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

Good morning. Welcome to Taysha Gene Therapies GM2 Gangliosidosis Program Update Conference Call and Webcast. [Operator Instructions] As a reminder, this webcast is being recorded today, January 27, 2022. I'll 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 GM2 Gangliosidosis Program Update Conference Call and Webcast. Earlier this morning, Taysha issued a press release reporting preliminary clinical safety and Hex A enzyme activity data for TSHA-101 and GM2 gangliosidosis. A copy of this press release is available on the company's website and through our SEC filings. On this call, we will review the reported data and discuss next steps for our clinical development program. 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 Research and Development. We will hold a question-and-answer session following our prepared remarks where Kamran Alam, our Chief Financial Officer; and Dr. Fred Porter, our Chief Technical Officer, will join as well. Please note that on today's call, we will be making forward-looking statements, including statements relating to the existing clinical data and the therapeutic and commercial potential of the GM2 gangliosidosis and our investigational product candidates. These statements may include the expected timing and results of clinical trials for our product candidates and the regulatory status and market opportunities for this program. This call may also contain forward-looking statements relating to Taysha's growth and future operating results, discovering development of product candidates, strategic alliances and intellectual property as well as matters that are not of historical facts or information. Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements. These risks include uncertainties related to the timing and results of clinical trials and preclinical studies of our product candidates, are dependent 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 protect our research and development activities. For a list and a description of the risks and uncertainties that we face, please see the reports we have filed with the Securities and Exchange Commission. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, January 27, 2022. 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. I would now like to turn the call over to our President, CEO and Founder, RA Session, II. RA?

Thank you, Kim, and thank you, everyone, for joining us on the call this morning. We are very excited to share with you an important first for the field of gene therapy. Next slide. To date, we will review positive initial biomarker data for TSHA-101, the first bicistronic gene therapy in clinical development. TSHA-101 is designed to deliver 2 genes within a single vector for the treatment of both Tay-Sachs and Sandhoff disease, 2 forms of GM2 gangliosidosis. Currently, there are no approved treatments for this severe and devastating neurodegenerative lysosomal storage disease. I will start off by giving a brief introduction and overall summary of the program. Suyash Prasad, our Chief Medical Officer and Head of R&D, will then provide a disease overview and review natural history data before discussing the TSHA-101 program and the initial biomarker data for the first 2 patients eligible for analysis at the time of evaluation. Afterwards, I will review upcoming milestones before opening the call for questions. GM2 gangliosidosis is a challenging disease to address because it requires restoration of an enzyme that is comprised of 2 subunits expressed by different genes. The clinical data that Suyash will present shortly are supportive of the first-ever bicistronic vector approach in humans. Next slide. Suyash will elaborate on these points in greater detail, but as an overview, TSHA-101 was well tolerated with no significant drug-related events. Importantly, the biomarker data demonstrated a restoration and normalization of serum Hex A enzyme activity by month 1. Today we are presenting Hex A enzyme activity data for 2 patients who were eligible for the month 1 analysis. Patient 1, who had Sandhoff disease, achieved Hex A enzyme activity of 190% of normal at month 1 and 288% of normal at month 3. This represents 38-fold and 58-fold above the 5% enzyme activity level of asymptomatic patients identified by natural history. Patient 2, who had Tay-Sachs disease, achieved Hex A enzyme activity of 25% of normal at month 1. This represents fivefold above the 5% enzyme activity level of asymptomatic patients identified by natural history. Patient 3 has been dosed but have not yet reached the 1-month time point. Lastly, we have data that confirms the restoration of the metabolic pathway of converting GM2 to GM3 ganglioside and provide evidence of functional Hex A enzyme activity. With that, I will now turn the call over to Suyash to provide a disease overview and an update on our GM2 gangliosidosis clinical program. Suyash?

