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spk04: Greetings. Welcome to the Tayshia Jean Therapy's second quarter 2022 financial results and corporate update conference call. At this time, all participants are in a 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.
spk09: Good morning and welcome to Tayshia's second quarter 2022 financial results and corporate update conference call. Joining me on today's call are Ari Session II, Tayshia's president, founder, and CEO, Dr. Fred Porter, chief technical officer, Dr. Suresh Prasad, chief medical officer and head of R&D, and Cameron Alam, chief financial officer. After our formal remarks, we will conduct a question and answer session and instructions will follow at that time. The lawyer today issued a press release announcing financial results for the second quarter ended 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, are expectations regarding the data necessary to support regulatory approval of TASHA 120 and a regulatory status and market opportunity for those programs, as well as TASHA's manufacturing plans. This call may also contain foreign-looking statements relating to TASHA'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 patients' actual results to differ materially from those stated or implied in such forward-looking statements. These risks include uncertainties related to the timing and results of clinical trials and preclinical studies of our product candidates, our dependence upon strategic alliances and other third-party relationships, our ability to obtain patent protection for our discoveries, limitations imposed by patents owned or controlled by third parties, and the requirements of substantial funding to conduct our research and development activities. For a list and description of the risks and uncertainties that we face, please see the reports we 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. TASIA 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, Ari Session II. Ari?
spk15: Thank you, Kim. Good morning and welcome, everyone, to our 2022 second quarter financial results and corporate update conference call. We continue to execute on the advancement of our core clinical programs and are excited to announce important data from our gynecological neuropathy, organ program, and Rett syndrome programs These data include stabilization and recovery of sensory nerve conduction in patients with GAN following treatment with TASIA-120, despite expectations of a rapid and irreversible decline in sensory function in untreated patients observed in natural history. Importantly, the measure of sensory nerve conduction represent a definitive clinical endpoint. In addition, we now have positive analytical comparability data demonstrating that our commercial grade and clinical trial material are functionally indistinguishable across all key quality attributes. Fred Porter, our Chief Technical Officer, will provide more details shortly. On the regulatory front, we had positive discussions with the UK's Medicine and Healthcare Products Regulatory Agency, or MHRA, and received feedback that we believe support our regulatory strategy. With full comparability data, in hand in conjunction with additional clinical data plus feedback from the MHRA, we believe this provides the most robust package to support our ongoing regulatory engagement. We expect to provide additional regulatory feedback, including from the FDA, by the end of this year. For Rett Syndrome, we are highly encouraged by late-breaking neonatal data in preclinical mouse models, demonstrating near normalization of survival and normalization of behavior. As you will hear from Suya shortly, we believe the totality of preclinical data generated to date by TASHA 102 is a comprehensive data set in Rett syndrome that further supports earlier treatment and clinical advancement of this promising product candidate. We look forward to reporting preliminary phase one slash two clinical data in adult females with Rett syndrome by the end of this year. Now we'll turn the call over to Fred to discuss updates on our comparability data for TASHA 120 and GAN. Fred?
spk14: Thanks, R.A., 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 TASHA 120 was kicked off in mid-2021, when 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-liter pivotal batch in April of this year. In parallel, we've 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 two 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 clinical, critical shelf life data in support of our BLA filing. The 500 liter 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 assures 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 four 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 methods selected align 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 eight 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 three lots, and host cell protein contamination was below detection. Aggregation of all lots was also very low. Host cell and plasmid DNA contamination are also important attributes to discuss with regulatory agencies since carryover represents a theoretical immunogenicity or oncogenicity risk. Residual plasmid and host cell DNA were similar for all lots, indicating a consistent product profile for both lots. Empty capsids are a key attribute for AAV vectors since empty capsids can stimulate immune responses to the vector and reduce potency. All three lots were highly enriched in full particles and meet recent FDA draft guidance in terms of analytical methodologies and percent 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 TASHA 120, where the AAV transduction process of cell entry, DNA unpackaging, gene transcription, and translation occur in an immortalized mammalian cell line. Functional activity is measured by quantitation of TASHA 120 transgene RNA levels or gigaxin and protein expression as two independent and complementary readouts. We observe good agreement with both methodologies and the activity of all three 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 in 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 six batches of TASHA 120. Our pivotal 500-liter scale GMP batch was productive, yielding over 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 Siyash to discuss additional program updates for GAN. Siyash?
