanks, Kamran. We are pleased to have shared with you our success over the first quarter. Looking ahead, we will continue to focus on rapidly advancing our pipeline with many key milestones anticipated over the next 18 months. We have made a significant transition into a pivotal stage gene therapy company with our acquisition of TSHA-120, and we expect to provide both clinical and regulatory updates by year-end.

Further, we remain on track to report first-in-human clinical data for TSHA-101 and GM2 gangliosidosis as well as initiate a Phase 1/2 trial for TSHA-118 in CLN1 disease, that currently has an open IND. As you've heard today, we have an extensive pipeline of preclinical programs that are advancing quickly. We expect to open four INDs or CTAs and have a total of five programs in clinical development, including for Rett syndrome and SURF1-associated Leigh syndrome by year-end and have additional six programs currently in IND or CTA enabling studies. In parallel, we will continue to support our R&D initiatives by expanding our team to approximately 150 employees by year-end, completing the build-out of our Dallas corporate headquarters by midyear, as well as continuing with the construction on our internal GMP manufacturing facility in Durham, North Carolina.

With numerous potentially value-creating near term milestones, we expect this year to continue to be a transformational period, and we look forward to providing further updates on our progress at our upcoming R&D day event next month. Lastly, I would like to give special thanks for the continued support and dedication of our Taysha employees, board of directors, scientific advisory board, collaborators, and the patients and advocates who remain our motivation every day to continue on our mission to develop curative gene therapies to eradicate devastating monogenic CNS disease. I will now ask the operator to begin our Q&A session. Operator?

Questions & Answers:


[Operator instructions] The first question comes from Salveen Richter from Goldman Sachs. Please go ahead.

Salveen Richter -- Goldman Sachs -- Analyst

Good morning. Thanks for taking my question.

RA Session II -- President, Chief Executive Officer, and Founder

Good morning.

Salveen Richter -- Goldman Sachs -- Analyst

Good morning. So one question here about -- one question here about capital and resource allocation. As you're running multiple trials, building out a GMP facility and hiring employees, so how should we think about that over time? And secondly, with regard to the Rett program, maybe if you could touch on the registration path here and what you'd like to see from that first clinical data set to inform the pivotal program?

RA Session II -- President, Chief Executive Officer, and Founder

No, I appreciate the question, Salveen. Good morning. So I'll take the first one and Suyash, if you could address the question on Rett. As far as capital allocation goes, we reaffirmed our guidance this morning that we still have the capital resources to take us into 2023.

As it pertains to gene therapy, drug development, it's much different than kind of classic drug development from a time and cost to test because you're not doing kind of high throughput screening, trying to identify a target, you already know the target. And so it's actually much more capital-efficient to go after gene therapy versus other forms or other modalities. And so the way that we're thinking about this is, again, because our portfolio is appropriately staged, we have some programs that are moving into the clinic, some programs that have just hit animal proof-of-concept and some early discovery programs. Most of our translational and discovery work is being done by our collaborator at UT Southwestern and having an academic partner is a really capital-efficient way to do kind of your early translational discovery work.

As it pertains to the clinical development, again, this is a pretty capital-efficient modality because the number of patients you need to actually get a signal and to achieve human proof-of-concept is quite small compared to some other modalities. So again, I think and we feel very strongly about this, moving five programs into clinical development this year, already having a few programs in the clinic, we still feel strongly that our capital takes us into 2023. I'll stop there. And Suyash, do you want to address the question around Rett syndrome and kind of what our thoughts are on the path in the clinic and our path to approval?

Suyash Prasad -- Chief Medical Officer and Head of R&D

Absolutely. Thanks, RA and thanks for the question Salveen. Yes, so for Rett syndrome, I think we've been spending a lot of time thinking about the clinical development program and the pathway to approval. And we're going to take a slightly more cautious approach for some of our other conditions such as GM2, CLN1 GAN where the diseases are a little less common and where there is an ongoing relatively high-risk of mortality quite early on.

So the way we think about Rett is that the first study of a group of two will be more of a Phase 1/2 primarily safety study with some exploration of preliminary efficacy. Following on from that, we will then perform a Phase 2/3 study, which focuses -- it takes learnings from the initial Phase 1/2 study, takes the learnings from that and applies it into a more extensive Phase 2/3 pivotal efficacy study. Now with regard to the first study, the Phase 1/2 study, likely, we will be doing it in older patients. As you know, the FDA tends to push you away from children toward adults first.