Thank you, RA, and good morning, everyone. First, let's start with a brief overview of GM2 gangliosidosis, which is a rare and devastating lysosomal storage disorder that is part of a family of neurodegenerative genetic diseases that included the Sandhoff disease and the Tay-Sachs disease. GM2 gangliosidosis is caused by defects in the HEXA or HEXB genes that's encoded to subunits, the alpha-subunit and the beta-subunit of the beta-hexosaminidase A or Hex A enzyme. These genetic defects result in progressive dysfunction and degeneration of the central nervous system. Mutates of the HEXA gene, the alpha-subunit causes Tay-Sachs disease, while mutation of the HEXB gene, the beta-subunit causes Sandhoff disease. The severity of the disease is dependent on the amount of residual Hex A enzyme activity. There were no approved therapies for the treatment of the disease, and current treatment is limited to supportive care. The estimated prevalence of GM2 gangliosidosis is about 500 total patients in the United States and European Union. Next slide, please. It's important to note there are 2 forms of GM2 gangliosidosis. Both forms the disease cause progressive deterioration of nerve cells, are generally clinically indistinguishable and ultimately fatal. Sandhoff disease is a rare inherited lipid storage disorder and caused by mutation in the HEXB gene, which codes to the beta-subunit of beta-hexosaminidase A. It is described as being a little more rapidly progressive than Tay-Sachs with death occurring by 3 years of age. Tay-Sachs disease results from a deficiency in the alpha-subunit of beta-hexosaminidase A caused by mutation of the HEXA gene. This typically leads to death in children around the age of 4. Next slide. We are fortunate to have survival data from natural history studies that help inform us of the devastating nature of the disease. This diagram illustrates a rapid clinical progression and fatal nature of the disease. Disease onset during infancy leads to aggressive neurodegeneration with about 50% mortality by 3.5 years of age and about 75% mortality by 5 years of age. On the left, you can see the clinical progression starting as early as 5 months of age with rapid deterioration between 10 and 20 months of age. Next slide, please. The clinical phenotype for GM2 gangliosidosis is well characterized, and natural history data has demonstrated that beta-hexosaminidase A enzyme activity in the serum correlates with the spectrum of disease severity. The infantile form of the disease, which is the most common, has an onset of symptoms around 5 months of age with residual Hex A enzyme activity of less than 0.1% and a life expectancy of around 3 to 4 years. Juvenile onset occurs between 2 and 6 years of age with about 0.5% of normal Hex A activity and the life expectancy between 10 and 15 years. The other form of this disease occurs in patients 18 years and older, has a residual Hex A enzyme activity between 2% and 4% and a relatively normal life span. Asymptomatic is characterized by 5% to 10% of normal Hex A activity and a life expectancy similar to disease-free life. Lastly, there are parents who are carriers who have 50% of normal Hex A activity and have a normal life span. A small increase in enzyme activity can improve clinical phenotype significantly. Based on these findings, 5% or above in beta-hexosaminidase A enzyme activity in the serum correlates with asymptomatic patients with GM2 based on natural history. Next slide. Now we considered how beta-hexosaminidase A activity is measured. Assay development of progressive sciences is known to often vary from lab to lab. And while assays for GM2 gangliosidosis are standard, given that the reason the assay was initially developed was for the diagnosis of the disease, the assays are typically more reliable at the lower ends of enzyme function. My Taysha colleagues in our translational lab in partnership with highly regarded vendor partners developed our own GM2 enzymatic assays to ascertain enzymatic function robustly, completely and accurately. Indeed, given the subtle variations from lab to lab, we also developed normal values for the assays in question by using human serum from healthy subjects. This enabled us to characterize a normal range of beta-hexosaminidase A activity, which served as a benchmark for the patient information. More specifically, we obtained 120 samples of normal serum and measured the enzymatic activity of beta-hexosaminidase A, both at the top contract lab partners and at Taysha's own internal translational laboratory. We were therefore able to rigorously develop normative levels of beta-hexosaminidase A alpha-subunit enzyme activity. In the data to be reviewed shortly, we will compare the beta-hexosaminidase A activity of patients treated with TSHA-101 to normal subjects and also to published natural history data. Next slide. Now that we have reviewed the physiological context of the disease, we will discuss the design of TSHA-101 and our treatment approach. Historically, gene replacement strategies for GM2 gangliosidosis have been somewhat challenging since 2 genes, one encoded in the alpha-subunit HEXA and one encoded in the beta-subunit HEXB are required to produce functional heterodimeric beta-hexosaminidase A enzyme. TSHA-101 is the first bicistronic gene therapy in clinical development, with clinical data supporting this approach in humans. In simple terms, bicistronic means 2 genes within 1 capsid. The novel bicistronic vector design enables consistent expression of the alpha-subunit, HEXA, and beta-subunit, HEXB, under the control of a single promoter with a P2A-self-cleaving linker. Because both the gene coding for the alpha-subunit and the gene coding for the beta-subunit are driven by the same promoter, this allows for production to the alpha and beta-subunit in the endogenous 1:1 ratio within each cell, which affords the most efficient way of producing functional, heterodimeric beta-hexosaminidase A. This is an important first for the field of gene therapy. Next slide. TSHA-101 is currently being evaluated in an open-label Phase I/II adaptive trial for the treatment of infants with GM2 gangliosidosis sponsored by Queens University and led by Chief Scientific Adviser, Dr. Jagdeep Walia, from the Division of Medical Genetics and Department of Pediatrics in Canada and principal investigator Dr. Anupam Sehgal, Assistant Professor of Pediatrics and Pediatric Intensivist at Queens University. The target recruitment for the trial is 4 subjects with GM2 gangliosidosis, including patients with either Sandhoff or Tay-Sachs disease while 15 months of age or younger at the time of enrollment. We have dosed 3 patients to date with the fourth patient currently in prescreening. Interestingly, we were able to identify over 40 GM2 patients who are unfortunately unable to enroll in the study, either because there was no engaged cutoff at screening or were older than the 15 months age limit. Thus, it appears that there are significant numbers of patients out there in the community and who would be potentially suitable for the gene therapy approach. The primary endpoint for the trial is safety, including both clinical and laboratory assessments. The secondary endpoints evaluate efficacy, including pathologic, physiologic, functional and clinical markers. Patients are dosed intrathecal at a dose of 5 x 10 to the 14th total vg. As we have discussed before, we use an immunosuppression regime of prednisolone and sirolimus. There's an independent data safety monitoring board, or DSMB, that is providing oversight for safety matters on the conduct of the study. Next slide. The key inclusion criteria include an age requirement of 15 months of age or younger at the time of dosing. All patients need to have disease confirmation by both biochemical confirmation of reduced serum beta-hexosaminidase A activity as well as molecular confirmation of the infantile form of the disease. Next slide. The data we are presenting today include the Sandhoff patient from whom we have the month 1 and month 3 analysis and the Tay-Sachs patient from whom we have the month 1 analysis. Patient 3 has recently been dosed and has no available biomarker data available yet. Patient 1 was a male with Sandhoff disease carrying a homozygous mutation in HEXB who experienced symptom onset at 6 months of age and was 13 months old at the time of consent. Clinical features at onset for patient 1 included regression of milestones, visual problems, loss of motor skills and hearing loss. Patient 1 was commenced on our standard immunosuppressive regime of prednisolone as a general anti-inflammatory immunosuppressive agent and sirolimus also known as rapamycin as a T-cell modulator. In addition to this severe developmental delay, past medical history for patient 1 include the hearing loss and visual deficits. Patient 2 is a female patient with Tay-Sachs disease harboring a proband biallelic mutation for HEXA. Patient 2 was 12 months old at disease onset and 13 months old at the time of consent. Clinical features at onset for patient 2 included failing to acquire developmental milestones at an appropriate rate and the regression of milestones already acquired, fine motor problems, seizures, loss of motor skills and hearing loss. Patient 2 has also commenced on our standard immunosuppressive regime of prednisolone and sirolimus. Past medical history for patient 2 includes hearing loss and dysphagia. Next slide. Now as I discuss the data, I'll refer to the beta-hexosaminidase A by standard abbreviation of Hex A, not to confuse it with the HEXA gene, which caused -- codes for the alpha-subunit. There, patient 1 serum Hex A enzyme activity results. Normal Hex A enzyme activity is denoted by the dotted black line at 100% Hex A enzyme activity. Patient 1 achieved Hex A enzyme activity of 190% of normal at month 1 and 288% of normal at month 3. Recall that 5% of Hex A enzyme activity correlates with asystematic patients with GM2 based on natural history. When we compare the patient's Hex A enzyme activity to the 5% activity level, which is deemed to be asymptomatic from a natural history and which is denoted by the lower dotted horizontal black line in the graph, we see his Hex A enzyme activity was 38-fold above this presumed asymptomatic level at month 1 and 58-fold above the 5% asymptomatic level at month 3. So very significant increases. Next slide. In addition to presenting data by percent change, I wanted to share the absolute enzyme activity values also. To orient you, we have plotted the absolute value for the 5% normal Hex A enzyme activity of asymptomatic patients identified by natural history, which is 0.4 nanomoles per hour per mL. The graph shows patient 1's absolute levels of enzyme activity in serum at 1 and 3 months. As you can see, the absolute value at 1 month is 15.2 nanomoles per hour per mL, and the absolute value at 3 months is 23.0 nanomoles per hour per mL, which is within and above normal range. Next slide. Here is the serum Hex A enzyme activity for patient 2 with Tay-Sachs disease. As a reminder, patient 2 is only eligible for the 1-month analysis at the time of evaluation. Patient 2 achieved Hex A enzyme activity of 25% of normal, representing fivefold above the presumed asymptomatic level of 5% at month 1, also a significant increase. Next slide. Again, here are patient 2's absolute values of enzyme activity from the lab compared to the presumed asymptomatic level per natural history. You can see that patient 2's Hex A enzyme activity of 2.0 nanomole per hour per mL is fivefold above the presumed asymptomatic level at month 1. Next slide. Let me orientate you here. There are 3 parts to this graph. The graph represents the serum beta-hexosaminidase A activity as a percentage of normal levels of activity with data from patients treated with TSHA-101 on the left, published data for patients treated with another gene therapy approach, AXO-AAV-GM2 in the middle, and natural history data on the right. We were pleased to see TSHA-101 restore serum beta-hexosaminidase A's activity to levels around and above the normal range, surpassing the levels achieved for the AXO-AAV-GM2 compassionate use data as well as the levels observed in natural history patients. Following treatment with TSHA-101, patient 1 in blue achieved 190% of normal levels at month 1 and 288% of normal levels at month 3, while patient 2 in orange achieved 25% of normal levels at month 1. To reiterate, 3-month data for patient 2 was not available at the time of data analysis. AXO-AAV-GM2 is another clinical stage investigational gene therapy for Tay-Sachs and Sandhoff diseases that use a different approach by delivering 2 vectors encoding the HEXA and HEXB genes separately. Data from our compassionate use trial that was shared at the end of 2019 demonstrated that after 1 month, despite showing an increase in comparison to the patient's baseline values, both patients were below 0.5% of normal HEXA levels. After 3 months, there was incremental improvement, with patient 2 reaching 0.5% of normal. The 0.5% of normal HEXA activity achieved with this approach is considered to be disease modifying and comparable to the levels of enzymatic activity of patients with the juvenile form of GM2 gangliosidosis, which typically has a disease onset of 2 to 6 years and a shorter lifespan. TSHA-101 surpasses the enzymatic levels of adult patients with GM2 gangliosidosis who have disease onset of 18 years or older and have a normal life span and achieve levels around the normal range at about 4 weeks and 12 weeks. The ability of TSHA-101 to restore serum beta-hexosaminidase A activity around a normal range, coupled with a favorable safety profile, is highly encouraging and supports the ability of TSHA-101 to make a meaningful difference in the life of these patients. Next slide. Aside from beta-hexosaminidase A enzyme activity, we sought to identify additional ways to demonstrate recapitulation of a functional enzyme. Taking a step back, let's examine the overall enzymatic pathway. Under normal conditions, GM1 ganglioside is converted to GM2 ganglioside by GM1 beta galactosidase. And then subsequently, GM2 ganglioside is converted to GM3 ganglioside by beta-hexosaminidase A. GM2 gangliosidosis is a result of a lack of the beta-hexosaminidase A enzyme, resulting in a significantly elevated level of GM2 ganglioside substrate and a reduced level of GM3 ganglioside substrate. Restoration of the functional beta-hexosaminidase A enzyme should result in a decrease in GM2 ganglioside substrate over time and an increase in GM3 ganglioside substrate with eventual equalization of both at a relatively low level. Next slide. Another way to look at whether the enzyme is functionally doing what it should be doing, i.e., act on GM2 ganglioside and converting it to GM3 ganglioside is to examine what the GM3 ganglioside level's increase in patients following treatment with TSHA-101. In effective patients, GM3 levels remain consistent at a very low level over time due to the blockage in the metabolic pathway. Substrate levels in patient 1 with Sandhoff disease demonstrates the greater rate of increase in GM3 ganglioside versus GM2 ganglioside in the cerebral spinal fluid, or CSF, suggesting restoration of metabolic pathway and Hex A enzyme function. Within 1 month, GM3 ganglioside increased 50% over baseline, suggesting conversion of GM2 to GM3 ganglioside and initial restoration of functional enzymatic pathway. Further normalization is expected to continue over time, and we will continue to monitor substrate levels and anticipate sharing additional GM3 and GM2 ganglioside substrate data by year-end. Next slide. Preliminary data suggests that TSHA-101 was well tolerated with no significant drug-related events. Pretreatment AST elevations were observed in both subjects, a finding that is common in GM2 gangliosidosis with mild to moderate elevations that were asymptomatic, which are also noted after gene transfer. Lastly, there were no related serious adverse events. Next slide. The data that we have discussed thus far are positive and hopeful for the Tay-Sachs and Sandhoff community. However, they have to be tempered by some sad news. The fact that patient 1 died recently of a nondrug-related adverse event as assessed by the PI. If we look at patient 1's journey following treatment in September, Patient 1 demonstrated encouraging Hex A activity that was 190% of normal at month 1 in October and 288% of normal at month 3 in December. Following clinical examination, patient 1 was displaying preliminary signs of clinical improvement, was deemed stable to return home in early December. Shortly after arriving home, patient 1 was exposed to an upper respiratory tract infection from a family member, possibly COVID-19, was hospitalized with a chest infection that rapidly progressed to pneumonia. While in the hospital, patient 1 contracted hospital-acquired Methicillin-resistant Staphylococcus aureus, or MRSA. Patient 1 succumbed to pneumonia and the pulmonary effusion with a secondary MRSA infection on Friday, January 14, 2022. The principal investigator made the initial assessment that death was unrelated to study drug. Final determination from the DSMB is anticipated in the near term. Our hearts go out the child and their family. To conclude, I will hand the call back to RA.