spk16: Thank you, Fred, and good morning, everyone. As I already 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 TASHA 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 TASHA 120 in GAN. We are grateful to our partners at the NINDS for leading the GAN natural history study and interventional trial under the leadership of Dr. Carsten Bonneman, 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 action potential at a point further along the nerve. There are three main parameters. The first is the amplitude of the action potential, which is the peak to baseline measurement. And the 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 demyelinating 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 suggests rapid and irreversible decline in sensory 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 child in this graph is approximately two years of age and has a SNAP well within the normal range. As children reach the ages of three or four years, which is the usual age of symptom presentation, the SNAP deteriorates markedly. You may recall that the initial symptomatology in the three to four year old includes unsteadiness and a wide-based gait, 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 four 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 nine 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 amplitude from normal to absent at an early age. Next slide. Of the patients treated in the efficacy dose arms of the study, 42% or five of 12 patients had a positive SNAP past the age of nine years and of the last patient visit, which is remarkable considering that none of the natural history patients had a positive SNAP past the age of nine years. The specific values for the five 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 zero at the time of treatment. Next slide. Many of the patients who were dosed in the interventional 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 TASHA 120 who had a positive sensor response initially maintained a positive response after treatment, rather than continuing to decline to zero, as would normally be expected. Once SNAP reaches zero, sensory function is considered non-recoverable. Notably, 100% of these patients, which is three of three, had a positive value at baseline and maintained a positive SNAP at the last study visit. The longest span is three years to date, and the patients continue to maintain an upward trajectory. Next slide, please. These five graphs demonstrate individually plotted patient SNAP changes from baseline and, importantly, includes the patient run-in 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, two 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 that treatment with TASHA-120 can stimulate active regeneration of axons. We now have the entire dataset demonstrating 100% of TASHA-120 treated patients had regenerative nerve clusters present one year after treatment in the biopsies. Peripheral nerve biopsies were obtained at baseline and at one-year post-gene therapy transfer in the superficial 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 one compared to baseline. The remaining two samples were unable to be assessed due to biopsy limitations. Collectively, these data confirm the presence of regenerating nerve 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 cannot only respond to treatment, but actually improve as opposed to just stabilize. Here we've included a representative patient case study showing the superficial radial sensory nerve at baseline and one year post-treatment with TASIA 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 one 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 TASHA 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 TASHA 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 provide a definitive clinical endpoint and support recoverability, stabilization, and in some cases, improvement in sensory response in patients treated with TASIA-120. Nerve biopsy histopathology confirmed that treatment with TASIA-120 detected the presence of regenerative nerve clusters suggestive of active regeneration of nerve fibers. Pathological biomarker measurements of retinal nerve fiber layer thickness, as assessed by optical coherence tomography, demonstrated stabilization and prevention of further visual loss following TASIA 120 treatment. Visual acuity, as assessed by LOGMA, also stabilized after treatment. And lastly, we heard from Fred earlier about how an extensive panel of release assays demonstrated that 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 CMT comparability data that Fred discussed, positions us well to further advance TASIA 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, point 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 Ellicell for the treatment of cerebral leukodystrophy, Upstaza for the treatment of AADC deficiency, SRP9001 for Duchenne muscular dystrophy, and tefersin, the 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, they were supportive of our proposal to perform validation work, including patient and family feedback, which is ongoing on the MFM32 as a key clinical endpoint. We believe this positive feedback from the MHRA, in conjunction with the totality of preclinical data generated to date for TASHA 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 registration requirements from regulatory agencies including the FDA and EMA, we have outlined some possible scenarios for approval. For the EMA, we believe there is potential to file for conditional approval based on current data set per EMA guidance documents. For the FDA, the first scenario is 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 Zolgesma 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, TASHA 120 previously received orphan drug and rare pediatric disease designations from the FDA. Next slide. Let's turn to the late-breaking preclinical data we reported today for TASIA-102 in Rett syndrome. Next slide. As a reminder, Rett syndrome is an X-linked neurodevelopmental disorder that is characterized by mutations in MEKP2, a protein essential for neuronal and synaptic function in the brain. Female heterozygous patients with Rett syndrome are mosaic carriers of normal and mutated MEKP2. The challenge in gene replacement therapy of MECP2 is finding the appropriate balance for sufficient physiological expression to correct the deficiency, whilst also avoiding overexpression and the associated toxicity. The estimated prevalence of Rett syndrome is 350,000 patients worldwide, with an incidence 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 have caused dose-dependent side effects after intra-CSF administration in wild-type and Rett syndrome knockout mice. We have developed a novel miRNA-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. TASHA-102 regulates expression of MeCP2 using a novel microRNA-responsive autoregulatory element platform known as MiRAIR that is exclusively licensed to TASHA and developed by Drs. Sarah 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 targeting panel for endogenous microRNAs, which regulate MeCP2 expression. In the presence of high levels of intracellular MeCP2, endogenous downregulatory microRNAs are secreted as part of the cell's normal feedback inhibitory process, which then bind to the MRI 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 in a mosaic patient, stay within appropriate physiological levels. Next slide. Today, we're excited to share near normalization of survival in neonatal mouse models of Rett syndrome following TASHA-102 administration. Survival was significantly extended in MECP2 knockout male mice following a single CSF injection at day two of TASHA-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 nine weeks in a vehicle treated mice. All cohorts, including vehicle, were sacrificed at 34 weeks. Next slide. We then looked at the BIRD score, which is a composite measure of six different phenotypic abilities that relate to Rett syndrome. These include breathing, gait, general condition, hind limb clasping, mobility, and tremor. Over the course of the study, TASIA-102 appeared to normalize behavior as assessed by the BIRD score. Next slide. The totality of preclinical data generated to date for TASIA-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 BirdScore. 