Taysha Gene Therapies, Inc. (TSHA) Earnings Call Transcript & Summary

Greetings, and welcome to Taysha Gene Therapy's GAN Program Acquisition Conference Call. [Operator Instructions] As a reminder, this conference call is being recorded today, April 12, 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 GAN Program Acquisition Conference Call. Joining me on today's call are RA Session II, Taysha's President, CEO and Founder; and Dr. Suyash Prasad, Chief Medical Officer and Head of R&D; Dr. Steven Gray, Chief Scientific Adviser at Taysha and Associate Professor in the Department of Pediatrics at UT Southwestern; Kamran Alam, Chief Financial Officer; and Fred Porter, Chief Technical Officer, will join us for the question-and-answer session. Earlier today, Taysha issued a press release announcing the acquisition of exclusive worldwide rights to TSHA-120 for the treatment of GAN, which is currently being evaluated in a GAN clinical trial. 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 existing clinical data and therapeutic and commercial potential of TSHA-120 and our investigational drug 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. 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 discovery, limitations imposed by patents owned or controlled by third parties and the requirements of substantial funding to conduct our research and development activity. For a list and description of the risks and uncertainties that we face, please see the reports we have filed with the Securities and Exchange Commission. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, April 12, 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 would now like to turn the call over to our President, CEO and Founder, RA Session II.

Thank you, Kim, and thank you, everyone, for joining us on the call this morning. We are pleased to announce that we have acquired an exclusive license to a groundbreaking clinical-stage program, which we are now calling TSHA-120, an AAV9 intrathecally dosed gene therapy invented by our Chief Scientific Adviser, Dr. Steven Gray of UT Southwestern and currently in a clinical trial for the treatment of giant axonal neuropathy or GAN. This deal is the culmination of diligence and discussions with the leading patient advocacy group that were initiated over a year ago at Taysha's inception and with the NIH. We are excited to now acquire TSHA-120, which we believe validates our scientific approach, provides read-through to our existing pipeline and informs the development of our entire portfolio. Our strategy is focused on the use of validated gene therapy technology coupled with novel targeted payload design, depending on the disease. We are advancing a broad pipeline of gene therapy programs that aim to serve patients suffering from a range of monogenic CNS disorders with significant unmet medical need. Our scientific approach to building our pipeline is based on leveraging a clinically and commercially proven capsid, manufacturing process and route of administration. We believe this reduces overall program risk and increases probability of success. The GAN program is a clear validation of this approach with read-through to our existing portfolio, consistent with all of our pipeline candidates. TSHA-120 utilizes an AAV9 vector, which has demonstrated efficacy, safety and durability of response across multiple CNS indications and it's intrathecally dosed. It also uses the proven HEK293 suspension manufacturing process, which is highly scalable and provides excellent yields. The GAN program originated from the lab of Dr. Steven Gray, our Chief Scientific Adviser and an expert in the development of AAV-based gene therapies targeting CNS disorders and is supportive of the additional translational work being generated from his lab at the UT Southwestern Gene Therapy Program and of our scientific approach. The GAN program is the first intrathecally dosed AAV gene therapy study in history. Notably, it immediately transforms Taysha into a sustainable pivotal-stage gene therapy company. The human proof-of-concept trial demonstrated a halt in disease progression at therapeutic doses. Of note, TSHA-120 demonstrated improved pathology of the dorsal root ganglia or DRG in GAN knockout rodent models, which is an emerging area of interest in gene therapy. In addition, this program may support the opportunity to achieve human proof-of-concept for our vagus nerve redosing platform with previously treated low-dose patients. We believe this is an extremely robust data package, and we plan to engage with regulatory agencies in the U.S., Europe and Japan as soon as possible. In parallel, we will be accelerating the build-out of our commercial infrastructure to support patient identification, payer engagement and product distribution. We estimate that there are approximately 2,400 prevalent patients in the U.S. and Europe alone, which potentially represents a near-term commercial opportunity of more than $2 billion. For all these reasons, we are excited to carry on the work initiated by Dr. Gray, the NIH and the leading patient advocacy group. We see the program as a strategic and value-accretive opportunity and a natural fit with our pipeline and mission. As I mentioned, the GAN program originated from the lab of Dr. Steven Gray, and his work on GAN launched all the other translational research programs that we are collaborating on today. If you ask me, he will tell you that he considers the day the first GAN patient was dosed as his proudest professional achievement. TSHA-120 was the first successful in-human intrathecal gene transfer in the history of gene therapy and has had significant impact across the field. Importantly, this program has laid the foundation for our robust pipeline of intrathecally delivered AAV9 gene therapy. It further supports our approach to treating monogenic diseases of the CNS and provides animal proof-of-concept for our redosing platform. It aligns with our core competencies, derisk and diversifies our portfolio, accelerates the build-out of our commercial infrastructure, which will support our existing portfolio and targets a meaningful market opportunity with an estimated 2,400 prevalent patients in the U.S. and Europe. TSHA-120 has a comprehensive preclinical data package, upon which the IND was accepted, and the product candidate has been successfully tested in an ongoing clinical trial run by the NIH for the last 5 years in close collaboration with the leading patient advocacy group. The clinical data generated by TSHA-120 in patients with GAN are statistically significant, clinically relevant, dose-dependent and durable. We are very encouraged that TSHA-120 represents significant value, first and foremost, for patients, who currently have no other treatment alternatives. With that, I will now turn the call over to Suyash to provide an overview of the disease, program and data generated to date. Suyash?