Thank you, Suyash. Patient 1 is a pioneer, and his legacy will live on in the many children with Sandhoff and Tay-Sachs disease who will be treated with TSHA-101. Next slide. Collectively, these data validate the novelty of the bicistronic vector design of TSHA-101. The therapy has demonstrated the ability to deliver 2 genes within a single vector to treat both Sandhoff and Tay-Sachs disease while restoring and normalizing Hex A enzyme activity. We believe TSHA-101 has the potential to make a meaningful difference for patients living with GM2 gangliosidosis. Next slide. We plan to submit a protocol amendment to expand target enrollment from 4 patients up to 15 and look forward to sharing additional clinical safety and efficacy data by the end of the year. Next slide. We have a busy year ahead of us. This month, we intend to provide clinical data from the high-dose cohort for TSHA-120 in giant axonal neuropathy, along with long-term safety and durability data, from an analysis of all 3 therapeutic doses. In February, preliminary clinical safety and efficacy data for our CLN7 program will be presented at WORLDSymposium. Also, in the first half of this year, we plan to share biomarker data for TSHA-118, in CLN1 disease and by year-end preliminary clinical data for Rett syndrome and SLC13A5 deficiency. Next slide. Lastly, we would like to thank the patients, families and caregivers for their participation in our clinical study. We'd also like to thank our partners at Queens University and UT Southwestern for their collaboration and dedication. Finally, we'd like to thank our advocacy partners for their continued support. 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 Debjit Chattopadhyay with Guggenheim Securities.

