Taysha Gene Therapies, Inc.
Q2 2022 Earnings Call Transcript

Published: 13 Aug 2022

[Operator:]

Greetings. Welcome to the Taysha Gene Therapies Second Quarter 2022 Financial Results and Corporate Update Conference Call. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a brief question-and-answer session. As a reminder, this call is being recorded today, August 11, 2022. I'll now turn the call over to Dr. Kimberly Lee, Chief Corporate Affairs Officer. Please go ahead.

[Dr. Kimberly Lee:]

Good morning, and welcome to Taysha's Second Quarter 2022 Financial Results and Corporate Update Conference Call. Joining me on today's call are RA Session, II Taysha's President, Founder and CEO; Dr. Frederick Porter, Chief Technical Officer; Dr. Suyash Prasad, Chief Medical Officer and Head of R&D; and Kamran Alam, Chief Financial Officer. After our formal remarks, we will conduct a question-and-answer session and instructions will follow at that time. Earlier today, Taysha issued a press release announcing financial results for the second quarter ending June 30, 2022. A copy of this press release is available on the company's website and through our SEC filings. Please note that on today's call, we will be making forward-looking statements, including statements relating to the safety and efficacy and the therapeutic and commercial potential of our investigational product candidates. These statements may include the expected timing and results of clinical trials for our product candidates, our expectations regarding the data necessary to support regulatory approval of TSHA-120 and the regulatory status and market opportunity for those programs as well as Taysha's manufacturing plans. This call may also contain forward-looking statements relating to Taysha's growth and future operating results, discovery and 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 the uncertainties related to the timing and results of clinical trials and preclinical studies of our product candidates, or dependence upon strategic alliances and other third-party relationships, our ability to obtain patent protection for discoveries, limitations imposed by patents owned or controlled by third parties and the requirements of substantial funding to conduct our research and development activities. For a list in 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, August 11, 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 law. I would now like to turn the call over to our President, Founder and CEO, RA Session II. RA?

[Dr. Frederick Porter:]

Thanks, RA, and good morning, everyone. In the next few slides, I'll review our manufacturing progress for the GAN program and our comparability package that supports the transition to our final commercial manufacturing process. Next slide. Our manufacturing development program for TSHA-120 was kicked off in mid-2021, one we initiated our partnership with our CDMO partner to deliver our commercial-ready manufacturing process. We've rapidly executed several tech transfer runs leading up to production of our 500-litre pivotal batch in April of this year. In parallel, we progressed several key analytical development efforts internally to deliver a comprehensive data package to support product release and comparability in line with agency guidance for pivotal stage programs. Next slide. Our commercial grade manufacturing run was highly productive, yielding over 200 vials of finished drug product filled into 2 separate lots that are currently undergoing release testing. After inspection and testing, over 50 patient doses are available for clinical use. In addition to supporting the ongoing clinical study, these lots were enrolled in a comprehensive stability study to provide critical shelf-life data in support of our BLA filing. The 500-litre production also represents our final commercial scale, which aligns with our commercial projections. We believe this high-yielding process supports a favorable cost of goods and ensures us that we will be able to meet commercial demand with a reasonable number of batches annually. Next slide. In considering the analytical panel for product release and comparability, there are 4 key areas of importance for gene therapies, strength, purity, potency and safety. These important attributes have informed the panel of assays that were in the process of validating at our CDMO partner to support both product release and comparability. The analytical method selected aligned with agency expectations in terms of accuracy, precision and robustness for measuring each product attribute. Next slide. In order to assess comparability of our clinical trial material and the newly manufactured material from our commercial manufacturing process, we've applied this panel of release assays for side-by-side testing with our comprehensive assay panel. Shown here are 8 of the most critical attributes that reflect on the purity, potency and safety of our product. First, all results demonstrated that both clinical trial material and commercial grade material are a high purity and lack significant levels of host cell or process contaminants such as protein and DNA or aggregated species. Vector purity was in excess of 95% for all 3 lots, and host cell protein contamination was below detection. Aggregation of all lots was also very low. Both cell and plasma DNA contamination are also important attributes to discuss with regulatory agencies since carryover represents a theoretical immunogenicity or oncogenicity risk. Residual plasma and wholesale DNA were similar for all lots indicating a consistent product profile for both lines. Empty capsids are a key attribute for AAV vectors since empty capsids can stimulate immune responses to the vector and reduce potency. All 3 lots were highly enriched in full particles and meet recent FDA draft guidance in terms of analytical methodologies and present full capsids. Finally, potency of AAV vectors is a key measure that is intended to correlate with clinical efficacy. We developed several product-specific potency assays to measure functional activity of our product, which is reported relative to a reference standard. These assays recapitulate the biological activity of TSHA-120 where the AAV transduction process of cell entry, DNA and packaging, gene transcription and translation occur in an immortalized mammalian cell line. Functional activity is measured by quantitation of TSHA-120 transgene RNA levels or gigaxinin protein expression as 2 independent and complementary readouts. We observed good agreement with both methodologies and the activity of all 3 GMP lots against our reference, which gives us confidence that the lots are of high and comparable activity. Overall, these results support our view that our early clinical trial material and commercial-grade material are biochemically and biophysically similar and should perform identically in a clinical study. We plan to present these final study results with additional regulatory agencies and anticipate regulatory feedback by the end of this year. Next slide. Recently, regulators have encouraged sponsors to conduct deeper analysis of product contaminants not covered by standard release assays to better assess product safety and comparability. To comply with this guidance, we have added PacBio next-generation sequencing to our product characterization panel to better understand the nucleic acid composition of our products. This method not only allows us to identify the source of nucleic acid, but also the fragment size, sequence variability, which also need to be considered when assessing AAV safety and efficacy. Our analysis of clinical trial material and commercial-grade pivotal batches demonstrates that the source and composition of transgene and contaminating host and plasma DNA is nearly identical and provides further support that the nature of our product is unchanged between our early clinical and commercial-grade batches. Next slide. In summary, we have successfully executed 6 batches of TSHA-120, our pivotal 500-litre scale GMP batch was productive, yielding over 5 -- excuse me, 50 doses for the high-dose cohort, which positions us for future BLA-enabling activities and commercial production. Importantly, our comprehensive comparability analysis demonstrated that the clinical grade material and commercial-grade material are nearly identical by key critical quality attribute measures, including next-generation sequencing analysis. We've also made rapid progress developing a product-specific potency method, which is on track for validation and product release, which aligns with regulatory expectations. We feel this progress supports a strong regulatory package that we will discuss with additional regulatory agencies this year, including the FDA. I'll now turn over the call to Suyash to discuss additional program updates for GAN. Suyash?