And in this particular situation, we actually tend to agree with that approach. There are these risks of toxicity with over-expression of MECP2. So we just have to be quite mindful when we design this initial study. So the first study will be Phase 1/2 clinical proof-of-concept, safety, preliminary efficacy in the adult population.

In terms of endpoints, we'll be looking at the safety aspects of safety initially and then, we will be looking at efficacy, really in three different buckets. The efficacy will be looked at, firstly, with a number of the different Rett-specific clinically rated scales, for example, the Rett syndrome motor behavior assessment, the Rett syndrome behavior questionnaire, so they are the Rett scales. We'll also be looking at seizures in some detail because children with Rett syndrome have significant seizure activity. So we'll be looking at how frequent the seizures are, how many medications the child is on, what triggers the seizures, how durable the seizures are and over time, hopefully, we will be able to see a reduction in seizure activity and bring them off medications and also see an improvement in the EEG.

And then the third bucket kind of assessments will include a general multi systemic, multi-organ type aspects of Rett syndrome disease characteristics, such as the respiratory assessments, which as you know, you have respiratory abnormalities in Rett syndrome, sleep apnea issues, cardiac issues such as QT prolongation. So I think that the first -- we once again will look at safety initially and some of these areas of preliminary efficacy, we will build on that and design the Phase 2/3 study subsequent to that. As we've already talked about, we'll be engaging with regulatory agencies during the course of this year to pressure test our thinking around these particular plans, and we'll be starting the clinical study toward the end of the year.

Salveen Richter -- Goldman Sachs -- Analyst

Thank you.

RA Session II -- President, Chief Executive Officer, and Founder

Thanks for the question.


The next question comes from Matthew Harrison from Morgan Stanley. Please go ahead.

Unknown speaker -- Morgan Stanley -- Analyst

Good morning. This is Thomas on for Matthew. Can you give an update on where you are with manufacturing for the GAN program? In particular, what sort of assay work do you still need to complete? Thank you.

RA Session II -- President, Chief Executive Officer, and Founder

Thanks, Thomas for the question. I'll turn this question over to Fred Porter, our chief technical officer, on the line to talk about our manufacturing. Fred?

Fred Porter -- Chief Technical Officer -- Analyst

Yes. Thanks, RA. Thanks for the question, Matthew. Obviously, we're in the process of onboarding the GAN program.

And so where we're really beginning is with the assays, reviewing the assays that were conducted by the NIH for the Phase 1, Phase 2 clinical material. And what our intention is, is to try to update those methods to qualify and then validate them to prepare for a late-stage pivotal work. So we're actively engaging on all the critical quality attribute assays with our partners to move that forward with our CMO. In addition, we're looking very deeply into the potency assay development work, and this is something that's happening jointly between Suyash's group and my own to move forward a potency assay very quickly to kind of synchronize a fully developed and qualified potency assay with pivotal lot manufacturing.

Happy to answer any questions about that.

Suyash Prasad -- Chief Medical Officer and Head of R&D

I can add one more comment. I can add one more comment on top of Fred. And it's an important question to ask about an assay. The other assay that we're spending some time thinking about and really pulling the trigger on with some considerable effort is more in the qPCR same to the ddPCR.

So we get some slightly more accurate numbers in terms of titrate. So that's another arm of what happened parallel with the potency of the other CMC characterization that Fred mentioned.

Unknown speaker -- Morgan Stanley -- Analyst

Thank you.

RA Session II -- President, Chief Executive Officer, and Founder

Thanks, Tom.


[Operator instructions] The next question comes from Raju Prasad from William Blair. Please go ahead.

Raju Prasad -- William Blair -- Analyst

Hey, guys. Thanks for taking the question and congrats on the progress.

RA Session II -- President, Chief Executive Officer, and Founder

Thank you, Raj.

Raju Prasad -- William Blair -- Analyst

I'm kind of looking down your pipeline, and I see a lot of technologies that you're derisking from a payload perspective, the miRARE platform, the bicistronic vector, and I could see follow-on indications once those technologies are derisked. But my question was more on the regulatory side. As you're kind of dealing with regulators on these different indications, what types of aspects of the programs do you think will be derisked by clinical data there? Is it on endpoints and dealing with endpoints with the FDA, is it on the IT administration? Maybe some color there would be great.