This is Robert on for Debjit. First of all, congrats on the excellent preliminary data. One question from us today, and we'll keep it to one. Are there any plans to amend the immunosuppression going forward? And can you provide any color around the duration of the immunosuppression that these patients are receiving? Once again, congrats.

Thanks, Robert. What I'll do is I'll turn that question over to Suyash to address, but we appreciate the kind remarks. Suyash?

Yes. Thanks, RA, and thanks, Robert, for the question. So the current immunosuppression regime is one that we've used and has been modeled from our GAN program, actually you may be aware 14 patients have been dosed there, and we've used this regime very, very successfully. It comprises of 6 months of prednisolone and 1 year of sirolimus or rapamycin. The 6-month of prednisolone at 4 months at 1 milligram per kilogram, and then you taper down over the next 2 months, so the child is off steroid by the 6-month time point. And the 1 year of rapamycin, you give 9 months reaching a target serum level of between 10 and 15 nanograms per mL, and then you tail that off over the next 3 months. So the child is off by the -- off all the immunosuppression by the 1-year time point. That's the current regime. And the -- conceptually, immunosuppression regimes are different from program to program. And part of the reason they're different is because nobody knows exactly what the right approach is and what the right combination of drugs or the right duration is. So there's always a lot of judgment used here. I think what you may be alluding to is that with the patient that passed away, because it's due to an infection, does the immunosuppression regime contribute to that? And it's possible that, that was the case. You heard that the serious adverse event, the death was deemed unrelated to study drug, but there could have been a contribution by the immunosuppression regime. So that is something that we are monitoring, we are talking about with the DSMB and our immunology advisers. It's possible that we may reduce the duration or we may reduce the dose a little bit, but not too much. And it's also possible we'll bring in a bit more flexibility and use PI discretion with regards specifically to the immunosuppression regime that's used. What we will continue doing is, of course, just monitoring the patient and monitoring appropriate immuno-function parameters on an ongoing basis, for example, specific liver function tests. I'll stop there, Robert.

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

I guess maybe just one question with respect to patient 1. Any thoughts on the magnitude of expression observed? I think there is a pretty distinct difference between the patients. And I believe in prior commentary, you've indicated a small amount of therapy can go a long way. So I guess are there any challenges associated with the super physiological expression here? And just related to that, have you had the opportunity prior to the patients passing? Were there any assessments done to evaluate endpoints such as hearing impact, quality of life?

Laura, so maybe I'll start with a few comments, and I'll turn it over to Suyash. I want to be clear that the range of Hex A enzyme activity ranges from a lower limit of normal up to a higher limit of normal. And what we use to calculate our percentages were at the lower limit of normal. So the patient 1 was actually within that range of normal, of lower limit to higher limit, right? So they weren't yet over that higher limit, so they were not deemed super physiological levels. So I just wanted to be clear with that. Our measurement was at the lower limit of normal. Suyash, maybe you want to address the other parts of Laura's question.

Sure. Yes. Thank you. All right. Yes. So I think RA is quite right, we calculated our norms on a series of 120 normal samples, and we have some very good, robust data there. And it's certainly -- if you look at the numbers for patient 1, we talk about 58-fold above the presumed asymptomatic level, that is 58-fold over the 5% level that we assume is going to be asymptomatic, but it's actually at the top end of the normal range. And from our toxicology studies, we've been able to dramatically over express enzyme far, far more than that without any adverse consequences. So one of the useful things about GM2 as a disease, and then perhaps -- this is generally true for the lysosomal storage disorders. You have a very, very wide therapeutic window. So a small amount of enzyme goes a long way, which is why we think that -- and from a [indiscernible] only 5% levels will likely give you a normal phenotype, but also dramatically over expressing shouldn't cause any toxicity. And that was true from what we saw in the -- in our toxicology studies and also true in what we've seen in the patients thus far. With regard to clinical response, we're not -- we haven't officially -- we're not planning to share clinical data from an efficacy perspective on this call. We'll plan to do that towards the end of the year. What I will say, though, is that the patient's -- safety profile of patients as they relate to the drug, of course, was very promising, was very favorable. And the first patient dosed, we had the opportunity to observe from the principle of -- had the opportunity to observe them over 3 months. And the suggestion was that anecdotally, the patient was showing some signs of improvement. But as I said, we have not assessed the endpoints for dissemination at today's event. We will be doing that in a subsequent call towards the end of the year.

Our next question comes from the line of Joon Lee with Truist Securities.

Patient 2's Sirolimus dose was reduced compared to that of patient 1. What was the reason behind that? And he was also on Topiramate. Did the patient have seizure disorder? And is that an independent risk factor for respiratory disease, maybe an increased risk of aspiration? And finally, did you guys do microbiology on the patient and the contact relatives? And were there any similar -- common strains identified?

Thanks, Joon. Suyash, do you want to address?