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 why we were able to ascertain a minimally effective dose. We've also previously discussed toxicology data supporting a favorable safety profile of Tayshia-102 in Sprague-Dawley wild-type rats up to a six-month time point, and up to human equivalent doses fourfold over the clinical starting dose. The nerve conduction studies performed remained the normal range for all groups at all time points, signifying no evidence of dorsal root ganglia inflammatory change. And lastly, toxicology data supporting TASHA-102 was well tolerated at human equivalent doses of up to 2E15 total VG, and demonstrated a broad by distribution to brain, spinal cord, and systemically in non-human primates. Perhaps most importantly, the toxicology studies demonstrated that the down-regulatory MI-RARE platform is working well, and that there was minimal expression of MEKP2 in a wild-type cell with normal pre-existing levels of MEKP2. These four preclinical studies together represent a comprehensive and a robust package supporting the clinical advancement of TASHA-102 for Rett syndrome. Next slide. Our first in-human phase 1-2 study of TASHA-102 for Rett syndrome, also known as the REVEAL study, is ongoing. St. Justine 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 Rossignol. Target recruitment is up to 18 adult females. It is a three plus three study design with three randomly selected delayed treatment control participants in each dose cohort. And each cohort may be expanded with up to three additional participants. Next slide. We look forward to preliminary Phase 1-2 clinical safety and efficacy data in adult females by year-end 2022. We have completed GMP manufacturing for RET using our commercial process. And lastly, a study in the pediatric female RET population and a rescue study in RET males are planned for 2023. As a reminder, TASHA 102 has been granted a rare pediatric disease designation. an 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 Cameron to review our financial results. Cameron?
spk06: 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 three months ended June 30, 2022, compared to $30.6 million for the three 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 three months ended June 30, 2022, compared to $10.1 million for the three 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 in incremental employee compensation expenses. Net loss for the three months ended June 30th, 2022 was $33.9 million or 84 cents per share as compared to a net loss of $40.9 million or $1.09 per share for the three months ended June 30th, 2021. As of June 30th, 2022, the company had cash and cash equivalents of $66.2 million compared to $149.1 million on December 31st, 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.
spk15: Thanks, Cameron. We remain focused on achieving our anticipated near-term milestones in 2022 and building long-term value. Our programs in GAN and Rett Syndrome continue to advance and demonstrate exciting disease-modifying potential, as further supported by the new clinical nerve conduction data in GAN and neonatal preclinical data in Rett Syndrome, presented today. As we look ahead, we expect a regulatory update for our GAN program and preliminary Phase I-II data for TASHA-102 in adult females with Rett Syndrome by year-end. I will now ask the operator to begin our Q&A session. Operator?
spk04: Thank you. And at this time, we'll be conducting a question and answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for questions.
spk02: And our first question comes from the line of June Lee with Truist Securities.
spk04: Please proceed with your question.
spk08: Good morning. Thanks for taking the questions. It's actually awesome on for June. I'm just wondering, have there been any discussions with the FDA on regulatory alignment for 120? Just thinking mostly in terms of the three scenarios that you've previously laid out on whether or not the FDA might ask to re-dose patients with GMP material. Also, said discussions have occurred, you know, will safety data be sufficient or, you know, has the FDA maybe indicated additional need for efficacy biomarker or clinical data? Thank you.
spk15: Good morning. Maybe I'll start and then I'll turn it over to Suyesh to provide some additional insight. What we've guided to this morning was that we'll have additional feedback from regulatory agencies, including the FDA, by the end of the year. I think the regulatory feedback that we denoted from MHRA kind of aligns ourselves with what we considered scenario two, which is the need to dose additional patients using the commercial You know, we kind of see that as our base case, and that's what we've been planning for. The good thing about that is the patients are already identified. They're currently in our natural history study, and what we would do is just roll over patients from the natural history study into the current ongoing trial. We would do that once our GMP material is actually fully released, which should happen here in the next few weeks, which we're quite excited about. And the fact that, as we've denoted on the call, that the original clinical trial material and the new commercial grade material are virtually identical across all key quality metrics. So I think when you look at all of those things in consideration, I think that lines up nicely for how we're planning to move forward, which we consider scenario two is probably the most likely case. That would be the need to dose a few more patients using the commercial materials. I think ultimately our discussion with the agencies will really be about how to accelerate whatever the potential filing would be. And I think the use of a rolling submission would be something that I think we would be more encouraged to ask the agencies about. I think this environment, what we're seeing from a regulatory perspective, is a good environment, particularly for gene therapy and CNS therapy. The agency has shown significant flexibility, and I think we've listed off a number of those examples, both the FDA and EMA. So we feel pretty good about our approach. Keep in mind, we've now shown you data across multiple functional endpoints. We've now shown you data across pathological endpoints. We've now shown you data across definitive endpoints that, again, are hard endpoints that don't include any type of perceived bias. So with all of that totality of data, coupled with the comparability data that we now have in hand, we feel pretty good about our discussions moving forward with the agencies. So I'll pause there to Jesse. Suyas, do you have anything to add, or we can move on?