RA Session II -- President, Chief Executive Officer, and Founder

No. It's a great question and it's kind of central to our scientific thesis. And really our focus on the use of validated gene therapy technology kind of coupled with very targeted novel payload design and really trying to achieve an economy to scale that really allow us to go after this kind of large portfolio of product candidates. And we're able to do that because we hold a couple of things constant.

The first thing is all of our programs are AAV9. The second thing, they all use HEK293 suspension manufacturing as a platform. And the third is really around this notion of intrathecal delivery. And this really allows us to take learnings and achieve economies of scale from one program to the next.

I'll pause there, and Suyash, I'll allow you to kind of talk about maybe some of the things that we plan to discuss with regulators and how we plan to apply those learnings from one program to the next.

Suyash Prasad -- Chief Medical Officer and Head of R&D

Thanks, RA and thanks, Raju for the question. Yes, there's lots -- there's lots and lots of commonalities, I think, between our programs, over and above the simple -- the trifecta of comments were about AAV9, HEK293 and IT administration. There's many, many other commonalities, I think we shared. And we're as a platform more than anything.

Let me touch on a couple of things. So you mentioned -- I think we're going to learn a huge amount from just one program to inform the next. We -- there's a lot of debate in the field about IT versus ICM versus ICV and subtle distribution between them all. I keep coming back to the perspective that IT administration works has worked for decades.

I've given it myself in the world of oncology and anesthesiology, and it's worked for decades there. And when you look at the clinical data from GAN from CLN3, CLN6, and another in, Zolgensma, you see it works, and it works beautifully. And I think as we continue to build our portfolio of programs, we can really -- I think the FDA and other regulators will just become increasingly comfortable with intrathecal administration. And there's many nuances around that but -- many details.

For example, we spent some time yesterday talking about different types of infusion kits you might use to give intrathecal drug and the comparability -- compatibility test you might need to do for some of these different methods of administration. So I think there's lots and lots of learning, in particular from GAN that will inform the rest of our portfolio. Another piece of learning, I think that's important from GAN and as our programs progress, is just on the immunosuppression regime we like to use. So the whole world of the immunology of gene therapy has evolved and evolved rapidly over the past few years.

Initially, people didn't give any immunological therapy and just treated liver inflammation reactively with oral prednisolone. Then it was decided that let's give the prednisolone first to try and prevent it. And then additional medications have been tried than added. And we've settled very -- on this very nice regime of six months of oral prednisolone plus 12 months of rapamycin at specific doses that we have a lot of experience with now and learnings from the GAN program, where a number of patients have been managed with this regime in this special therapy very, very successfully to the point where, actually, we're not seeing any evidence of any T cell-mediated inflammation in any of the patients who received this regime from the GAN study.

We're using that approach in GM2, in CLN1, in SURF1. And I think once again, we're going to build up this body of evidence for that particular regime. I think the first thing I'll mention, and you touched on it is endpoints in the clinical trial and what we can learn from one to the other. I think for a lot of our diseases, where there are these neurological features, there's a developmental regression and a lack of failure to gain milestones.

And we've set from a very nice group of developmental assessments, the Bayley scale, the Vineland, the CHOP INTEND, and there's one or two others of are more disease specific. We know how to train the raters that do these particular assessments. We know to video the assessments in a particular way, we know to upload the videos to a server, where they can then be reviewed externally by a second rater or a second group of raters who are blinded to what the patients have been treated or not. All these things add a lot of robustness to the clinical development program and learnings from one to the other.

The other thing I mentioned when we were talking about Rett a few minutes ago, was just seizures, how we collect seizure information, seizure activity, EEG, the medications the patients are on, etc. So I think that in our discussions with the regulators, there are many, many commonalities, in particular, on the clinical development side that I think are going to be applicable to all programs and will constitute additional learnings from one to the other. I hope that answers your question, Raju.

Raju Prasad -- William Blair -- Analyst

Yes. No, that's extremely helpful. Maybe just a quick follow-up on that last point. As it relates to the upcoming FDA discussions on the GAN program, how should we be looking at the results of those discussions as it relates to the potential request from the FDA? I'm thinking particularly about natural history comparator versus having to run a placebo arm or a sham-controlled treated arm.