Sure. So I think there were 3 questions in the midst of that. So the -- just the second question first, the one about topiramate. You're right about patient 2 being on topiramate, which is an antiepileptic drug. And this child, as part of the normal disease process, had started to have seizures. Your specific question as it relates to aspiration is, yes. All these children -- al children with Tay-Sachs and Sandhoff, at some point during the course of their natural history will develop aspiration or a risk of aspiration. And as that point, usually, what happens is we insert a nasogastric tube through the nose into the stomach or you put a tube in -- directly into the stomach and feed the baby that way. That's actually an exclusion criteria for the study. So Patient 2 was deemed -- although having seizures, not a great risk of aspiration, because if he have been, we wouldn't have included him in the study because that -- when a baby starts aspirating, that's really quite a high risk for some kind of respiratory adverse event. Now on to your third question about the particular patient that died due to the respiratory infection, just following on the -- following your question on aspiration, it is possible this baby aspirated as well as part of the disease process, as a part of the process leading up to his death. But what was clear from the serology testing was that there was a clinical exposure to somebody with -- a family member with some kind of respiratory pathogen. Once again, it could be COVID. We're not sure about that. There was a COVID test that was negative. But with the Omicron variant, there's a lot of negative COVID tests out there that actually ultimately turn out to be positive. So clearly, some viral respiratory pathogen exposure. Because the child had poor reserve, the child deteriorated quite quickly into a pneumonia and then developed pleural effusion, which is where your -- one side of your lung fills up with fluid and then became colonized sadly with a hospital-acquired infection. And once you get colonized with MRSA, it's a very, very difficult bacteria to get rid of. And at that point, we knew that the situation with the child was dire. I was in contact with the physicians managing the patient and the principal investigator since really -- it was around about Christmas Day. And when the MRSA colonization had occurred, we knew that this was not a good situation whatsoever. And the MRSA was absolutely well proven on -- biochemically. So Joon, I answered the topiramate question and the bacteria question. You had 1 question right at the beginning about Sandhoff specifically. Is that right?

So the sirolimus dose was reduced for the second patient.

Yes, yes. Yes. So the sirolimus dose -- yes, so it's interesting. For Prednisolone, we dosed specifically on milligrams per kilogram. So the actual dose you give is dependent on the patient's weight. And we give 1 milligram per kilogram as a standard monitor LFTs appropriately. Sirolimus is dosed differently. The reason it's dosed differently is because it's a renally excreted drug and different individuals have different degrees of renal function. And so the way you titrate sirolimus dosing is based on serum levels of sirolimus. So you actually measure the levels of sirolimus, and you titrate the dose based on the level. So our target level is between 10 and 15 nanograms per mL. And so the reason that the second patient had a lower dose is because he is needing much less sirolimus to maintain the same serum level. So both babies will have received the same immunosuppression. It's just that patient 2 needed less sirolimus to actually get into that serum level of sirolimus to give that to the immunosuppression.

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

Just one from us. Is there any hypothesis on the variation in activity seen between the 2 patients about a twofold difference in absolute levels? Is this kind of what you would expect in this kind of study?

Thanks, Gil. Suyash, I'll turn the question over to you, and I may give some comment afterwards.

Sure. Yes. I don't think twofold difference is that different. And I think what I would say is that what we actually found with our -- when we actually run the normals is that we found a wider variation of normal than we were expecting. And we've talked previously about this is an enzyme, which has a very wide therapeutic window. You don't need much to be clinically normal. And if you over express dramatically, it probably won't have any adverse effects. And this was actually reflected in the series of 120 normals that we did, both in our own lab and actually in our contract vendor partner as well. So we actually ran the assay twice. And we found that all [indiscernible] nicely, and we found it was a very wide normal distribution. So I don't think it's that unexpected that even in the degree of response to the gene therapy, you're going to get a relatively wide distribution. What I will say, though, is it's only a small number of patients and a small number of data points. So I think as time progresses, we will see -- we'll just be able to understand and appreciate the data a bit better. But I'm not that surprised that we're seeing this degree of -- that degree of difference. Regardless, you're well within the range of what would be -- well within the range of what would give you a normal asymptomatic individual, and you're very much above baseline levels in both patients.

Yes. The only thing that I would add to Suyash's comments are I think this is something that we've seen in other lysosomal storage disorders that have reported data recently where you could kind of get this variation between patient to patient. I think what's most important to us is that both patients were well above the presumed asymptomatic level of 5% where patient 1 was actually at the normal level, which we were quite excited about and hopeful for. And then even at the 1-month time point, Patient 2 was 25% of normal. And what we would hope is that we see a similar increase in Hex A enzyme activity at the 3-month time point, ultimately approaching that normal level. So for us, from a biomarker perspective, we were quite encouraged by what we were seeing.

Our next question comes from the line of Eun Yang with Jefferies.

So the enzyme activity that you've seen, how long do you think it's going to be sustained?

Very good question, Eun. Suyash, do you want to address, and I'm happy to add some comments after the fact.

Yes. I think we're going to see -- I mean it's a good question. The reason I'm smiling is that in some respects, the question is how long is a piece of string? From what we've seen in our preclinical data, we've seen a very long-lasting expression. We run a chronic mouse safety and efficacy study that's seen expression out to over a year. And in principle, what we're transducing here is brain tissue. We give the drug intrathecally. We expect the brain and the spinal cord to be transfused. So once the brain cells are transduced, they should stay transduced producing enzyme in perpetuity, i.e., for the longer term because there's no turnover of brain cells the way there is turnover, for example, of liver tissues. So we don't anticipate seeing any decline at all. Now if there's some kind of immunological consequence or, infective consequence, maybe you'd see a drop off in durability, but we don't anticipate seeing that with this particular disease. And I'd probably draw a parallel to our giant axonal neuropathy program where, once again, we give the drug intrathecally. We cover the same immunosuppression regime. And we've seen patients out 5 or 6 years on the giant axonal neuropathy program, still demonstrating very clear functional benefit. So to answer your question, my guess is this is going to be long-lasting persistent protein production from long-lasting persistent gene expression.

Our next question comes from the line of Salveen Richter with Goldman Sachs.

Congratulations on the data. Could you maybe speak to the read-through here to the rest of your pipeline from this program? And secondly, are there any changes being implemented on the core to this program, in particular? And are you at commercial-grade manufacturing? I'm just trying to understand whether or not this could serve as a pivotal registrational program and how ready you are in that context.