spk03: I think you said it all right. Perfect.
spk08: All right. Well, thank you. And then if I could just ask, you know, 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.
spk15: The answer to that is yes. That's 50 doses at the high dose, which is 3.5E to the 14th.
spk03: Okay. Sounds great. Thank you.
spk02: Thank you.
spk04: And our next question comes from the line of Joe Bloom with Needham and Company. Please proceed with your question.
spk05: Good morning, everyone, and thanks for taking our questions. 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?
spk15: So thanks, Gil, for the question, and good morning. So our previous guidance was that we would have regulatory feedback by year end. We didn't disclose from what agency we would have that feedback from, so essentially the feedback that we provided on the call today is in line with that previous guidance. What we've decided to do, because of the success of our commercial-grade manufacturing run and the comparability data that we've generated from that, including potency assays, including release assays, as well as the additional clinical trial data that we showed you guys today, what we decided to do was essentially hold the submission to the FDA until we had a fully robust, baked CMC package. We now have that. I think you would probably consider that package extremely comprehensive, again, across all the clinical endpoints that we've shown you. But more importantly, I think the CMC data, which is really where I think the crux of the conversation was going to be, the fact that we're seeing virtually identical material across a number of key attributes, including next generation sequencing, I think is going to be extremely compelling to the agency. So we wanted to make sure we actually had that data in hand as the manufacturer run got underway and we saw the progress that it was making and the good progress that it was making, we decided to hold that. And so now we'll be submitting that full data package to additional regulatory agencies, including the FDA. And so we expect that to provide the FDA the information to be able to provide clear guidance around what the registration pathway would look like. And for us, we think that aligns with probably most likely scenario two, the use of the accelerated pathway, but the need to dose a few patients using that material, which is actually released in September. So this all lines up nicely, and it's pretty consistent with what we said when we talk about what a potential launch date could be.
spk05: Okay. And maybe a question on SNAP. How well established is SNAP as a surrogate endpoint for function in GANs? I mean, it is remarkable to see something going from zero to something, but just to help us understand the functional benefits.
spk15: No, absolutely. So, yes, do you want to answer, and I can provide some comments after?
spk02: Sure.
spk15: Yeah, hi, Gil.
spk16: You know, 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 two, the snaps are well within the normal range, and they rapidly decline from the age of about two and a half, three, to the point where by the age of four, every child has an abnormal snap. By the age of nine, everyone has an absent snap. And what I would say is that this kind of pattern is quite consistent with other axon neuropathies and other similar hereditary sensory motor neuropathies where you do see the nerve conduction studies being affected quite dramatically. What I think is important with GAN is the fact it really mirrors what's happening clinically and correlates very nicely. You know, we've talked before about how patients with this disease generally are symptom-free in the first few months of life. They may have slightly delayed motor milestones. Around the age of two, two and a half, these children present with unsteadiness and a wide base gait. and a high stepping gait, because they can't feel the ground beneath their feet. And this is exactly what these nerve conduction studies are demonstrating. I think one point I will make is that what you're looking at, and I tried to get into this in the presentation, there are three parameters you'll get 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 the actual nerve and nerve conduction is really in that earlier times were used in the demyelinating disorders such as 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 axons, amplitude is the key parameter. And you can see how it correlates very nicely in the natural history. But more importantly, actually, clearly stabilizes or even improves. And you're right, Gil, the fact that a handful of patients improved from zero and are still continuing on an upward trajectory is very impressive. And it's also reflected in what I shared in the biopsy data where you saw an increasing presence of regenerating nerve clusters. Let me stop there.
spk15: I could go on even longer, but let me stop there. The only thing that I would add, and thanks, Suyesh, the only thing that I would add to what Suyesh mentioned is I think it's important to note that SNAP is a definitive clinical endpoint. Essentially, it's a hard endpoint, and it's functional. And I think when you look at that in correlation to what Suyesh mentioned around how it correlates to MFM32, how it correlates to biopsy data, how it correlates to the LogMar data that we've shown before, I really start to think all these things are moving the exact same way. You really start to put together a really nice clinical package, and really you have to look at the totality of the data sets. It's all moving the exact same way. So we feel really good about this, and again, You know, having this data in hand allows us to just have even more robust engagement with regulatory agencies around the most accelerated pathway.