[Dr. Suyash Prasad:]

Thank you, Fred, and good morning, everyone. As RA noted earlier, we continue to make notable progress in advancing our clinical programs for GAN and Rett Syndrome and expect exciting milestones throughout the remainder of the year. I'll begin with recent updates on TSHA-120 for GAN. Building on the positive clinical efficacy and safety data and long-term durability data that we reported earlier this year, we are pleased to report new nerve conduction study data for TSHA-120 in GAN. We are grateful to our partners of the NINDS for leading the GAN natural history study and the interventional trial under the leadership of Dr. Carsten Bonnemann, principal investigator at the NIH. Next slide. Nerve conduction studies are a neurophysiological measure and the specific measure of relevance to GAN is the sensory nerve action potential or SNAP which is considered a definitive clinical endpoint. The test is performed by applying an electrical stimulus to the sensory nerve fibers and recording the actual potential at a point further along the nerve. There are 3 main parameters. The first is the amplitude of the action potential, which is the peak-to-baseline measurement and functional significance is that this is related to the number of axons in a nerve. With axonal degeneration neuropathies, the primary feature is a markedly reduced sensory nerve action potential or SNAP amplitude. The next parameter is latency, which is the time from stimulus to an initial electrical deflection. This can be compromised in the demyelinated neuropathies. Lastly, conduction velocity is the speed with which the electrical signal travels down the nerve. This can be affected by axonal loss, but more so with demyelination. The NIH natural history study suggest rapid and irreversible decline in centric function early in life in patients with GAN. SNAPs are within the normal range early in life and then undergo a rapid reduction in SNAP amplitude around the age of symptom presentation. This graph depicts the median SNAP amplitude per age for the natural history population in the NIH study. The horizontal black line represents the lower limit of normal. As you can see, the youngest chart on this graph is approximately 2 years of age and as a SNAP well within the normal range. As children reached the ages of 3 or 4 years, which is the usual age of symptom presentation, the SNAP deteriorates markedly. You may recall that the initial symptomatology in the 3- to 4-year old includes unsteadiness and a wide-based gate, reflecting the fact that they lose the ability to feel the ground beneath their feet. It is, therefore, unsurprising that the nerve conduction studies reflect this symptomatology. The first green line depicts the fact that every patient with GAN has an abnormally low SNAP amplitude by the age of 4 years, reflective of compromised sensory neural function. The second green line indicates that 100% of patients have a fully absent snap by the age of 9 years, which will be considered to be irreversible. Next slide. This image is the same data as the previous slide, but with a line of best fit added to demonstrate the rapid decline in SNAP attitude from normal to absent at an early age. Next slide. Of the patients treated in the efficacy dose onto the study, 42% or 5 of 12 patients had a positive SNAP past the age of 9 years and of the last patient visit, which is remarkable considering that none of the natural history of patients had a positive snap past the age of 9 years. The specific values for the 5 patients in question are shown in the graph on the right, where one of the patients demonstrated near-complete recovery and continued on an upward trajectory from a baseline of 0 at the time of treatment. Next slide. Many of the patients who were dosed in the intervational trial had an absent SNAP response and would not be expected to recover. From this graph, you can see that 100% of patients treated with TSHA-120, who had a positive sensor response initially maintained a positive response after treatment rather than continuing to decline to 0 as would normally be expected. Once SNAP reaches 0, sensory function is considered non-recoverable. Notably, 100% of these patients, which is 3 of 3, have a positive value at baseline and maintained a positive SNAP at the last study visit. The longest span is 3 years to date and the patients continue to maintain an upward trajectory. Next slide, please. These 5 graphs demonstrate individually plotted patient SNAP changes from baseline and importantly, includes the patient running data from the natural history study. There is continuing improvement in SNAP amplitude from either a declining snap or an absent snap. Importantly, and remarkably, 2 patients had a SNAP amplitude that had been absent for over a year in the natural history study and after dosing, demonstrated consistent and sustained improvement. This recovery of function in a neurophysiological measure that is definitive and consistent over time is contrary to natural history and exciting to see. Next slide. Earlier this year, we shared positive pathology data from nerve biopsies which confirmed the fat treatment with TSHA-120 can stimulate active regeneration of axons. We now have the entire data set demonstrating 100% of TSHA-120 treated patients had regenerative nerve clusters present 1 year after treatment in the biopsies. Peripheral nerve biopsies were obtained at baseline and a 1-year post gene therapy transfer and superficial and radial sensory nerve. Analysis of 11 of 11 evaluable samples completed to date, consistently demonstrates an increase in the number of regenerative clusters at year 1 compared to baseline. The remaining 2 samples were unable to be assessed