Thanks, RA, and good morning, everyone. We are incredibly excited to add TSHA-120 to our pipeline, making it our most advanced program. As RA mentioned, TSHA-120 originated from Dr. Steven Gray's lab. Steve has been one of the key investigators of the ongoing study, collaborating with Dr. Carsten Bönnemann, the principal investigator for the trial that has been conducted at the National Institute of Neurological Disorders and Stroke or NINDS at the NIH. So why is GAN such a good target for gene therapy? Researchers have discovered at least 47 different mutations in the GAN gene, which provides instructions for making a protein called gigaxonin. The protein is part of the ubiquitin-proteasome system or UPS, a multi-step process that identifies and eliminates excess or damaged proteins or structures within cells. In neurons, gigaxonin is part of the UPS and helps break down specialized intermediate filaments called neurofilaments, which comprise the structural framework that establishes the size and shape of the nerve cell extensions called axons, the essential section of the nerve that transmits nerve impulses. As shown on the right side of this slide, the buildup of gigaxonin causes a normal, healthy axon to swell due to the accumulation of neurofilaments. This swelling impairs electrochemical nerve impulses, which leads to the progressive worsening of neuromuscular symptoms observed in GAN patients. The GAN gene is a good target for gene therapy for a number of reasons. First, it is a small gene that fits well into the AAV9 capsid. Secondly, there is high transduction of the target organ and, in addition, there is evidence that even a low-level expression of gigaxonin may restore function in humans. This construct is also clearly a model for other product candidates in our pipeline that is designed for the treatment of similar neurodegenerative diseases like GM2 gangliosidosis, CLN1 and SURF1-associated Leigh syndrome. So let's now talk about the disease. GAN or giant axonal neuropathy is a rare inherited genetic disorder that affects both the central and peripheral nervous systems caused by loss of function mutations in the gigaxonin gene. Children with early-onset GAN become symptomatic before the age of 5. An unusual and important clinical feature of the disease, which points clinicians to a diagnosis of GAN, is dull, tightly curled hair that is markedly different from the parents in color and texture. Signs of GAN usually begin in the peripheral nervous system, which controls movement and sensation in the arms, legs and other parts of the body. This may manifest the sensory ataxia, progressive weakness, clumsiness and hyporeflexia. Children progressed from a mildly abnormal wobbling gait to a pronounced difficulty in walking. Additional symptoms include numbness or lack of feeling in the arms and legs, seizures, nystagmus, which is rapid back and forth movement of the eyes and impaired cognitive development. Invariably, patients develop progressive optic neuropathy and visual loss. Common radiologic findings include spinal cord atrophy and white matter abnormality on MRI. Pathological examination of the nerve demonstrates giant axons with significant inclusions. The disease progresses relentlessly and at a steady pace, progressively worsening scoliosis and contractures are common features. Most children lose the ability to independently ambulate and become wheelchair-dependent in the second decade of life. As time progresses, serious CNS dysfunction and respiratory failure requiring tracheostomy and ventilator support develop and death occurs in the late teens or early 20s. Currently, there are no approved therapies for GAN. There are 2 phenotypes of GAN, early and late onset. Individuals with late onset or clinically heterogeneous cases have a phenotype, which is milder with respect to motory and sensory dysfunction, and they lack a characteristic feature of tightly curled hair. The disease is slower in progression, and ultimately, their quality of life is poor, but the disease may not be life-limiting. Due to the nonspecific features, these individuals are often categorized as having Charcot–Marie–Tooth Type 2 or CMT2 disease. For this reason, we believe the estimated prevalence of GAN, including both subtypes, is around 2,400 patients in the U.S. and in Europe. Doctors have typically diagnosed GAN using a variety of tests, including nerve conduction studies, a brain MRI and the peripheral nerve biopsy, where a small piece of tissue from a peripheral nerve is removed and examined histologically to look for swollen axons with abnormal morphology. However, peripheral nerve biopsy alone is not sufficient to diagnose GAN as a presence of giant axons appear in other diseases as well. Molecular genetic testing for abnormalities in the GAN gene or immunodetection of gigaxonin confirms diagnosis. And as with many rare genetic diseases, earlier genetic testing has now replaced some of the more invasive diagnostic tests. As you can see on this slide, early-onset GAN usually presents before the age of 5 years and, as described previously, progresses relentlessly with deteriorating central and peripheral nervous system function, resulting in death usually in the 20s. Late-onset GAN is usually not detected until the teenage years and has a slower rate of progression. As with the majority of neurodegenerative diseases, the earlier the patients are identified and treated, the more likely and optimal clinical outcome. There is an ongoing natural history study being led by the NIH that has already identified and followed a number of patients with GAN for over 5 years with disease progression characterized by a number of clinical assessments. We believe it's extremely important to be able to identify patients and to maximize their access to care as early as possible. In our view, the key is to establish early diagnosis by supporting newborn screening efforts, partnering with and creating centers of excellence and engaging patient advocacy groups. Increasing awareness of not only of the disease but the various phenotypes through education and scientific publications will help identify patients. Finally, we view genetic testing is an important aspect of patient identification and believe key partnerships with companies, such as GeneDX and Invitae should accomplish just that. Increasing access to genetic testing can support early diagnosis of neurogenerative diseases, which, in turn, enables clinicians to provide precision therapies sooner and to better overall outcomes. These cross-company collaborations have been shown to help increase access to testing and reduce time to diagnosis. As mentioned, disease progression in patients with GAN has been characterized in a natural history study by a number of clinical assessments, most notably of which is a motor function measure 32 or MFM32. The MFM32 is a well-known validated scale for motor function measurement, originally developed for neuromuscular diseases. It reliably assesses the severity and progression of motor function across a broad spectrum and explores 3 functional domains. And included items evaluating head support, hip and knee flexion, upper limb function, sitting, standing, finger and wrist movement, walking, running and hopping. There are 32 items that are scored between 0 and 3 with the highest score indicating that individual was able to complete the task. The total maximum score for the MFM32 is 96, although sometimes this value is converted to a percentage. Importantly, as part of the GAN NIH natural history study, multiple measures of disease severity were evaluated. And the MFM32 was identified as having the highest correlation between all tested measures of mobility, neurophysiologic measures and muscle strength, reflecting its suitability as an endpoint. In neuromuscular diseases, a 4-point change in the MFM32 is considered clinically meaningful. So now that we understand where the MFM32 is, let's jump into the natural history data. The GAN natural history study was initiated in 2013 and includes 45 GAN patients aged 3 to 21 years. As would be expected for a neurodegenerative disease, younger patients have higher baseline scores. However, the rate of decline in the MFM32 scores demonstrated consistency across patients of all ages with most demonstrating an average 8-point decline per year regardless of age and/or baseline MFM32 score, as shown in the natural history plot on the right side of the slide. A 4-point score change in the MFM32 is considered clinically meaningful, suggesting that GAN patients lose significant function annually. Given the consistency, reliability and clinical relevance of the MFM32 across patients with GAN, we believe it would likely be the primary efficacy endpoint for a future potential confirmatory trial. 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 provides us with a head start in identifying patients for potential registrational study and has already proven invaluable in analyzing patient data to identify optimal markers and endpoints that can be used to gauge clinical success. Now let's get into the program. TSHA-120 and AAV9 self-complementary viral vector encoding the full-length human gigaxonin protein. The construct was invented by Dr. Steven Gray and is the first AAV9 gene therapy candidate to deliver a functional copy of the GAN gene. TSHA-120 is currently being evaluated in an ongoing clinical trial at the NIH, led by Dr. Carsten Bönnemann. 