spk05: Thank you. That was very helpful. And the last one on red, when would you need to dose a male rescue study? The timing there seems pretty important, but if you can help us understand that.
spk15: It's a really good question. Siyush, maybe you just want to comment on kind of the phenotype of the males and how they correlate to the knockout animal, and then maybe go deeper into Gil's question. Sure.
spk16: Yeah, so the important thing here is that the males are knockouts, and for an X-linked disease, this means that they have no metabt whatsoever. In contrast to the females, where the females are are mosaics and half their cells have normal levels of MeCP2, the other half have mutated or absent MeCP2. And so in the clinical setting, the males actually are more severely affected and the vast majority in the human situation actually die in utero. A handful survive and not survive through early infancy and may die in the first few months of life or sometimes live up to the age of two or three. and then succumb usually to due to a respiratory infection or some respiratory compromise. So it's a very, very severe form of rep. And there aren't many of these patients, the male knockout males, um, that survived and perhaps 200 in the world. So, and they've also been a fairly, um, I guess a forgotten group and the rep, um, patient community are actually very pleased that there's part of our clinical development program, which, as we alluded to earlier in the call, we're starting in adults initially. During the course of 2023, we'll start a pediatric girl study, and then we'll also do a pediatric boy study, a rescue study. And the patient community are very happy that we're actually addressing this kind of underserved population. Specific on your question around dose skill, it's a really interesting question. You know, on the one hand, there's an argument to go, with a higher dose because these boys, the higher dose that we're starting for our pediatric, our girls' study, which is starting at 5E14 total VG. And from our previous pharmacology, mass pharmacology study, we ascertained that the minimally effective dose was around 3E14 total VG. So we're actually going in above that at the 5E14 total VG. There's nothing to go slightly higher than that in the males, but actually our plan is to start at the same dose. that 5E14 total VGE in the pediatric boys study I think will be quite significant in improving that phenotype. Likely, we will go up to a second dose of a 1E15 as well.
spk02: All right. Thank you for taking all of our questions, and good luck. Thank you. Thank you.
spk04: And in the interest of time, We do ask that each person limit themselves to only one question. Again, in the interest of time, please limit yourself to only one question. Our next question comes from the line of Salveen Richter with Goldman Sachs. Please proceed with your question.
spk12: Hi, thanks for taking our question. Congrats on the progress. This is Tommy on for Salveen. We have 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 timelines? Thank you.
spk15: Thanks for the question. I'll turn it over to Suresh, and maybe I'll provide some additional comments once he's done.
spk05: Suresh?
spk15: Sure.
spk16: Yeah, I mean, that'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 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 a 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 can treat before the SNAP is lost, before it becomes absent, you're more likely to see an improvement 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 absent SNAP and an absent SNAP for a period of time, we actually saw improvements in the nerve conduction SNAP amplitude that continued on the upward trajectory. With regard to the MHRA, yeah, 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 two, i.e., a handful more patients with clinical trial material. We tried in that discussion, and it was a very collegial, fruitful, long, in-depth discussion across all aspects of the program. I mean, I was there. It was over two hours. We talked about 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 and 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 three to five patients for about six months. So our thinking was well let's also continue with other agencies. And once we've got the feedback from all agencies, we can 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 three to five patients for about six months.
spk03: Thank you.
spk02: Thank you for the question.
spk04: Our next question comes from the line of Mike with Morgan Stanley. Steve, we'll see what your question is.
spk01: Hey, guys. Thanks for taking the question. Just on GAN, you mentioned doing some additional validation work on the MFM32 endpoint. Can you just give us a sense of your plans there and maybe how long that validation work might take? Thanks.
spk15: Thanks, Mike. Good morning. One comment I'll make before I turn it over to Suyesh is that that validation work has actually been ongoing for quite some time, so we feel pretty good about the timeline there. And the fact that MSM32 has been used as a regulatory accepted endpoint in a number of neuromuscular diseases. So, we also feel good about that there. The particular work on GAN, I'll turn over to Sush to discuss further.