due to biopsy limitations. Collectively, these data confirm the presence of regenerating node clusters, suggesting active regeneration of nerve fibers and improvement in disease pathology. This, coupled with the nerve conduction study data provides evidence that the peripheral nervous system can not only respond to treatment, but actually improve as opposed to just stabilize. Here, we have included a representative patient case study showing the superficial radial sensory nerve at baseline and 1 year post treatment with TSHA-120. At baseline on the left, the arrow identifies a giant degenerating Axon and the star identifies a regenerating cluster. On the right is what the nerve looks like 1 year after treatment. The yellow arrows are indicating regenerative clusters, which as you can see, are notable in number. This pathology data and the neurophysiology are suggestive of recovery of neuronal tissue after administration of TSHA-120 and such endpoints, given their unbiased and definitive nature are often viewed favorably by regulatory agencies. Next slide. We believe our GAN program includes a comprehensive set of evidence generated across diverse disease manifestations, supporting a robust clinical package. These include MFM32 motor function assessment of TSHA-120 treatment demonstrating clinically meaningful slowing of disease progression across all therapeutic dose cohorts compared to natural history decline with a durability of effect. Electrophysiologic nerve conduction studies provided definitive clinical endpoint and support recoverability, stabilization and, in some cases, improvement in sensory response in patients treated with TSHA-120. Nerve biopsy histopathology confirmed that treatment with TSHA-120 detected the presence of regenerative nerve clusters suggestive of active regeneration of nerve fibers. Pathological biomarker measurements of rectal nerve fiber layer thickness as assessed by optical coherence tomography, demonstrated stabilization and prevention of the visual loss following TSHA-120 treatment. Visual acuity, as assessed by LogMAR also stabilized after treatment. And lastly, we heard from Fred earlier about how an extensive panel of release assays demonstrated that the clinical and commercial-grade material were comparable across key quality attributes and confirmed by next-generation sequencing. Next slide, please. Now let's review the MHRA regulatory feedback we have received to date for our GAN program and discuss how this feedback supports our continued regulatory discussions. We believe this initial feedback, coupled with the CMC comparability data that Fred discussed, positions us well to further advance TSHA-120 through regulatory approval. Next slide. A number of recent product approvals and positive regulatory opinions for therapies targeting rare CNS indications and indeed non-CNS gene therapies, especially in the context of unmet clinical need, points to flexibility in the current environment from a regulatory filing perspective. This includes a number of agreements from regulatory agencies for the use of accelerated or conditional pathways to approval. Some examples include EliCell with treatment of cerebral leukodystrophy, or STARZ, the treatment of AADC deficiency, SRP-9001 for Duchenne muscular dystrophy and tofersen SOD1-ALS. Next slide. Our discussions with the MHRA have been collegial, collaborative and helpful. The MHRA agreed with our commercial manufacturing and release testing strategy, including potency assays. They recommended dosing a few patients with commercial-grade material, which will be released in September 2022. And lastly, it was supportive of our proposal to perform validation work, including patient and family feedback, which is ongoing on the MFM32 as a key clinical end point. We believe this positive feedback from the MHRA in conjunction with the totality of preclinical data generated to date for TSHA-120 represents a robust package supporting additional discussions with regulatory agencies. We expect additional regulatory feedback, including from the FDA by year-end. Next slide. We continue to work with regulatory agencies with the goal of achieving conditional approval in Europe and accelerated approval in the United States based on EMA and FDA industry guidance for gene therapies in neurodegenerative diseases. Based on key registrational requirements from regulatory agencies, including the FDA and EMA, we have outlined some possible scenarios for approval. With the EMA, we believe there is potential to file for conditional approval based on current data set for EMA guidance documents. For the FDA, the first scenario was immediate filing for approval based on the current data set and comparability. Alternatively, we may need to dose a few more patients to demonstrate comparability of clinical effect between clinical and commercial-grade material, which is a similar approval pathway for Zolgensma in spinal muscular atrophy. The last scenario is to perform a new pivotal trial, which we think is unlikely, given the recently published FDA guidance document on gene therapies for neurodegenerative diseases and the extensive long-term safety and efficacy data set available. MHRA feedback further aligns us with scenario 2, which is our base case. We expect to have additional regulatory guidance, including the FDA by year-end. As a reminder, TSHA-120 previously received orphan drug and rare pediatric disease designations from the FDA. Next slide. Now let's turn to the late-breaking preclinical data we reported today for TSHA-102 in Rett Syndrome. Next slide. As a reminder, Rett Syndrome is an X-linked neurodevelopmental disorder that is characterized by mutations in MECP2, a protein essential for neuronal and