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 to advance TSHA-120 through clinical development. The GAN program is supported by a comprehensive preclinical package that demonstrated strong proof-of-concept data in both the construct and the delivery modality. TSHA-120 performed extremely well across in vitro and in vivo studies, demonstrating improved motor function and nerve pathology and long-term safety across several animal models. Of note, improved dorsal root ganglia or DRG pathology was demonstrated in TSHA-120 treated GAN knockout mice. These preclinical results were made publish in a number of peer-reviewed journals. Additional preclinical data from the GAN knockout rodent model that had received AAV9-mediated GAN gene therapy demonstrated that GAN rodents treated at 16 months performed significantly better than 18-month-old untreated GAN rodents and equivalently to controls. These rodents were evaluated using a rotarod performance test, which is designed to evaluate endurance, balance, grip strength and motor coordination in rodents. The time to fall off the rotarod known as latency was also evaluated. And you can see the clear difference in latency in treated versus untreated GAN rodents. A topic of considerable interest within gene therapy circles is the matter of DRG inflammation that has been observed in some nonhuman primate, or NHP, AAV gene therapy studies. Reports thus far suggest that this is a finding on necropsy without any observed functional decline. Interestingly, in GAN and in the majority of diseases in our neurodegenerative franchise, the DRG has 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. Here, you can see tissue from a GAN knockout mouse model with numerous abnormal neuronal inclusions containing aggregates of damaged neurofilament in the DRG. This is indicated by the yellow arrows on Slide A. As can be seen on Image C on the right side of the slide, the tissue from the GAN knockout mice treated with an intrathecal injection, TSHA-120, has a notable improvement in the reduction of these neuronal inclusions in the DRG. In addition to a qualitative review of histological samples by expert neuropathologists, a quantitative approach to the reduction in inclusions in the DRG was applied. Specifically, it was observed that TSHA-120-treated mice experienced a statistically significant reduction in the average number of neuronal inclusions versus the GAN knockout mice that received vehicle, once again demonstrating an improvement in the appearance of the DRG. Based on the positive results from the preclinical data package, a human proof-of-concept clinical trial for TSHA-120 in patients with GAN was initiated at the NIH. Here, we detailed the trial design. The ongoing study is a single-site, open-label, nonrandomized dose escalation trial, in which patients are intrathecally dosed with 1 of 4 dose levels of TSHA-120. 3.5x10^13 total vg, 1.2x10^14 total vg, 1.8x10^14 total vg and 3.5x10^14 total vg. 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 intrathecally dosed and 6 patients have at least 3 years' worth of long-term follow-up data. Here, we present data on the first 3 cohorts. At the first in-human intrathecal gene transfer study, we are incredibly excited to present promising safety and efficacy results for TSHA-120. As I mentioned earlier, the MFM32 score is the primary measure of clinical success in the trial. You can see that the 1.8x10^14 total vg dose and then 1.2x10^14 total vg cohorts demonstrated dose-related and meaningful slowing of disease progression in the first year post dosing. In fact, the 1.8x10^14 total vg dose affected a statistically significant 8-point improvement versus the historical control and the 1.2x10^14 total vg dose affected a statistically significant 6-point improvement. As a reminder, a 4-point change on the MFM32 score is considered clinically meaningful, so these are very promising results so far. In addition, TSHA-120 is well tolerated. Furthermore, we now have the results for 6 patients that's been followed for more than 3 years. Patients dosed with 1.8x10^14 total vg and 1.2x10^14 total vg have shown sustained and dose-dependent improvement in MFM32 scores for more than 3 years. We are also pleased to report that long-term results support that treatment with TSHA-120 was well tolerated at multiple doses with no signs of significant acute or subacute inflammation, no sudden sensory changes and no drug-related or persistent elevation of transaminases. We expect the availability of additional data from this study later this year, including results from the highest-dose cohort, a 3.5x10^14 total vg. We also plan to engage with regulatory agencies in the U.S., in Europe and in Japan to discuss the regulatory pathway for TSHA-120 as soon as possible. To gain further insight into the impact of TSHA-120 treatment on GAN disease progression and to add more robustness to the data, an additional analysis utilizing Bayesian statistical methodology was performed. Bayesian analysis is a useful method that enables direct probability statements about any unknown quantity of interest to be made. In this case, statements around the probability of a clinically meaningful improvement in MFM32. Bayesian analysis also enables immediate incorporation into the analysis of data gathered as the trial progresses. It is a particularly appropriate approach for a clinical trial in a rare disease and is a way of statistically increasing the power of the clinical trial in a small patient population when used to incorporate auxiliary information like historical data. Importantly, it is accepted by regulatory agencies in such cases. Here, we show the results of the Bayesian analysis of patient data from cohorts treated at 1.8x10^14 total vg and 1.2x10^14 total vg. As seen in the table, the analysis confirms both the natural history data of an 8-point decline in the MFM32 total percent score per year. And importantly, the patients treated with 1.8x10^14 total vg experienced an arrest of disease progression that was statistically significant. The Bayesian analysis confirms the positive findings that were seen with the frequentist approach. The Bayesian efficacy analysis confirmed that TSHA-120 halted patients' pretreatment rate of decline when compared to individual historical data. As shown on these graphs, the 1.8x10^14 total vg dose halted patient pretreatment rate of declining an average annual slope improvement of 7.78 points, while the 1.2x10^14 total vg dose resulted in a clinically meaningful slowing of disease progression with an average annual slope improvement of 6.09 points. These results are consistent with a dose response relationship. Furthermore, and most importantly, if I can direct your attention to the table on the lower right side of the slide, there was a nearly 100% probability of clinically meaningful slowing of disease progression as confirmed by the Bayesian analysis. The 1.8x10^14 total vg dose confirmed a nearly 100% probability of clinically meaningful slowing of disease compared to natural history decline of GAN patients, while the 1.2x10^14 total vg dose confirmed an approximately 85% probability of clinically meaningful slowing of disease and a 100% probability on any slowing of disease. We are incredibly encouraged by these results and look forward to reporting further data, in particular, on the higher dose, 3.5x10^14 total vg cohort from the study later in the year. The success of this clinical program represents substantial work from Dr. Steven Gray's research team. I'd also like to acknowledge Carsten Bönnemann and his exceptional team at the NIH with a high-quality, thoughtful and diligently executed clinical trial, which has resulted in the robust clinical trial results, which we have seen thus far. We are very encouraged about the long-term durable expression in patients with GAN with 6 patients dosed beyond 3 years. We intend to engage with EMA, MHRA and the Pharmaceuticals and Medical Devices Agency or PMDA in Japan to discuss the regulatory pathway for TSHA-120 and look forward to updating you on our progress by year-end. I'd like to move on to a related separate topic now, that's a direct administration of viral vector to the vagus nerve. As you are likely aware, a key challenge with viral gene therapies is the redosing of gene therapies when there is a lot of efficacy over time. This is because the initial dose of gene therapy elicits an immune response, specifically an antibody response, which then precludes a repeat administration of the same product. The second issue is the increasing understanding that within the realm of neurological disease, autonomic nervous system dysfunction is a key contributor to disability and poor quality of life. Direct administration of gene therapy viral vector for vagus nerve can go a long way to meeting both these challenges. Preclinical research from UT Southwestern has shown an approach to redosing gene therapy products by direct delivery to the vagus nerve, thereby avoiding the previously elicited tumoral immune response. In addition, this method provides broad coverage of the autonomic nervous system, thereby improving clinical features of the disease, such as breathing disturbances, gastrointestinal side effects and blood pressure control. Proof-of-concept research in the preclinical setting has supported by combined intrathecal and vagus nerve injection of TSHA-120 may ameliorate autonomic nervous system dysfunction, as I will show you on the next slide. At either 4 or 16 weeks after wild-type rats were injected intrathecally with TSHA-120, they received the second dose via direct injection of the AAV9 vector into the vagus nerve. 4 weeks after the second injection, tissues were assessed for expression of our redosed virus by staining for the GFP reporter carried by the second AAV9 vector. Examination of the injected vagus nerve and associated no-dose ganglia showed a robust expression of GFP, as represented by the brown staining, indicating that in rats, AAV9 can be redosed through a direct nerve injection following intrathecal delivery. Consistent with single-dosing studies, redose animals showed expression in the medulla vagus nerve nuclei. As shown on this slide, GFP expression was seen in the nucleus ambiguous, which controls motor functions critical for vocalization, swallowing and peristalsis and in the pre-Bötzinger complex, which contains respiratory, rhythm-generating neurons, all of which are autonomic functions compromised in GAN and indeed many other neurological diseases. Further evidence of how vagus nerve injection permits AAV9 redosing was demonstrated in the brain of a naive animal, shown on the left, compared to an intrathecally AAV9-immunized rat on the right. Efficient GFP transduction was observed in vagal nerve fibers and in brain neurons. In the area postrema, which has a reduced blood-brain barrier and is a target for vagal afferent fiber trafficking, there was reduced GFP expression in pre-immunized animals at 4 and 16 weeks as compared to naive animals. This suggests that preexisting neutralization antibodies may dampen the overall transduction of vagal nerve delivered AAV9, that efficient transduction of autonomic relevant neurons can still be achieved. These results supported the vagus nerve space is immune privileged enough to allow for redosing. In short, we are very encouraged by these results as our vagus nerve delivery platform could be utilized to facilitate redosing of previously treated gene therapy patients. The potential clinical implications of this technology platform are far reaching. Now I'd like to turn the call back over to RA.