I mean, is that something that you're looking to see kind of as to extrapolate to the rest of the pipeline? Like, if they do give you a natural history comparator for pivotal, that's something that you might try for GM2 and some of the rare diseases? Or do you think that the discussions on GAN are only going to be related to GAN, and each individual indication will probably be a different kind of discussions with the agency.

Suyash Prasad -- Chief Medical Officer and Head of R&D

So it's a really important point. The -- how much data are already existing for a particular disease. And it's -- there are certainly commonalities there from program to program, but there are also some subtle differences, and we're doing things a little bit differently from program to program. What I will say is a higher level is, there is some very nice guidance that was published by the FDA on gene therapy development for neurodegenerative disease, and they have a specific section on natural history study in historical controls.

They said very clearly, this may be appropriate for gene therapy product to treat a rare or serious neurodegenerative disease if there's a clear unmet medical need, which is absolutely the case for most of our programs, where the inclusion of concurrent control is not practical or ethical, which is also true, certainly for programs like GM2 or CLN1, where there is this ongoing higher risk of mortality. They also talk about the disease course is well documented, and the expected treatment effect is large. It may be very, very suitable to use a natural history comparator as a control. Now for GAN, specifically, we have 45 patients, in fact, more than that.

We've presented data of 45 patients in the natural history study. With data, the patients were enrollments in 2013. So it has summary of data on some of these patients. And we've got very, very clear indication that there's a consistent drop in the primary efficacy endpoint, the MFM32 of eight points per year.

I think because of that, it's also predictable -- the disease course is predictable. And so for GAN, very rare disease with -- and we're seeing a very nice treatment effect with our clinical study. So all those things really contribute to the fact that for GAN, in particular, I think is -- you don't know what the FDA you're going to say, but I think it checks all the boxes for a natural history study being an appropriate comparator. So my guess is it's unlikely they will ask us to do any kind of more formal concurrent control.

Once again, you don't know what the FDA are going to say, but it checks all the boxes from that perspective. GM2, there's a lot of already good natural history data out there in publications. And so we're making use of that. CLN1, there is a prospective natural history study ongoing currently with about 40 to 50 patients in it.

This is international. So we'll be using that. So it's a little bit different from program to program. Rett syndrome, there is huge natural history databases that are available, although for Rett, we will likely build in a concurrent control for a randomized, but non blinded concurrent control to add a little more robustness to the clinical development plan.

So let me stop there. I hope I've answered your question and gave you some context but I can stop. I think we can go into more detail if you like Raju but I stop now.

Raju Prasad -- William Blair -- Analyst

That was extremely helpful. Thank you. Thank you for the question.

RA Session II -- President, Chief Executive Officer, and Founder

Thanks, Raj.


The next question comes from Yun Yang from Jefferies. Please go ahead.

Unknown speaker -- Morgan Stanley -- Analyst

Thank you. So today, when we talk about address the patient population for your gene therapy programs, it's been kind of a focus on the U.S. and Europe. But now you look to potential approval of 120 in 2023.

What are you thinking about market opportunity outside the U.S. and Europe?

RA Session II -- President, Chief Executive Officer, and Founder

Thank you for the question. That's a great question. And what's interesting about rare disease commercialization is the fact that you're able to leverage a major market approval pretty much all over the world. And what I mean by that, an approval in the U.S.

or in the EU, you're able to initiate almost immediately reimbursed name patient or early access programs and some of the more highly reimbursable markets where you also have an over-expression of genetic diseases. And so in some countries, like the GCC region of the Middle East, Saudi Arabia, Israel, Turkey, some of the Latin American companies -- countries where reimbursement is actually quite good, Brazil, Colombia, these are areas that we would actually look to commercialize post a major market approval, either under a reimbursed name patient program or early access program, would have eventually -- you would seek a marketing approval over time. So that's really the way that we're thinking about commercialization. We are looking globally.

We would most likely do this through some of your more established distribution partners. There's a number of partners, particularly in Israel, the Middle East, Turkey, Brazil that are highly skilled in achieving reimbursement for specialized products, gene therapies, high-priced products. And so we would probably most likely go this route. We most likely would not look to out-license our product from a commercialization perspective early on but really do our commercialization through distribution collaborations in some of these areas that I mentioned.