Thanks, Salveen, for the question. Maybe I'll take the last question first, and then I'll turn it over to Suyash. Your question around are we at commercial-grade material? Yes, we are. This product that we're dosing would be the product that we would be moving forward to registration with. So we're quite excited about that. And that's kind of consistent with our portfolio, the ability to be able to start initially with commercial-grade material. So we're pretty excited about that. And so for your other questions, I'll turn it over to Suyash to address.

That's all right. And thanks, Salveen. So the -- with regards to -- you asked a bit about readthrough for the programs and changes to the current program. With regard to changes to the current program, the main change we're going to do is actually just increase the number of patients in the study. The original protocol is designed for 4 to 6 patients. We've now dosed 3 patients, and we have additional patients in prescreening. As you heard me say on the call, we actually identified many, many patients. We have over 40 patients, many of whom were not eligible simply because they were too old for our cutoff, which was 15 months. So the first one is increase the number of patients likely to 12 to 15. The second thing we'll do, not yet, but at some point, perhaps during the course of the year, we may actually increase the age of inclusion into the study. We could certainly maybe go up to 18 months. And we may even include a handful of juvenile patients with this particular disease as well. So -- but I don't think we'll make that change just yet. And as we alluded to on the call earlier from one of the earlier questions, we may make some slight modifications to immunosuppression regime. But the main change we're going to make is just the numbers of patients. In terms of read-through to other programs, yes, I think there's tremendous readthrough to other programs in the pipeline. And I think that's one of the benefits of our approach at Taysha, everything you do is AAV9 [indiscernible] and intrathecally delivered. We were particularly pleased to see the nice enzyme levels in this particular program with intrathecal delivery. We think our immunosuppression regime is working well, not just from the GM2 program, but also from the GAN program. And I think that the way the study has been conducted, there's a lot of read-through as well, just a method of how we deliver drug intrathecally, the actual infusion set, the way we're moving our operational model to smaller numbers of [indiscernible] transporting patients from different parts of the world is another thing that I think we're going to start applying to the rest of our programs. So yes, there's tremendous read-through from this program to the next. And in particular, just -- you've heard me say before that we've had lots of regulatory meetings. We had 9 by the end of 2021. We've had more during the course of 2022 already. And the learnings in one regulatory interaction to another are really quite profound. So yes, lots of read-through.

Yes. Salveen, the only thing that I would add to Suyash's comments are the fact that just from a biology perspective, GM2, being a lysosomal storage disorder where there's a buildup in substrate, that ultimately needs to be converted and metabolized and cleared in order to keep the cell healthy, is very similar to our CLN1 disease program where we're trying to restore PPT1 enzyme activity. And when you start to think about the levels that we need to hit there, they're almost right on. It's 5% of normal that ultimately normalizes survival in those more severe patients. And then when you start to think about additional readthrough, our GAN program is very similar. Again, there's a buildup of substrate that ultimately affects the electrical chemical conduction of the nerve. And so just by restoring gigaxonin, you are able to restore that function and actually clear out that substrate. And so when you start to think about just the biology of these diseases, particularly on the neurodegenerative side, there is significant overlap, which gives us confidence that the approach is indeed working. So we appreciate the question. But hopefully, we addressed it.

[Operator Instructions] Our next question comes from the line of Mike Ulz with Morgan Stanley.

I just had one follow-up on some of the prior questions here. Just given some of the variability and high expression levels you're seeing and realizing this is only 2 patients so far, but how does that impact your thinking on dosing at all at this point?

So I'll let -- thanks, Mike, for the question. I'll let Suyash address. And Suyash, maybe you might want to provide some context from preclinical studies, but also some of the clinical data that we have without sharing too much.

Sure. I think it's a really good question, and it relates somewhat to an earlier question about how we're going to, if at all, modify the protocol. What we're seeing -- we went in with a high dose. We're giving [ 5 x 10 to the14th total vg ] which is a significant dose. It's a high dose targeted to brain and spinal cord but actually a low dose in terms of systemic exposure. So -- but this is a meaningful dose that we expected to give good clinical benefit. When you reflect on the preclinical data, we have a very nice dose-ranging [indiscernible] studying the Sandhoff mouse model, and we showed dose response in that study. And this dose we selected for the humans was between the medium and the high dose based on the preclinical data. And we were fully expecting to make a dramatic improvement, both from a biomarker perspective and from a clinical perspective with that particular dose. Having said that, we could actually go up higher, if need be. We do have tops coverage. We could go to [ 5 x 10 to the15th total vg ], which will be fine. We've actually -- it sounds like a high dose. We've actually dosed patients with our CLN7 program at that level. So it's -- there is precedent for it. We could go up to the [ 5 x 10 to the15th ] dose if need be. I think the decision on dosing will be taken at a bit of a later stage during the course of this year. We've already seen a more than adequate biomarker, but I think we'll need to see a little bit more clinical endpoint data before we decide whether or not we're going to go to the [ 5 x 10 to the15th ] dose. From the initial discussions with the principal investigator, patient 1 definitely showed signs of improvement, disease stabilization. And he felt that qualitatively, there was definite improvement in the physical function of the child from a clinical perspective. We will go into more detail on that on a subsequent call. If I had to guess, my guess is probably [ 5 x 10 to the14th ] would be enough for this group of patients with GM2, but it's possible, depending on how the clinical data emerges, that will go up [ 5 x 10 to the15th ]. And we absolutely have the ability to do that based on our preclinical modeling and toxicology data.

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

Maybe just following up on how we think about selecting dose. In terms of biomarker, should we be thinking about Hex A expression as being the most informative metric? Or should we be looking at GM2 and GM3 substrate levels as potentially being more informative alongside the clinical data as in the charts?

Thanks, Kevin, for the question. It's actually -- I was just saying thanks for the question. It's actually a really good question. Maybe I'll start, Suyash, and then you can continue. But what I would probably say, Kevin, the short answer there is both. You need to look at both of them together because, one, you need to know if you're actually producing Hex A in kind of the ratios of what you need to actually get it to. But then you need to know if that's actually active. And I think showing both the production of Hex A activity in the normal range, but also showing the restoration of the metabolic pathway of GM2 to GM3 confirms the activity. And so I think you have to look at them both together to really make a judgment of is the drug doing exactly what we hope it's doing. And we were quite encouraged by that data at 1 month, and hopefully, we'll continue to see that at additional time points. But I'll stop there. Suyash, you probably want to give a more in-depth answer.