Thanks, Suyash. In summary, the GAN program immediately transforms Taysha into a sustainable pivotal stage gene therapy company. TSHA-120 has been tested in a groundbreaking human proof-of-concept trial as the first intrathecally dosed AAV9 gene therapy study. Clinical data has demonstrated an arrest of disease progression and durability at therapeutic dose levels, which support strong translation of the preclinical data from Dr. Steven Gray's lab into the clinic. We now have several years of human clinical data spanning 14 patients at 3 dose cohorts with durability of effects seen in several patients for more than 3 years. We look forward to engaging with agencies to discuss the regulatory pathway for TSHA-120 in the U.S., Europe and in Japan. And in parallel, we will accelerate the build-out of our commercial infrastructure to support patient identification, payer engagement and product distribution. With an estimated 2,400 prevalent patients in the U.S. and Europe alone, we view GAN as a greater than $2 billion near-term commercial opportunity. We expect a steady flow of near-term clinical and regulatory milestones for TSHA-120. Now that the deal has closed, we will complete the transfer of data from the NIH in preparation for regulatory discussions. In parallel, we intend to begin manufacturing of commercial-grade GMP material and to initiate new clinical sites in the U.S. and in Europe. We also anticipate a clinical update by year-end that includes data from the 3.5e total vg dose cohort. On the regulatory front, we plan to request an end-of-phase meeting with the FDA and to engage with the EMA, MHRA and PMDA by year-end to discuss the approval pathway for TSHA-120. We are incredibly excited to add the GAN program to our pipeline, now our most advanced clinical stage asset. With our new addition, we remain focused on expeditiously moving our gene therapy candidates through development with many near-term milestones over the next 18 months. In the second half of this year, beyond announcing results from our highest dose cohort in the GAN trial, we expect to report preliminary biomarker data from our Phase I/II trial of TSHA-101 in GM2 gangliosidosis and to dose the first patient in a Phase I/II trial for TSHA-118 in CLN1 disease, which is currently under an open IND. We expect to open 4 INDs or CTAs by the end of this year, including for Rett syndrome, and have 5 additional programs, currently in IND or CTA-enabling studies. We support our extensive pipeline by leveraging the many synergies across our programs and with a comprehensive manufacturing strategy. That includes the construction of our state-of-the-art GMP-compliant manufacturing facility. We look forward to building further long-term value as we continue to advance our gene therapy candidates and to keeping you updated on our progress at our R&D Day in June. We would like to conclude our prepared remarks by giving special thanks to Dr. Steven Gray and his team at UT Southwestern, Hannah's Hope Fund and Carsten Bönnemann and his team at the NIH for pioneering the first clinical-stage gene therapy treatment for GAN, which is also the first intrathecally dosed AAV gene therapy in clinical development. We look forward to partnering with the NIH and the patient community to make TSHA-120 available to patients with GAN as quickly as possible. With that, I will now ask the operator to begin our Q&A session. Operator?