synaptic function in the brain. Female heterozygous patients with Rett syndrome on Mosaic carriers of normal and mutated MECP2. The challenge in gene replacement therapy of MECP2 is finding the appropriate balance of sufficient physiological expression to correct the deficiency whilst also avoiding overexpression on the associated toxicity. The estimated prevalence of Rett Syndrome is 350,000 patients worldwide with an instance of 1 in 10,000 female births worldwide. Next slide. Because of this spectrum and risk of toxicity, development of a gene therapy for Rett Syndrome requires a regulated expression of MECP2. Previous MECP2 gene therapy approaches, of course, dose-dependent side effects after intra-CSF administration in wild-type and Rett Syndrome knockout mice. We have developed a novel mRNA responsive target sequence called miRARE to regulate the expression of the MECP2 transgene and prevent the risk of overexpression toxicity. We believe our approach provides a superior therapeutic profile to that of unregulated MECP2 gene replacement. Next slide. TSHA-102 regulates expression of MECP2 is a novel microRNA responsive auto-regulatory element platform, known as miRARE that is exclusively licensed to Taysha developed by Dr. Sara Sinnott and Stephen Gray of UT Southwestern Medical Center. miRARE provides sophisticated regulation of transgene expression, genotypically on a cell-by-cell basis, ensuring controlled expression that avoids excessive levels. miRARE is a targeted panel for endogenous microRNAs, which regulate MECP2 expression. In the presence of high levels of intracellular MECP2, endogenous down regulatory micro RNAs are secreted as part of the cell's normal feedback inhibitory process. Which then bind the miRARE platform on the construct and reduce output and expression of MECP2 from the construct. This ensures that intracellular levels of MECP2 whether in a wild-type cell or a mutated cell and immune mosaic patient stay within appropriate physiological levels. Next slide. Today, we are excited to share near normalization of survival in neonatal mass bonds of Rett Syndrome following Taysha administration. Survival was significantly extended in MECP2 knockout male mice following a single CSF injection after day 2 of TSHA-102 at 8.8 E10 VG per mouse, which is the human equivalent dose of 2.86 E14 total VG and a little lower than planned for the human clinical trial. Preliminary data demonstrated approximately 70% of the treated knockout males survived study conclusion at 34 weeks of age versus 9 weeks in vehicle-treated mice. All cohorts, including vehicle were sacrificed to 34 weeks. Next slide. We then looked at the Bird score, which is a composite measure of 6 different phenotypic abilities that relates to Rett syndrome. These include breathing, gate, general condition, high blend classing, mobility and treme. Over the course of the study, TSHA-102 appeared to normalized behavior, as assessed by the Bird score. Next slide. The totality of preclinical data generates the date for TSHA-102 represents the most robust package supporting Rett syndrome clinical advancement for gene therapy. I've just reviewed the recent preclinical study in neonatal Rett knockout mice, demonstrating near normalization of survival, normalization of body weight and normalization of behavior as assessed by bird score. We have previously discussed the pharmacology data demonstrating significant improvement in survival, body weight, motor function and respiratory health across treatment ages in knockout mouse models and while we were able to ascertain a minimally effective dose. We've also previously discussed toxicology data supporting a favorable safety profile of TSHA-102 in Sprague Dawley wild-type rats up to a 6-month time point and the human equivalent doses fourfold over the clinical starting dose. The nerve conduction studies performed remains the normal range for all groups at all time points, signifying no evidence of dose or ganglia inflammatory change. And lastly, toxicology data supporting TSHA-102 was well tolerated at human equivalent doses of up to 2 E15 total VG and demonstrated abroad by distribution to brain, spinal cord and systemically in non-human primates. Perhaps most importantly, the toxicology studies have demonstrated that the down regulatory miRARE platform is working well and that there was minimal expression of MECP2 in a wild-type cell with normal preexisting levels of MECP2. These 4 preclinical studies together represent a comprehensive and robust package supporting the clinical advancement of TSHA-102 for Rett syndrome. Next slide. Our first-in-human Phase I/II study of TSHA-102 for Rett syndrome, also known as the REVEAL study is ongoing. Centas you've seen a mother and child University Hospital Center in Montreal, Quebec, Canada is the initial clinical site for the study, which is under the direction of principal investigator, Dr. Elsa Rossinyol. Target recruitment is up to 18 adult females. It has a 3+3 study design with 3 randomly selected delayed treatment control participants in each dose cohort, and each cohort may be expanded with up to 3 additional participants. Next slide. We look forward to preliminary Phase I/II clinical safety and efficacy data in adult females by year-end 2022. We have completed GMP manufacturing for Rett using our commercial process. And lastly, a study the pediatric female rep population and the rescue study in rep males are planned for 2023. As a reminder, TSHA-102 has been granted rare pediatric disease designation and orphan drug designation from the FDA and more recently orphan drug designation from the European Commission. With that, I'll turn the call over to Kamran to review our financial results. Kamran?