Yes. I'll add to your comment, RA. This is a really important and insightful question. And RA is quite right, you have to look at both. But we did 3 things with the analysis of this data. We really wanted to do the biomarker data as robustly as possible. And there's 3 things we did to ensure that. The first is we did -- we looked at Hex A, of course. That's the enzyme that's missing. That's the enzyme we're trying to replace. And you have to see activity of that particular enzyme. And you can see there is really significant increases in activity. Secondly, one of the things -- and I touched on this in the call -- one of the things to sort of think about is labs are different. And a lot of the assays were developed really to diagnose this disease and not look at enzyme levels over time. And so we spent a lot of time and energy developing the robustness and quality of our assays, and we double-checked everything in our own labs and double-checked everything in our vendor partners who are very experienced in this. And we -- you saw earlier we presented normal normative data as well. So really it gave us a lot of confidence with the degree of improvement we're seeing based on that. The final thing is this level of substrate that's being broken down. And we did 2 things here, which I think is important. The substrate that's being broken as GM2 ganglioside, it gets converted to GM3. We measured both, GM2 and the GM3, and we did it in the CSF. So what you're seeing at baseline is dramatically elevated GM2 and very low GM3. And at the 1-month time point, you're seeing the GM2 staying about the same, but the GM3 level is starting to go up. So clearly, you're starting to produce -- it goes above about 50%. So clearly, you're starting to produce more GM3, which means that the enzymatic pathway from GM2 to GM3 is working. So I think you have to look at both. You have to look at the actual absolute levels of enzyme, but is it doing what is needed to do, which is we'll start to remove GM2 and convert it to GM3 yes, absolutely. So the Hex A level is important. The GM2 level is important. And the GM3 level is important. And having a background of very comprehensive normative levels using a very reliable assay is also important.

Suyash, maybe one additional comment that you'd like to make is our discussion recently with Dr. Sandhoff about these biomarker and how to interpret these things.

Yes. Thanks for bringing that up, RA. Yes, we were very excited to speak to Dr. Sandhoff himself who -- Sandhoff disease is named after him. And I have to say, he really knows [indiscernible] lipids and ganglioside metabolism like the back of his hand. He's written many, many of the key papers describing this pathway. And he was very excited to see what we're sharing and was really very excited to look at -- really appreciated the thought and care we're putting into our assay development and essentially said that we're doing things the right way. So yes, very, very nice discussion with Dr. Sandhoff who's -- I guess is pretty much retired, he's very elderly, but his brain is still working very, very well.

Our next question comes from the line Yun Zhong with BTIG.

And this is actually a follow-up question on what Suyash just talked about and about the GM2, GM3 versus the Hex A enzyme activity. Can you talk about your expectation on GM3 maybe quantitatively given that you have seen such a big increase in the enzyme activity? And also, why was there an increase in GM2 ganglioside? Shouldn't it decrease if the conversion is being increased? And also about normalization, how long do you think it will take for the level to kind of normalize based on what you have discussed on the call?

It's a really insightful question. Suyash, do you want to address?

Sure. Yes, I can address it. So when you think about the cadence of events, we were dosing the drug, and intrathecally, drug travels to the brain and spinal cord, capsid enters the cell, DNA pops out, starts producing enzyme. You're going to get maximal trans gene expression maybe 3 weeks after dosing. And then you're going to start to see the functional activity of the enzyme. So we presented 1 month data on the GM2 and GM3 ganglioside. We don't have the 3-month data as yet. It's still in the process of being analyzed. So my guess is as time progresses, you're going to see that GM3 level continue to go up. Now the important thing to realize is that -- and there is a slide in our deck that shows this to some degree, you've got GM2 being converted to GM3 by the action of Hex A activity. The GM3 goes on, and it gets converted to another substrate Lactosylceramide. And prior to GM2, you've got GM1. So GM1 gets converted to GM2 and then converts to GM3 that gets converted to Lactosylceramide and then on it keeps going. Don't forget every other enzyme in this pathway is working. So as the GM2 starts to get converted to GM3 with the increasing activity of Hex A, you start to see levels of GM3 go up. So GM2 then will start to go down. But don't forget, as GM2 goes down, you start to get more of the GM1 being converted to GM2 with the activity of Beta-galactosidase, which is not deficient, okay? So I didn't expect the GM2 to go down. It went up by about 20%, and that's probably within the -- it's probably not much change, frankly. But as time goes on, and I'm guessing it's probably going to be months before actually see the GM2 come down because as the GM2 gets converted to GM3, you're going to get more pull-through from GM1 to GM2. The GM3 is going to go up, but it's not going to go up dramatically even though we've got lots and lots of Hex A because there is a limit to the actual conversion because as GM3 goes up, you can get more GM3 also then converted to Lactosylceramide, which is the next step in the pathway. So my guess is that GM3 is going to go up a bit more and then going to stabilize. GM2 is going to stay high for some time and then come down slowly. And then at some future time point, both are going to stabilize at a relatively low level. That's my guess as to how these things -- how things are going to progress. Does that make sense?

Yes, I think so. It's a very dynamic process. And yes, I think that makes a lot of sense.

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

I wanted to ask about the DSMB process on patient 1 as well as any regulatory notification you have to make. I mean do you anticipate having to discuss this with the Canadian regulatory authorities? And just when we should we expect a kind of resolution to both processes?

Suyash, do you want to address that? And I'm happy to provide some comments.