[Operator Instructions] Our first question comes from the line of Salveen Richter with Goldman Sachs.

This is Elizabeth on for Salveen. 2 questions from us. One would be if you could expand on sort of the timing of this? And why now is the right time to pursue this program? And then second, could you help us just frame expectations for the data by year-end? And what you're hoping to see here?

Absolutely, great question. I'll take the first, and then I'll pass the second over to Suyash to talk about the clinical data. I think from a timing perspective, this is really the culmination of over a year worth of discussions with Hannah's Hope Fund, who is the advocacy group that controlled the intellectual property of this program as well as the NIH. When we kicked off those discussions, really a case of inception. And what I would probably say during COVID, things took a little bit longer than what we originally estimated. And obviously, the NIH turned their focus to working on vaccine discovery. And we were pretty fortunate to be able to continue those discussions, although in a little bit slower of a pace. But really, those discussions were able to accelerate towards the end of last year and really expedited as we got into 2021. And so really, this is something that we had been working on for quite some time. We were fortunate to have a little bit of proprietary deal flow and be able to have kind of a high-level access to the data that's been shared publicly. And we're really able to keep an eye on the program through our relationship with the advocacy group and Dr. Steven Gray as well as Dr. Bönnemann and we -- and for us, this is something that from a timing perspective, we wanted to bring in sooner versus later. As you can see, the data really speak for itself and really supports a conversation with the agency around what the regulatory pathway is, particularly at the 1.8 e vg dose. And so we want to make sure that we're appropriately moving this program forward and having those discussions and particularly with agencies around the world. So I'll pause there and turn it over to Suyash to answer your question around clinical expectations of the high-dose cohort.

Thanks, RA. As you can see from the slide deck and what we presented, we have 4 doses in this particular study, going from 3.5e13, which is total vg intrathecally, which is a really quite a low dose, all work to 3.5e14 total vg, which is a moderate dose. And we presented data on the first 3 cohorts. And as you can see, we saw a nice dose dependency and essentially halting of disease progression of the 1.8e 14 total vg dose. Now patients have been dosed in the higher dose group, 3.5e14 total vg, but we don't have that data as yet. I anticipate we will have data on that cohort towards the end of the year. And once again, I would anticipate seeing at least the stabilization of disease and maybe even a slight improvement, but that remains to be seen. In addition to the data from the high-dose cohorts, we will also have -- I also talked about 45 patients in the natural history data set, which is a really expensive data set. And as you know, the FDA are really very appreciative in these rare diseases and having a very comprehensive, robust long-term natural history data set. Additional patients have been enrolled into that and we have more data forthcoming from that natural history data set towards the end of the year. Regardless, we're still going to be planning to go ahead and have our discussions with the regulators in the U.S., EU and Japan in the second half of this year. We will likely incorporate the higher cohort data set into those discussions. And from a regulatory perspective, the study checks a lot of boxes. We show dose response. We show halting of disease progression. We show long-term efficacy. 6 patients have been dosed for over 3 years. And we also show long-term safety and durability of effect. I'll stop there.

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

Maybe just 2 questions for me. I'm not sure if Dr. Gray is on the line, but can we talk a little bit about the conditioning regimen in the clinical trial? And I think it's our understanding there was an evolution of that conditioning regimen throughout the patient dosing. Give us some clarity on that. And then with regard to the natural history study referenced in the prepared comments, I think there was a comment with regard to differences in early onset versus late onset in terms of the rate of decline in MFM32. That seemed a little less obvious to us looking at this scatter plot. So can you kind of clarify from a natural history standpoint, whether there are any clinically relevant differences in rate of decline with regard to time of onset?

Thanks, Kevin. So Suyash, how about you take the question around natural history first and maybe some comments on the immunosuppression regimen? And then Steve is on the line. We're fortunate to have Steve on the line with us this morning. Steve, maybe you can give some thoughts from a historical perspective around the immunosuppression and how it informs the rest of the portfolio? Suyash? Well, Steve, when we get Suyash back, maybe you can talk about the immunosuppression regimen.