spk16: Sure, thanks. And thanks for the question, Mike. So, the RA is quite correct. The MSM32 is actually validated for pediatric neuromuscular disease in general. and has been used several times previously 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 jaundice-only neuropathy. And we actually talked about this with the MHRA, and they were very open to and accepting and pleased that we'd actually started this work. Now, there's three pieces to this work. The first is to any kind of validation work. The first is this general qualitative feedback that's 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 in about six to eight weeks time. So you'll be able to see that work in detail in the near 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 called content validation. So that'll be the next step. And then once we've done the content validation, there's another whole additional process known as psychometric validation, where we take all the natural history study data, and we take all the data from the interventional study, look at how the MFM32 correlates with other aspects of other endpoints, other aspects of the disease, and also with the qualitative information we picked up in the qualitative interviews and in the content validation piece. And then we can do a formal psychometric validation. That all gets written up as a package. We'll usually publish this work, and it'll end up being quite a significant report that goes in with the actual BLA filing and sort of other regulatory interactions. In terms of timing, The process, it can usually take quite a long time, you know, 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 the people who have done the MFM, this truncates the timeline somewhat. So it's probably going to be, I would guess, a 9 to 12-month process from now.
spk02: Got it. Thank you. Thanks, Mike.
spk04: Our next question comes from the line of Ewan Yang with Jefferies. Please proceed with your question.
spk11: Thank you very much for squeezing me in. So I have one question and another very quick question. So first the question is, for the Rett syndrome data that we are expecting, you know, you studied the study in Canada probably, you know, early 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 that still on track? Thank you.
spk15: Good morning, Yoon. Thanks for the question. Maybe I'll take the question, and if Suyash had anything to add, I'll turn it over to him. But on your first question, we typically haven't commented on how many patients' worth of data that we provide in any of our other indications or data updates. You know, so I think we're going to remain consistent with, you know, with that operating procedure. What we will guide to is that you will have data in Rett syndrome by the end of the year, patient data in Rett syndrome by the end of the year that will disclose to the street. So we're staying consistent with that guidance. Your second question around, you know, kind of what we've guided to in the past from a timing perspective in GANs, I think, again, I think we're staying relatively consistent. You know, I think the initial regulatory feedback that we've received aligns itself with scenario two. I think, you know, some of the recent discussions that have happened in other indications and other companies with both the FDA and the EMA is showing a nice flexibility around the use of the accelerated approval pathway. I think the way that our comparability protocol has evolved played itself out, as well as the commercial yields or the yields that we've gotten from our commercial runs all support, you know, this notion of being ready to follow BLA as soon as possible. And so, ultimately, I think we're still on that same time period. I think what I've guided to the past is always by the end of 2023 or early 2024 from a commercial launch perspective, and I think we're still on that time period. Ultimately, this is going to be a discussion point for the regulators, but certainly the preclinical data is all completed. The majority of the preclinical data has been published for quite some time. We now have a strong CMC comparability package that basically shows that our material from the clinical trial and our commercial grade material are virtually identical by a number of key attributes. And we now have significant clinical data across multiple functional pathological hard endpoints, you know, coupled with biopsy, right? I think when you look at that, it's probably one of the most robust packages, you know, from a rare disease perspective. And so we feel pretty good about it and the fact that all the data is moving the exact same way. So what I'll say is I think we're consistent with that timing. Previously, I think I've always guided you by the end of the year, the end of 2023 or early 2024. And so I think we're still within that time.
spk11: Thank you.
spk02: Thank you.
spk04: Our next question comes from the line of Jack Allenwood-Baird. Please proceed with your question.
spk05: 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 we'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 in GAN, any comments you can make with regard to the doses those patients received and any dose dependence you saw in those SNAP results would be great. Thank you so much.
spk15: Hey, Jack. Good morning, and thank you for your question. So to your first question, I don't think we would guide to whether we had a meeting or have a meeting on the books. I think what we are confirming is that we will have feedback from the FDA around the regulatory pathway by the end of the year. We feel pretty good about that guidance. And I think that is not only the FDA, but that'll be also other regulatory agencies. We would be able to provide a pretty robust update on that by the end of the year. So we're staying kind of with that guidance, but I do think the data that we've shown you guys this morning, more particularly the comparability data that Fred and his team have done a great job being able to generate, is really what the key outstanding question, I think, you know, probably more so from the, you know, from the analyst community, but also the fact that are you able to produce at commercial scale, identical products in order to get those same clinical results, right? And, you know, again, I think the approach that Fred has taken has just been phenomenal. And the team has done a great job in generating these results, not only across a bunch of key attributes, but also being able to confirm it by next-generation sequencing. And I think that's a very important point as well, that we're basically seeing identical products. I look back at the old Zolgensma pathway back in the day when we were having these similar discussions around the clinical trial material generated at Nationwide and then eventually what became the commercial material that was generated at the Libertyville facility. It literally was night and day. It was night and day to what we're actually seeing and what Fred's team has been able to do. So we feel pretty good. about going into those meetings having solved the big question. That's always been the big question. Also around potency assay. And Brett and his team, along with Suyesh and his team, have now generated a matrix of potency assays across, again, a number of key quality attributes that we feel extremely good about that are functional in nature and reproducible. And we've now finished that work in-house and have tech transferred that work out. um to a cro so again everything is moving exactly the the way that we'd like it in order to hit the timeline that i just laid out so we feel pretty good about that so hopefully that answers your first question jack could you um could you repeat your second question yep yep thank you so much for the color on the first question that does a great job of uh answering that uh the second question is really briefly any comments you can make around dose dependence of the snap results
spk05: I realize there's a limited cohort here, but I'd love to hear about what doses those patients received.