Sure. I can address that. Yes. So of course, the DSMB has been very actively engaged in this study. We have a very good DSMB, 3 members. The Chair is a metabolic geneticists who has expertise in gene therapy. We have a hemophilia gene therapy expert and another pediatric neurology methodology [indiscernible] all very reasonable, thoughtful individuals. They've been heavily involved in the study because every time we've dosed a patient from a safety perspective, we have the DSMB as an independent body to look at our data before we then go ahead and dose the next patient. So we already have several discussions going from patient 1 to patient 2 and then dosing from patient 2 to patient 3. Specifically on the matter of this patient that passed away, we actually had a DSMB meeting on the same day that the baby died. As I say, we had known the baby was unwell for about 2 weeks prior to the baby succumbing. And we were hoping it would turn around. But as I say, after we realized he was colonized with MRSA, many things were not looking good. So we'd actually had a DSMB meeting plan to talk through the specifics of this particular child. And he died that morning, and we spoke to the DSMB at length in -- later that day. The nature of the conversation was a very positive thoughtful conversation. Of course, one of the big discussions is assessment of causality. So the principal investigator felt this was not drug-related. I was in agreement as the senior physician at Taysha and the DSMB. In general, we're in agreement with that statement. But then before they make the final determination we needed a bit more information, which included looking through some more specific hospital records and getting some sense of findings from an autopsy. So those are the outstanding items before the DSMB can make a final determination and sign off on the -- around causality. But in general, as I say, everything is looking at this as a nondrug-related event. With regards to Health Canada, yes, of course, we have to let Health Canada know. And in fact, once the baby was admitted onto the intensive care unit, we sent a report into Health Canada. At the time and on an ongoing basis, it was not deemed as being a drug-related adverse event. So there is less time pressure to get the information to Health Canada. But just through goodwill and through our relationship with Health Canada, we felt it was appropriate to inform them and let them know. So we had to get the file with Health Canada saying, hey, the baby is remitted. This is the situation. And they asked a few further questions, and it was not really -- we just kept that file open, and we were going to update on an ongoing basis with more information. After the patient -- after the baby passed away, we then send them updated information. And that file is still open, and we're waiting for final pieces of information before Health Canada can also make their determination. What we're planning to do with regard to the study and with regard to timing is that we're continuing to prescreen patients, but we won't dose a patient until we -- we voluntarily decided we won't dose a patient until the case is finalized and closed and all the i's are dotted and all the t's crossed, which I anticipate it will be about 2 or 3 weeks to complete and collate all the information to make those final determinations.

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

From a high level, how do you believe that this enzyme activity over time could correlate with some of the clinical manifestations both from the perspective that some have already been apparent, which you listed for each patient, but also considering that at the age you're treating patients, natural history suggests the onset of additional symptoms at this time?

Thanks, Kristen, for the question. So just -- well, just to summarize your question is really around how does enzyme activity correlate to essentially symptomatology and the effect of symptomatology. I just wanted to kind of summarize it for Suyash. Suyash, do you want to address?

Yes. Sure. Thanks for the question, Kristen. It's a good question. And to a degree, we don't exactly know what to expect and that's one of the reasons we're running the clinical trial. What I would say is this, pathophysiologically, the earlier you treat these babies, the better. There is an ongoing progressive loss of neurons. If you think about what's happening pathophysiologically, the GM2 ganglioside is building up in the lysosome of the cells, the lysosome swell over time, they rupture. They leak out their acidic enzymatic content, which starts to break down neuronal tissue. You get inflammation in the neuronal tissue which then becomes fibrosis that scars and then you're losing neuron. And once you've lost neurons, you're not going to get them back. So in principle, for the majority of the neurodegenerative diseases we treat, and in particular, for lysosomal storage disorders, which are rapidly progressive, you just have to identify the patient early and treat them early to try and preserve as much neuronal function as possible. So we -- ideally, we'd end up with a situation where we're newborn screening babies and treat them either as they're starting to develop symptoms early on or prior to developing symptoms. These babies -- we had a cutoff of 15 months for the study because we didn't want patients to be -- we wanted to give them some chance of reversibility. We -- and this was a judgment call really just in context with our expert advisers, our Scientific Advisory Board and the PI. We said, look, let's say, 15 months. We should be able to diagnose patients by 15 months of age. And hopefully, they've lost -- we know they'll have lost some neuronal function, but maybe not lost too much. And so there's a degree of ability to stabilize and to reverse the disease. So we're hoping that some of the hypotonia will resolved. If they've lost the ability to sit, maybe they'll regain the ability to sit, we're not sure. I think if we -- we do make sure that -- as I said earlier, if a baby has lost the ability protect their gag reflex and are aspirating, we won't treat them. If they're on a ventilator, we won't treat them because by then, we think the chances of reversibility are very, very low. My guess is that from a clinical perspective, we're going to see some stabilization. And my hope is that we're going to see some signs of clinical improvement. And as I've mentioned earlier, the intent is to share some of that clinical data by the end of this year. But also the principal investigator did say the first patient was showing some subtle signs of stabilization and improvement in his mind.

Our final question this morning comes from the line of Silvan Tuerkcan with JMP Securities.

Congrats on the data. I just wanted to see if you could help me read the Hex A activity -- enzyme activity chart a little bit better. And do you know the baseline activity of Hex A enzyme considering you have it for GM2 to GM3 conversion? So what is the improvement to that baseline number? And from your measurements of 120 samples, do you roughly know what the error bars may be on these plots, meaning is there a day-to-day variability in these patients -- or what do you know about, I guess, normal Hex A levels in a normal patient?

So Suyash, I would probably just to simplify it, address the last question.

Sure. With regard to Hex A levels, so it's interesting. It's a good question. We don't really know the day-to-day variability of Hex A levels, and we didn't run the same patients sequentially. What we did, we took 120 samples, which we thought was quite a significant number just to develop norms. And we're probably going to do some more as time goes on. So I think there is a relatively large spread of normal activity, as I mentioned earlier. So the error bars are not going to be narrowed. Having said that, we have -- regardless of whether there's wide distribution or not, there is still significant elevation in enzyme activity. And we've looked at things at 2 levels. We've looked at the level of enzyme activity in comparison to normal levels. And we've also looked at levels of enzyme activity in comparison to what we think is going to be asymptomatic based on that ratio, which is a 5% level. So I think looking at it both ways is important. And to your question about baseline levels, there was a significant increase up in baseline levels. These individuals had very low levels of Hex A enzyme activity at baseline, and there's a significant increase upwards in that specific -- when you look at that specific parameter. Hopefully, that answers your question, Silvan.

Ladies and gentlemen, that concludes our question-and-answer session. I'll turn the floor back to Mr. Session for any final comments.

Thank you, operator. And again, thank you, everybody, for joining us on the call this morning. We appreciate the continued support and interest in Taysha and look forward to sharing additional progress on all of our clinical programs throughout the rest of this year. We appreciate the questions, and we wish you all a very happy and healthy new year and great rest of the day. Thank you.

Thank you. This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.