Sure. This is Steve Gray. So we have to think about the historical context here. When the clinical trial started in 2015, it was still not kind of standardized at that point to have a steroid regimen. This was being included in some clinical trials. It was just getting started with the SMA trial. So this clinical trial for GAN started also with a 30-day steroid regimen. But then as the trial evolved, we were trying to incorporate patients that would have a putative like no mutations where they wouldn't express any gigaxonin at all and where we would expect them to express -- mount an immune response against the transgene itself. So that approach was developed through looking at essentially transplant practices as well as nonhuman primate studies, and some of those were published by Ram Singh et al. that explored the use of rapamycin to kind of blunt immune responses against the transgene. So that kind of evolved where I think it might have been around the fifth patient or so that we altered an immune management strategy that incorporated rapamycin and tacrolimus. And then that's kind of evolved over time, where that's been tolerated well. And now all the patients in the trial get some course of rapamycin along with steroids that's eventually tapered off, but some of the kind of [ NOL ] patients that we'd still expect to mount an immune response against gigaxonin, then they're maintained on kind of low dose of rapamycin. So it's kind of the historical context. So it's -- the strategy behind this, this was all novel in the context of the GAN trial, any gene therapy trial, the immune management strategy that we did, but it was backed by nonhuman primate studies and also kind of standard of care around organ transplant.

So I believe we have Suyash years back on the line. His phone cut out. Suyash, Kevin asked a question around the natural history study, particularly pertaining to the data included in the natural history study around the 2 phenotypes, late onset and early onset and how that natural history progression is characterized.

Sure. Hopefully, you can hear me now. I apologize, I got cut off for a moment. Yes, there's 45 patients in the natural history study. The natural history study actually started in 2013. And the vast majority of patients, certainly early on, had the early-onset form of GAN, i.e., the more severely progressive, rapid form of the disease. As time has progressed, the study has also started to incorporate some of the patients with the later onset form of GAN, i.e., those patients who somewhat reflect the CMT type -- phenotype and have -- or mischaracterized often with a CMT type 2 phenotype. With regard to patients in the interventional trial, thus far, the vast majority of patients have been the early-onset form, and all patients have rolled over from the natural history study. And as times progress, the age cutoff for patients rolling over, the natural history study has dropped lower and lower. As RA has already made the point, the study actually started several years ago when our understanding of gene therapy was a little less than it is now. And so being more conservative, they initially dosed older patients and slowly becoming younger and younger.

Suyash, maybe you want to comment on how the immune suppression regimen that's been really pioneered here and again provide some significant read-through to our other development programs. Steve gave some nice historical context.

Great. Yes. So I think the immunology of gene therapy and various immunosuppression regimes have really evolved relatively rapidly in recent years. And I think that the approach that Carsten Bönnemann and Steve have pioneered at the NIH really is setting the scene. And essentially is what we're translating to the rest of our programs. A few years ago, people didn't use any immunosuppression, and they found this liver inflammation. They then started using short courses of steroids, which solved -- reactively to the liver inflammation. And then as time went on, they started using steroids prophylactically in short courses, and that's evolved to longer courses and an additional immunosuppressants. And I think you heard from Steve that, that evolution has happened also in the GAN trial. So initially, they started off with a short course of prophylactic prednisolone. As time progressed, that course of prednisolone got longer to the point where it's about 6 months. So 4 months at 1 milligram per kilogram with -- followed by tapering off over a couple of months. So the child is off by 6 months and then also years' worth of rapamycin or sirolimus. And that's the specific regimen that we'll be using in the rest of our programs. And I will say that none of the patients on that regime in the GAN trial have exhibited any of the T cell-mediated responses that we see in other gene therapy studies, most notably the elevation of the AST and the ALT that is often seen several weeks after dosing.

Our next question comes from the line of Gbolahan Amusa with Chardan.

Just wanted to tick the box on the potential for your ongoing trial to be a pivotal one. I know FDA has discussed in the past how early trials in a devastating disease when targeted by gene therapy could be potentially pivotal. So could you frame what you've shown so far or what you hope to show in terms of what the FDA has wanted to see for a pivotal trial? And I will follow up after.

Sounds good. Thanks, Gbola. So maybe I'll provide some comments and Suyash, please jump in. Really, I think we're quite excited about the data. We see the data as extraordinary. And as Suyash mentioned before, we see the data checking a lot of boxes from the FDA's perspective. The data here are statistically significant. They're long term, durable. We have dose response. We have a number of patients. The study has been going on for over 5 years. And so we're pretty fortunate to be in this position with a very robust data set. With that being said, obviously, we need to have a conversation with the agency as bullish as I am. But we're quite encouraged by the data today and the position that will go into those conversations. We really see the data kind of playing out in -- or the conversations playing out in 3 scenarios. The first being that the FDA says the data here are robust. We feel -- the drug here is well tolerated. We feel comfortable with you guys moving forward with the BLA, with some analytical comparability on the commercial-grade GMP material that would just go into the BLA. That would be scenario number one. The scenario number two would be, again, the FDA comes and says the data is robust, statistically significant. What we would do is we would like you guys to perform a little bit of clinical comparability, maybe 2 or 3 additional patients with the commercial-grade material that, again, would support the basis of a validation batch. And scenario 3 would be that the FDA says, we like the data, the data are supported, but we'd like for you guys to go and run a confirmatory study. And so we actually see that last scenario, although it's a real scenario, it's probably less likely, and we'll probably land somewhere between scenario 1 and scenario 2. But obviously, we need to have the conversation with the regulators. I'll stop there. Suyash, you want to give your thoughts?

Sure. Yes, thanks for the question. Yes, as RA has mentioned, there are so many great things about this data set that would be appreciated by regulators. Those responses demonstrated halting of disease progression is demonstrated. We have long-term durability, long-term safety, long-term efficacy. One of the things I didn't mention, but I think it's also important to consider is that the only endpoint I really shared was the MFM32, which looks at motor functioning. And it is a very well-validated scale. There is experience in its use across a whole host of neuromuscular measures. So that goes a long way also in the FDA's mind, especially when you contextualize it within this data set of 6 or 7 years' worth of natural history data that's been collected prospectively in this rare disease. But the other thing I will mention is that the NIH and Carsten, in particular, have done this really tremendous, comprehensive, robust study, and they've looked at a whole host of different endpoints. And as you know, the FDA likes to look at what they call the totality of data. So not only do we have really diligent, disciplined look at motor function, look at sensory function, there's a lot of neurophysiological assessments. There are imaging assessments. We're looking at CNS function. There's even biopsy assessments in this particular study also. So I think once we pull that data together, it's going to be a very, very compelling package for the FDA and certainly for the European regulators and Japanese regulators also.