So that's the way that we're thinking about things today. Obviously, as time goes on, you gain more information and you alter your thinking that way. But at least for now, that's the way that we're approaching our commercialization -- our pre-commercialization plans.

Unknown speaker -- Morgan Stanley -- Analyst

Thank you. And I have one more question on Rett syndrome program. So I'm sure that you're familiar with the Novartis program. And I don't know how much you can speak about it, but aside from your program, potentially have a better regulation of the transgene expression.

Can you talk about kind of a differentiation compared to Novartis and is Novartis actually pursuing their Rett program? Thank you.

RA Session II -- President, Chief Executive Officer, and Founder

Thank you for the question. So what I'll just do is highlight the difference -- the kind of the main difference in the two approaches. And then I'll turn it over to Suyash to kind of talk about the differences in more depth. So really, the main difference in the two programs is our program, TSHA-102, is a gene therapy product, AAV9, with a self regulatory feedback loop built into the transgene that caps gene expression on a cell by cell basis, or as we -- or what was described in the paper that was recently published that has a genotypic regulation of gene expression.

That's the term that we're using. Essentially, what we're doing is having a safety valve to guard against overexpression-associated toxicity. The Novartis AveXis construct is essentially self-complementary AAV9 with full MECP2 with no regulatory component. That at least is the last construct that was published that we are all publicly aware of.

I'll stop there. Suyash, maybe you want to go through in a little bit more detail some of the nuances.

Suyash Prasad -- Chief Medical Officer and Head of R&D

Yes. Thanks, RA and thanks for the question. I think it's an important question. As RA mentioned, the only -- the major difference really is the fact that we include -- we have the mini MECP2 gene, which was developed by Professor Sir Adrian Bird and very esteemed and eligible Rett experts from Edinburgh, who was actually the first person to demonstrate unequivocally that Rett syndrome is a highly reversible disease.

So we use his design for the mini MECP2 gene. And then we attach this strip of micro RNA binding sites, the miRARE platform, which stands for micro RNA a responsive auto regulatory element. So when MECP2 levels go up within the cell, as a consequence of the gene therapy, the down regulatory micro RNA binding sites are triggered, they bind to this miRARE platform, which is in the untranslated region of the construct and bring down levels of MECP2, as RA suggested, acting as a safety valve. Now we're very excited to be able to say to you that the first quantitative data demonstrating this reduction in MECP2 expression to the point where you have enough dose efficacious, but not too much that it's toxic, was published in Brain, which is a very prestigious neuroscience journal.

It went online on Friday and we issued a press release yesterday. And I would encourage you to look at the paper, the lead author is Sarah Sinnett, and senior authors are a good friend and colleague, chief scientific advisor, Steven Gray. There's a particular diagram in that paper, which I'd suggest you look at, which looks specifically at different levels of expression of MECP2 in different parts of the brain, in different parts of the spinal cord. And you can see very nicely that non mIRARE construct over expresses, whereas the miRARE construct expresses enough so that it is efficacious, but not toxic.

So we're very excited about that piece of paper. So I think that's the main difference, the fact that we can demonstrate this -- the ability to express MECP2 within these normal physiological parameters now, we have shown in different parts of the brain, and we've shown it quantitatively as well. My understanding is that Novartis is still moving forward with that program. Last I heard was they are planning to move forward as an IND, but I don't know exactly where they are with that.

But I think that's the main difference really between our products and theirs.


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

RA Session II -- President, Chief Executive Officer, and Founder

So again, we appreciate everyone joining us on the call this morning. As you can see, the company has made great strides during the first quarter. And we continue to make progress throughout the rest of this year. And so we hope that you guys join us at our R&D Day, which will take place over two days in June, June 28 and June 29 and we'll provide further updates as the year goes on.

Thank you for joining. Have a good day.


[Operator signoff]

Duration: 63 minutes

Call participants:

Kimberly Lee -- Senior Vice President of Corporate Communications and Investor Relations

RA Session II -- President, Chief Executive Officer, and Founder

Suyash Prasad -- Chief Medical Officer and Head of R&D

Kamran Alam -- Chief Financial Officer

Salveen Richter -- Goldman Sachs -- Analyst

Unknown speaker -- Morgan Stanley -- Analyst

Fred Porter -- Chief Technical Officer -- Analyst

Raju Prasad -- William Blair -- Analyst

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