spk15: No, it's actually a really good question. Suyas, do you want to comment there? Sure, yeah.
spk16: You know, 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 2 was a 1.2E14, cohort 3, 1.8E14, and cohort 4 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 four-dose cohorts, and we would have 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 dose cohorts two, three, and four were generally pretty comparable. And that was also true for the SNAP. You saw nothing for the very low-dose cohort, but you saw improvements in the higher-dose cohorts. There's 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 are all resulting in good improvements, both in SNAP and in the presence of regenerative nerve clusters.
spk02: Great. Thanks so much. Thanks, Jeremy.
spk04: Our next question comes from the line of Yun Zong with VTIG. Please proceed with your question.
spk10: 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 I also wanted to confirm that by year end when you provide feedback, will that feedback include EMA feedback as well? And because, you know, EMAs sometimes can be less flexible in terms of clinical endpoint versus surrogate endpoint that you talked on the call. Thank you very much.
spk15: Thanks, Ewan. Maybe I'll start and then I can turn it over to Suresh that can provide an update. I think, you know, from your second question, I think the EMA actually is a little bit of, I think it may be opposite of your assessment. They've actually shown quite a bit of flexibility, particularly around the use of their conditional approval pathway as well as this notion around the totality of data. What I would also say is the fact that there's no surrogate endpoints here. I think what's interesting is we have multiple functional endpoints. We have now shown you guys a definitive hard endpoint We've now shown you guys data around visual acuity and the stabilization of visual acuity, the stabilization and the loss of retinal nerve fiber thickness. We've now shown you guys biopsy data that correlates to all the functional outcomes. And couple that with, again, the comparability data that we've laid out. So we feel pretty good. about, we feel pretty good about going into those discussions, going into those discussions with a very robust package. And just on top of that, I think most important, the safety across, let's call it seven years. This was the first inerthically dosed gene therapy trial in history. So we now have seven years worth of safety data. And the safety has been consistent. And this drug seems to be extremely well tolerated in the clinical setting. And so for us, we feel, again, really, really good about it. I think to your first question around will that update by the end of the year include feedback specifically from the EMA, what I will say is we will have feedback from multiple regulatory agencies. including the FDA, by the end of the year. We do plan to engage the EMA within this time period as well.
spk02: Yoon, did that answer your question? Oh, yes, it did. Thank you very much. Okay, perfect. Thank you.
spk04: Our next question comes from the line of Sammy Corwin with William Blair. Please proceed with your question.
spk13: Hi, you 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 kind of speak about how dosing in the RET trial is going?
spk15: So to answer your second question, first, We typically don't guide around, you know, first patient dosed or kind of ongoing dosing of patients. We're just going to kind of remain consistent with that and just reiterate the guidance that you will have preliminary clinical data, patient data by the end of the year. And Rhett, we're pretty confident of that. I think most important was the late-breaking preclinical data that we showed you guys today, which just in my opinion was extremely remarkable in a disease like Rhett and in a extremely severe mouse model which is the male knockout model where we saw near normalization of survival and actually never got to a median survival throughout the life of throughout the conduct of the study was just extremely encouraging and for me just reinforces the need to keep moving this program forward quickly but also the ability to be able to get down into that pediatric girls population which are the most effective patients, but also those pediatric boys. That's the fact that we're able to see the results, not only consistent from a survival perspective, but also from a behavior, being able to normalize behavior as assessed by the BIRD score, being able to normalize body weight. I think taking that data in the neonatal model also correlates to what we've shown you from that large pharmacology study that we presented. We presented this data at ASDCT. where, again, we saw improvements in survival, motor function, behavior, but also respiratory function, which was quite remarkable. So for us, we think that, again, the totality of data, both efficacy and safety, puts this program, you know, kind of puts this program in rarefied air, to be quite honest, and just really encourages us to move quickly in order to get to those pediatric girls, as well as that rescue boys study. and to do it urgently for patients. So that's our question on red. And could you just repeat your question on GAN?
spk13: Yeah. Do you think these additional GAN patients you plan on dosing in September once the commercial material is released, do you think that quantity of patients and duration of follow-up will also satisfy the FDA if they want an additional patient's dose?