Yes. The last point I just want to make, Gbola, is we feel very -- we feel strongly that the data is quite compelling, so much so that we're going to begin to accelerate the build-out of our commercial organization, obviously, which we mentioned before, to support patient identification, payer engagement as well as product distribution and really see this as a near-term commercial opportunity. So with that, I think you could kind of tell that we're quite bullish on the data. But we do need to have the conversation with the regulators because they're going to have the final say.

Okay. That's helpful. And then a final question on the 3.5e14 cohort, could you discuss a little bit more the ideal phenotype or genotype you hope to treat? And whether, in fact, you can recruit that kind of patient quickly?

Absolutely. Suyash, you want to take that? And Steve, maybe you want to get some additional thoughts, if you like?

Sure. I can start, and Steve and RA can jump in as well. The ideal patient, really, is not that different from the patients across the whole range of our programs in these neurodegenerative diseases. And that is we have to identify the patient early and treat early and treat at a younger age. Because I think that way you can preserve function. If you think about in this particular disease, you're missing this protein gigaxonin, which is part of the UPS, ubiquitin-proteosome system, which breaks down waste neurofilaments product, which are the structural elements of the axons and the neurons. So you get this buildup of these degraded neurofilaments proteins, such as vimentin, peripherin, alpha-internexin, et cetera. And that causes a disruption to the actual flow of electrochemical transmission along the axon. And this buildup occurs over time and the associated inflammation and tissue damage occurs over time. So the sooner you can start treating that before the accumulation has a chance to build up and damage occurs, the better. And I think you see that in the actual natural history data set in the slide we've presented earlier, where you actually see that the younger patient is the greater the MFM32 score is. And regardless of the age at which we start treating, you see in the virtual arrest of disease progression at the 1.8e14 dosing. Likely, that was the case for the 3.5e14 dose. So the earlier you treat the patient, the sooner you can treat them at a higher level of functioning and stabilize that and before the chance -- before the pathology had a chance to accumulate and cause damage. So what has actually been happening in the interventional trial is initial patients were dosed at an older age range, and now the age of range of the patients has been dropping lower and lower. And ideally, we would get to a point several years in the future where we're actually newborn screening for this particular disease and then treating shortly after birth. Let me [indiscernible] to Steve.

Maybe you want to make a point around read-through to our existing portfolio, particularly GM2, CLN1, where you have diseases where you have a buildup of substrate?

Absolutely. And I think this is a really important point, RA. We can -- part of the value of this program is that we can actually learned so much from it and applied to the rest of our portfolio. I've already talked about the buildup of neurofilaments in the axons in this particular disease. But that's no different pathophysiologically to what's happening in GM2 and CLN1 where in those 2 disorders, you lack a particular enzyme in the lysosome. And so a waste product accumulates within the lysosome of the cells, there is less on accumulation, destruction of the lysosome, destruction of the neuronal tissue. Sure, they're a little more rapid in progression than GAN, but the pathophysiology is essentially or the pathophysiological process is essentially the same. And I think that's why it's important to learn from GAN and help inform our GM2, CLN1 and other programs in the neurodegenerative franchise.

Great. And I'm sure your progress will inspire hope with families affected, so good luck.

Thanks, Gbola. We appreciate the question.

Our next question comes from the line of Matthew Harrison with Morgan Stanley. Sorry, Mr. Harrison has disconnected. Our next question comes from the line of Raju Prasad with William Blair.

Just one on manufacturing and the hurdles that are needed for the potential regulatory meeting you're going to have. Do you think that your issues are going to be more clinical related or commercial related with manufacturing? And any color you can give on the potential for treating the market potentially as early as 2023 would be helpful.

Thanks, Raj. We appreciate it. So the way that I think we're thinking about this is that we feel, again, strongly that the data is quite compelling. And that we're going to immediately start to begin to manufacture of commercial-grade GMP material to support basically a validation run. Ultimately, that would go into the BLA. We're fortunate with this program. Like our other programs, it uses a highly scalable, HEK293, triple plasmid transfection in suspension manufacturing process. So really a process very similar to kind of what we're doing for the rest of the portfolio. And the fact of the matter we're using -- we're also using AAV9. So when you think about this, this would also be a single plasmid change. It's really the payload from the rest of our portfolio. So I'll stop there. We were fortunate to have Dr. Fred Porter on the line, our Chief Technical Officer, and he can talk about our manufacturing strategy. But we actually see that as quite seamless. And then Suyash, maybe you want to comment on kind of a focus from a regulatory aspect as it pertains to manufacturing. Fred?

Yes. Thanks, RA, and thanks for the question. And as RA already mentioned, I think this falls very neatly into our current manufacturing strategy. What we do intend to do though is move as quickly as we can to bring this process forward to a pivotal manufacturing process to generate pivotal material and really minimize, where possible, any process changes to have a really seamless conversation with the agency. I think all of this begins today with kind of engaging with the NIH and looking at the data together. But as RA mentioned, I think we have a process that's scalable to support this patient population, and we'll be moving as quickly as we can to have those conversations as part of this next round of planning for pivotal manufacturing. So that's I think our thinking as I think we're really well positioned with that.