[Kamran Alam:]

Thank you, Suyash. This morning, I will discuss key aspects of our financial results for the second quarter ended June 30, 2022. More details can be found in our Form 10-Q, which will be filed with the SEC shortly. Next slide. As indicated in our press release today, research and development expenses were $23.1 million for the 3 months ended June 30, 2022, compared to $30.6 million for the 3 months ended June 30, 2021. The $7.5 million decrease was primarily attributable to a decrease of $3.8 million in third-party R&D primarily related to GLP toxicology studies, a decrease of $3.2 million in R&D manufacturing costs and lower employee compensation expenses of $0.5 million. General and administrative expenses were $9.9 million for the 3 months ended June 30, 2022, compared to $10.1 million for the 3 months ended June 30, 2021. The decrease of approximately $0.2 million was primarily attributable to a decrease of $1.1 million in professional fees related to market research, recruiting, accounting and patient advocacy activities. This was partially offset by $0.9 million of incremental employee compensation expenses. Net loss for the 3 months ended June 30, 2022, with $33.9 million or $0.84 per share as compared to a net loss of $40.9 million or $1.09 per share for the 3 months ended June 30, 2021. As of June 30, 2022, the company had cash and cash equivalents of $66.2 million compared to $149.1 million on December 31, 2021. Taysha continues to expect that its current cash and cash equivalents in addition to full access to existing term loan facility, is sufficient to fund operating expenses into the fourth quarter of 2023. And with that, I will hand the call back to RA.

[Operator:]

Thank you and at this time, we'll be conducting a question-and-answer session. [Operator Instruction] And our first question comes from the line of Joon Lee with Jo Securities. Please proceed with your question.

[Joon Lee:]

Good morning, thanks for taking questions. My name is Joon. I'm just wondering, have there been any discussions with the FDA on regulatory lamina for 120, just thinking mostly in terms of the 3 scenarios that you've previously laid out on whether or not the FDA might have to redose patients with GMP material. Also, if such discussions have occurred, will the safety data be sufficient? Or has the FDA made or indicated additional need for efficacy biomarker or clinical data? Thank you.

[Dr. Suyash Prasad:]

I think you said it all, all right.

[Joon Lee:]

Thank you, and then if I could just ask the yield of the 50 doses that you've already manufactured, will that support the highest dose that was tested in clinical trials for all 50 of the doses that are ready to go? Thank you.

[Operator:]

And our next question comes from the line of Gil Blum with Needham & Company. Please proceed with your question.