spk15: Sure, I'll start and now let Siyesh take over. I think that's exactly what our plan calls for, is alignment around patient numbers. I think what we had always planned to do was to proactively dose patients, right? As soon as this commercial material is available, which should be here in the next few weeks, we expect this material to be fully released with all the comparability work completed. We plan on initiating patient dosing where these patients are essentially already identified. We've had a protocol amendment that went through about four or five months ago, if not longer, that allows us to dose down to age three, to actually start dosing younger patients. So it's always been our intent to continue dosing patients, but I would say to get alignment between all regulatory agencies, particularly around The number, but also the duration, I think is extremely important. But I think consistent with what these agencies have shown recently, which, you know, again, gives us a high degree of confidence, you know, I think the plan that Sue Yesh laid out, which is what we are, you know, internally are planning for three to five patients for about six months of follow-up, you know, I think should be sufficient. But again, we really do need to have that conversation with regulators. I'll stop there. Sue Yesh, do you have anything to add?
spk16: Not really to add, but just to emphasize the fact that, you know, we'll look at all the regulator 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 will 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.
spk15: The only thing that I would add to your point… Yep, thanks, Sammy. The only thing that I would add to Suresh's point is that, again, this timing is consistent with what we've kind of laid out. I think what the big piece and what the seminal ask for us will be is the fact that if we can initiate a rolling submission. Because, again, the CMC data, the comparability data is kind of all completed. The potency assay is completed. That work is being tech-transferred right now. When you start to think about the majority of the clinical data, you know, it's been ongoing for seven years, and both from a safety and efficacy perspective across multiple endpoints. Natural history data has been ongoing for two years before that, right? So we're approaching almost 10 years of natural history data. So it's a big wealth of data. It's a big – wealth of data in a relatively small population, which I think we are quite encouraged about, but certainly the FDA will need some time and other agencies will need some time to go through it. So, you know, we feel really strongly about this approach around a rolling submission in the use of an accelerated pathway. So that's ultimately going to be our ask.
spk02: And our last question comes from the
spk04: Our next question comes from the line of Kristen Kluska with Cancer Fitzgerald. Please proceed with your question.
spk07: 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 at dosing? Thanks.
spk15: Thanks for the question. I think what's probably more important is how you relate this towards natural history and the fact that this patient actually has a positive SNAP three years after dosing, which I think is extremely important. When you contrast this with natural history, virtually every patient in the natural history cohort at this particular time point, and this would be consistent with patient A, would have zero SNAP. So the fact that we're actually seeing stability in a positive response is extremely remarkable. So, you know, what I would say is it's a small data set, but even with patient A, showing stability in a positive way that's durable is extremely important, particularly in the context of a relentlessly progressive neurodegenerative disease, essentially. So this is consistent with what we're seeing in the biopsies. but this is in total contrast to what you would see in the natural history. I'll pause there. Do you have anything to add?
spk16: I'll just echo 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 their base level and their dose, their score is about six microvolts, and that is well below the normal limit and is from the actual history data is on a very rapid downward trajectory. So that SNAP 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 were hoping to see. The only reason it doesn't look so good is because the other patients have actually done so much better. So yeah, we were happy with that. We were very happy with that patient's performance. especially in comparison to the natural history, but simply because most of the other patients did significantly better. And once again, you know, 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 have a zero SNAP amplitude for well over a year. And for them to improve that, and for patient B in particular, to be close to normal at the three-and-a-half-year time point and still on an upward trajectory is really very significant. You would not have expected to see this in a neurodegenerative disease, so it's very powerful data.
spk02: Thank you. Thank you. Thanks for the question.
spk04: And we have reached the end of the question-and-answer session. I'll now turn the call back over to Mr. R.A. Session for closing remarks.
spk15: Thank you, Operator. And again, I think we've been quite excited about the progress that the company has made across our core programs, Angina Xenonaropathy and Rett Syndrome. I think we remain focused on these two key programs, moving these programs forward, particularly in the case of patient 120 again towards an accelerated regulatory pathway. We'll provide guidance and feedback from regulatory agencies by the end of the year, including from the FDA, but we're quite excited with the data that we've shown you guys today. I think, again, for us, this allows us the opportunity to have the most robust package and robust discussion with these agencies really around the totality of the data set that all is moving the exact same way. I think the data that our CMC group, led by Fred Porter, our Chief Technical Officer, presented today, again, shows the fact that we're getting almost virtually indistinguishable drug from our clinical trial material to our commercial scalable process, again, continues to support this notion around like-for-like material. And then turning to our Rett Syndrome program, we feel extremely encouraged by the late-breaking preclinical data that we've shown you guys today, which is showing near normalization of survival in a very severe mouse model. And again, we look forward to reporting preliminary clinical data by the end of the year from our ongoing Phase 1-2 study. I wish you guys a wonderful rest of the week, a wonderful day, and we look forward to connecting here in the near future.
spk04: And this concludes today's conference and you may disconnect your line at this time. Thank you for your participation.
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