Yes. I'll just add another comment. And I think some of you may have been familiar with the guidance of the FDA produced draft guidance in January 2021, which relates with regards to human gene therapy for neurodegenerative disease. And we're really following this approach across our programs as well. The [ FC ] assay, you have to really develop your characterization assays very early on, gene therapy [indiscernible] should be designed to reduce [ inflammatory ] in immune responses and reduce the possibility of a latent. And we have to spend a lot of time and energy thinking about process-related impurities, such as host cell proteins and the residual host cell DNA and endotoxin and balance of full and empty [ consideration ]. So all this work is being done at a very robust level at Taysha already. We actually -- several of us works on groundbreaking events for our new manufacturing plant in North Carolina last week, in fact. And part of that will include a very significant space dedicated for CMT characterization, potency assay work and just generally, the R&D process development that relates to manufacturing that Fred and I spend a lot of time talking about. And for GAN specifically, obviously, one of the things we have to do is bring that in-house. But given that the potential of the product is made in a very similar way to the rest of our products is AAV9, it's HEK293, its suspension. I don't think there's going to be too much of a translation from that current product to how we see things ourselves at Taysha.

Suyash, maybe you want to comment on this notion around DRG inflammation and how this data, I think, really changes the narrative on that and how we'll use that in our discussions with the regulators. I think that's an important point.

It is an important point, and thanks for reminding me, RA. Yes, it's an interesting topic. For the past few months, there's a lot of debate in the gene therapy field about this notion of DRG toxicity. I mean I have never personally like to call it DRG toxicity. When you look at the data, it is some inflammation in the dorsal root ganglia, that's been detected on necropsy in some nonhuman primates that seems to be independent of a vector and independent of route of administration. That has had no functional impairment whatsoever. It also seems a bit unusual to me that for many neurological diseases, you actually do have, as part of that disease abnormal pathology and abnormal function of the dorsal root ganglia, which contain the sensory pathways for the whole body. And it always makes sense to me that you'd actually need to get vector into the DRGs in order to actually affect a positive clinical and functional and pathological change within the dorsal root ganglia themselves. But we've never really had data to show that until now. And as you'll recall from one of the slides I presented earlier on during this talk, we actually now have proof-of-concept animal data that shows in the knockout GAN mouse model, you actually show abnormal DRG appearance. You have inclusions, i.e., aggregates of these neurofilaments, the dorsal root ganglia that is associated with inflammation. And after treatment with the gene therapy vector, you actually see a nice reduction in those inclusions and the reduction in inflammation. And I'm hoping this will change the way people think about DRG inflammation in that for many of the diseases that are neurological in nature, you actually have to get vector into the DRG and actually have to affect some change there.

And sorry if I have a follow-up. On the vagus nerve simulation redosing, can you just maybe discuss how that might help guide how you dose across the platform? And obviously, the intrathecal dosing in GAN is derisking across the rest of the platform, but maybe just discuss a little bit about the redosing aspect of it, that would be great.

Suyash, do you want to take that? And obviously, Steve is a pioneer in this space. And Steve, maybe you have some additional comments.

Sure. I'll jump in with a couple of comments. And then I mean, Steve's been pioneering this for years, he can add some more color. So I think the vagal nerve dosing is really important for 2 reasons. And practically speaking, the vagus nerve is the tenth cranial nerve. It exits the cervical spine and then passes kind of in the shoulder area, splits into 2. One goes kind of down the center of the body through to the heart, the other one goes around the side -- sorry, the one around the side gets to the heart, the one through the center goes to the lungs and throughout the rest of the body. And essentially, it helps manage the autonomic nervous system. And this is the part of the body -- that is part of the nervous system of the controls automatic functions, i.e. you don't need to be conscious for these functions to keep working, i.e., it controls heart rate, it controls blood pressure control, it controls gastrointestinal motility, it controls breathing. And so there's 2 real values to vagus nerve dosing. You can use it to actually ameliorate signs and symptoms of the autonomic nervous system. But you can also use it to redose the patient because that vagal nerve space is considerably immunoprivileged. Now what we've shown in the animal data, we show both of those things in the animal data. And we show that -- I'm saying we -- what I mean, Steve and his team have shown that you can improve autonomic nervous system features by direct injection of the vagus nerve. And you've also -- he can also show that you could dose the patient intrathecally and then some period of time later, you will also be able to dose a patient into the vagus nerve in addition to that. We're in the process of continuing the preclinical work for both those things. But if you look forward to the future, what you might anticipate, therefore, is some form of vagal nerve dosing can do 2 things. First of all, help ameliorate signs and symptoms of autonomic nervous system dysfunction, so the blood pressure control issues, the gastrointestinal issues that patients with GAN have, but not just patients with GAN, but the autonomic nervous system is very compromised in many different diseases. Rett syndrome, for example, is another one where patients would complain and -- about very severe gastrointestinal issues and issues with breathing abnormality, in particular, respiratory rhythm dysfunction. So that's one thing to think about potentially might happen at some point in the future, clinically. And the other is, of course, you might also be able to redose patients into the vagus nerve. Now for neurological indications such as ours, we actually don't think durability is too much of an issue because once you transduce a brain cell, it actually stays transduced for just quite some time. But it could be the case that over time, over some years, durability wanes a bit and certainly for other indications, and it may well be beneficial to be able to give a second dose of AAV9 gene therapy into the vagus nerve directly. Let me stop there and see if Steve has any additional color he would like to add?

Yes. No, I think we were interested in the redosing strategy because the intrathecal trials are going first, but we could see to comprehensively try to treat the autonomic nervous system. There may be an additional route like the vagus nerve that might be needed. So we tested the concept in rats and Suyash presented that data that we were able to successfully do the intrathecal injection in rats, wait over 3 months and then essentially redose via the vagus nerve and that approach worked. So this could be something where it's sequential, where we're going back to patients that have gotten intrathecal injections for GAN or perhaps for other diseases to treat some of these autonomic issues that may creep up later on or it could be something that we modeled this in rats about just doing a combination injection approach to treat the -- [indiscernible] the CNS through the intrathecal injection and then more comprehensively treat the autonomic nervous system through a vagal injection.

[Operator Instructions] Ladies and gentlemen, this concludes our question-and-answer session. I'll turn the floor back to Mr. Session for any final remarks.

Thank you, operator, and thank you again for joining us on the call today. We appreciate your continued interest and support in Taysha and look forward to reporting on the progress of our GAN program and other research developments at our upcoming R&D Day in June and throughout the rest of the year. We appreciate your support. Thank you, and have a good day.

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