[Gil Blum:]

So just a question to clarify and make sure that I fully understand this. The additional regulatory feedback that we will be getting by year-end 2022, is this a change from previous estimates?

[Gil Blum:]

Okay. And maybe a question on SNAP. How it's established was SNAP as a surrogate endpoint for function and GAN. I mean it is very -- it is remarkable to see something going from zero to something, but just to help us understand the functional benefits.

[Dr. Suyash Prasad:]

Sure. Oh yeah hi Gil, I think that this is really the first ever time SNAP amplitude data, SNAP data in general has been presented or published for a large body of patients with GAN. And it is quite remarkable. It's quite -- what is notable here is the consistency of what you see in the natural history and how it mirrors clinical progress of these patients. You saw in the earlier image that around the age of 2, the SNAPs are well within the normal range, and they rapidly decline from the age of about two and a half to 3 to the point where by the age of four every child has an abnormal SNAP. By the age of 9, everyone has an absent SNAP. And what I would say is that this kind of pattern is quite consistent with other axonal neuropathies, another similar hereditary centermost neuropathies where you do see the nerve conduction studies being affected quite dramatically. What I think is important with GAN is the fact that it really mirrors what's happening clinically and correlates very nicely. We've talked before about how patients with this disease generally is symptom free in the first few months of life. They may have slightly delayed motor milestones around the age of 2, 2.5, these children present with on steadiness and a wide-based gate and a high staffing gate because they can't feel the ground beneath their feet. And this is exactly what these conduction studies are demonstrating. I think one point I will make is that what you're looking -- and I tried to get into this in the presentation, there are 3 frames you'll look out with a nerve conduction study -- amplitude, which is the height of the electrical deflection; Latency, which is how quickly the electrical stimulation takes to start; And velocity, which is the actual speed down the actual nerve. And neuro really in that earlier times were used in the demyelinating disorder multiple sclerosis, where you tended to see more effects on latency and more effects on velocity. However, for these axonal neuropathies, where you're losing axonal amplitude as the key parameter and you can see how it correlates very nice in the natural industry. But more importantly, actually, clearly stabilizes or even improves -- and you're right to the fact that a handful of patients improved from 0 and are still continuing on an upward trajectory -- is very impressive and is also reflected in what I shared in the biopsy data you saw an increasing presence of regenerating the clusters. Let me stop there. I could go on even longer, but let me stop there.

[Gil Blum:]

Thank you. That was very helpful. And then last one on Rett. What would you need to dose male rescue study? That's -- the timing there seems pretty important. But if you can and that…

[Dr. Suyash Prasad:]

Sure. Yes. So the important thing here is that the males are knockouts. And for an X-linked disease, this means that they have no MECP2 whatsoever. In contrast to the females where the females are mosaics and half of themselves have normal levels of P2 or the other half have mutated or absent that P2. And so in the clinical setting, the males actually are more severely affected. And the vast majority in the human situation actually die in uteri. A handful survive and lots of life through early infancy and may die in the first few months of life or sometimes to live up to the age of 2 or 3. And then so come usually to due to respiratory infection or some respiratory compromise. So it's a very, very severe form of Rett. And there aren't many of these patients, the male, knockout males that survived perhaps 200 in the world. So -- and they've also been a fairly, I guess, a forgotten group and the Rett patient community are actually very pleased that's part of our clinical development program, which, as we alluded to earlier in the call, we're starting in avals initially during the course of 2023, we'll start a pediatric girl study, and then we'll also do a pediatric boys study, a rescue study. And the Rett patient community are very happy that we're actually addressing this kind of underserved population. Specifically on your question around GoSkill, it's a really interesting question. On the one hand, there's an argument to go with a higher dose because these boys -- the high dose starting our pediatric -- our girls study, which is starting at 5 E14 total VG. And from our previous pharmacology mass oncology study, we ascertained the minimally effective dose was around 3 E14 total VG. So we're actually going in above that for the 5 E14 total VG. There's not going to go slightly higher in the males, but actually, our time is to stop the same dose. That 5 E14 total VG and the pediatric boys study that I think will be quite significant in improving that phenotype. Likely, we will go to a second dose of a 1 E15 as well.

[Gil Blum:]

All right. Thank you for taking our questions. Good luck. Thank you.

[Operator:]

[Operator Instructions] Our next question comes from the line of Salveen Richter with Goldman Sachs. Please proceed with your question.

[Unidentified Analyst:]

Hi thanks for taking our question and congrats on the progress. This is Tommy on for Salveen. We had a follow-up on the SNAP question. Could you help us gauge the expected consistency in SNAP across treated patients? For example, if there's characteristics at baseline that might impact the response after treatment. And on the MHRA feedback, how many patients do you think will need to be dosed with the commercial-grade material? And how does this affect the time line? Thank you.

[Dr. Suyash Prasad:]

Sure. Yeah. I mean the stats, it's an interesting question. We -- it's hard to know exactly what characteristics of the patients would predict a good response. And it's also hard to know simply because there are not that many patient numbers that have been dosed to be able to ascertain that with that degree of accuracy. What I would say is that the suggestion it makes full sense is that the earlier you treat, the more likely you are to have a response, the younger patient you treat, the more likely you are to have a response. And also, I think importantly, and this makes perfect sense is that if you -- if you can treat before the SNAP is lost or is absent, you're more likely to see an improvement in the -- in this hard endpoint and more likely to see a functional improvement as well. Having said that, very surprisingly, and we were very pleased to see that in a number of patients who actually had an absence of that and an absence of that for a period of time, we actually saw improvements in the nerve conduction SNAP amplitude that continued on lower trajectory. With regards to the MHRA, yes, we -- this is -- this was one of the questions that we talked about in detail. It was clear that they wanted us to dose more patients. And this is in line with our thesis of option 2, i.e., a handful more patients with clinical trial material. We tried in our discussion, and it was a very collegial, fruitful, long, in-depth discussion across all aspects of the program. I mean was there was over 2 hours, we talked about the preclinical data, the clinical data in depth. And there's a lot of in-depth discussion on the CMC piece as well. But they would not really be held to a specific number. They essentially said a handful of patients for a period of time for us to come back with a proposal. So what we decided to do, and our previous thoughts have always been, it's probably going to be about 3 to 5 patients for about 6 months. So our thinking was less also continue with other agencies and also got the feedback from all agencies we've come up with a proposal on the specific number of patients. But my guess, as I say, is it's going to be around about 3 to 5 patients for about 6 months.

[Operator:]

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

[Mike Ulz:]

Just on GAN, you mentioned doing some additional validation work on the MSM32 endpoint. Can you just give us a sense of your plans there and maybe how long that validation work might take? Thanks.

[Dr. Suyash Prasad:]

Sure. Thanks. And thanks for the question, Mike. So the -- RA's quite correct, MFM32 is actually validated the pediatric neuromuscular disease in general and has been used several times previously as in supporting evidence in regulatory discussions before. Having said that, it's always best to do a formal validation as far as you can for the specific disease in question. So the plan has always been for us to formally validate the MFM32 for Giant Axonal Neuropathy. And we actually talked about this with the MHRA, and they were very open to and accepted and pleased that we've actually started this work. Now there are 3 pieces to this work. The first is to any kind of validation work. The first is a general qualitative feedback that solicited from patients and families and clinicians and PTs and OTs in a structured interview setting. And that work has been completed. And actually, we're just in the process of writing up that work, and we'll be submitting that for publication. I'm guessing about 6 to 8 weeks' time. So you'll be able to see that work in detail in the future. The second piece is to take all that information and run it through a specific -- there's a way of analyzing this qualitative semi-structured interview data, and this process is for content validation. So that that'll be the next step. And then once we've done the content validation, there's another whole additional process to the psychometric validation where we take all the natural history study data, and we take all the data from the interventional study, looked at how the MFM correlates with other aspects of other endpoints, other aspects of the disease and also with the qualitative information that we picked up in the qualitative interviews and in the content validation piece, and then we do a formal sacramental validation. That will get risk numbers of package will usually publish this work and it will end up being quite a significant report that goes in with the actual BLA filing and other regulatory interactions. In terms of timing, the process, it can take -- it can usually take quite a long time, 12 to 18 months to do it properly. Having said that, because we have this large natural history study with 50 patients worth of data, all of them have done the MFM, this truncate the time line somewhat. So it's probably going to be, I guess, a 9 to 12-month process from now.

[Operator:]

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

[Eun Yang:]

Thank you very much for squeezing me. I have one question and one -- another very quick question. So first question is for the Rett Syndrome data that we are expecting, you started the study in Canada probably only second quarter. So how many patient data are we going to be seeing? So that's question number one. And second question is kind of a quick question. So in the past, you consistently said that scenario number two is the most likely regulatory outcome, with that, you anticipated a potential launch by end of 2023 in the U.S. So is this still on track? Thank you.

[Operator:]

Our next question comes from the line of Jack Allen with Baird. Please proceed with your question.

[Jack Allen:]

Hi. Thank you so much for taking the questions, and congratulations on all the progress. Just two quick ones. One's really quite straightforward. I guess I'll start with that. Do you have a meeting with the FDA on the books for the second half of this year as you look to gain that guidance in GAN? And then I just wanted to ask on the SNAP results on GAN. Any comments you can make with regard to the doses those patients received and a dose-dependency you saw on the SNAP results would be great. Thank you so much.

[Jack Allen:]

Yep. Thank you so much for the call on the first question. That does a great job of answering that. The second question is really briefly, any comments you can make around dose dependence of the SNAP result. I realize there's a limited cohort there, but I'd love to hear about what doses doses those patients received.

[Dr. Suyash Prasad:]

Sure. Yeah. It's essentially in keeping with what we saw across the other endpoints. So you'll recall there's four different dose cohorts in the study. The initial dose, 3.5E13 is more of a safety dose that generally didn't show much efficacy. It was detectable, even though some families said that there's some qualitative improvements. Cohort two was a 1.2E14. Cohort three, 1.8E14. And cohort four was a 3.5E14 total VG. And those three upper doses are clustered quite close together. I think if we designed the study now, we would actually not have full dose cohorts and we would have -- or probably two dose cohorts. We'd have a bigger range between the two. And what I would say is that across all the endpoints, the data from those test scores two, three, and four were generally pretty comparable. And that was also true for the SNAP. We saw nothing for the very low dose cohort, but we saw improvements in the higher dose cohorts. It is a suggestion that you're teasing out a bit more of a dose response over the SNAP. There's a suggestion that the highest dose is getting a little bit more in the way of improvements on the amplitude than cohorts two or three. But in general, cohorts two, three, and four all results in good improvements, both in SNAP and in the presence of regions with no clusters.

[Operator:]

Our next question comes from the line of Yun Zhong with BTIG. Please proceed with your question.

[Yun Zhong:]

Hi. Thank you very much for taking the question. So I wanted to confirm that the feedback that you received from MHRA does not change your confidence that you will be able to file based on available data when you talk to the EMA and also want to confirm that by year end when you provide feedback, would that feedback include EMA feedback as well? Because EMA sometimes can be less flexible in terms of clinical endpoint versus surrogate endpoint that you talked on the call. Thank you very much.

[Yun Zhong:]

Yes, it did. Thank you very much.

[Operator:]

Our next question comes from the line of Sami Corwin with William Blair. Please proceed with your question.

[Sami Corwin:]

Hi, guys. Congrats on the progress, and thanks for taking my question. Do you think these additional patients you're going to dose -- the additional GAN patients you're going to dose will also satisfy the FDA if they wanted additional patients just as clinical material? And then can you just broadly speak about how dosing in the Rett trial is going?

[Sami Corwin:]

Yeah. Do you think these additional GAN patients you plan on dosing in September once the clinical trial material -- or sorry, once the commercial materials release, do you think that quantity of patients and duration of follow-up will also satisfy the FDA if they wanted additional patients dosed?

[Dr. Suyash Prasad:]

Not really to add, but just to emphasize the fact that we'll look at all the regulatory agency feedback in totality and conduct the study on an ongoing basis in order to meet all the needs. And my guess is, yes, it'll be three to five patients, six months' worth of data. And that should meet the needs of the MHRA, the EMA, the FDA, and any other agency we're in discussions with.

[Operator:]

And our last question comes from the line of Kristen Kluska with Cantor Fitzgerald. Please proceed with your question.

[Rick Miller:]

Good morning. This is Rick on for Kristen. Thank you for taking our question. Just a question on the individual patient SNAP data. It looks like patient A appeared to show little change from baseline. Could you talk about how you're thinking about the specific case and what it might be telling us potentially about baseline characteristics or time of dosing? Thanks.

[Dr. Suyash Prasad:]

I hear what you're saying. I mean, patient A on its own is actually what we were hoping to see. We would have been very pleased if all patients stabilized because this is a child. If you look at that based on what the dose there, that scores about six microvolts and that is well below the normal limit and -- from the actual history data is on a very rapid downward trajectory. So that's -- that would have disappeared probably six months after that time of dosing if they hadn't been dosed. And we saw stabilization. And that's what we're hoping to see. The only reason it doesn't look so good is because the other patients are actually doing so much better. So, yeah, we were happy with that. We were very happy with our patients' performance, especially in comparison to the natural history, but simply because most of the other patients did significantly better. And once again, just to emphasize the fact that to go from a zero SNAP, if you look at patient B and you look at patient D, those patients had zero SNAP amplitude for well over a year. And for them to improve and for patient B in particular to be close to normal of the three and a half year time period, and still on an upward trajectory is really very significant and you would not expect to see this in a neurodegenerative disease. So it's very powerful data.

[Operator:]

And we have reached the end of the question-and-answer session. I'll now turn the call back over to Mr. RA Session for closing remarks.

[Operator:]

And this concludes today’s conference, and you may disconnect your lines at this time. Thank you for your participation.