This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk09: Welcome to the Tayshia Gene Therapy's fourth quarter and full year 2021 financial results and corporate update. At this time, all participants are in listen-only mode. Following management's prepared remarks, we'll hold a brief question and answer session. As a reminder, this call is being recorded today, March 31st, 2022. I'll now turn the call over to Dr. Kimberly Lee, Chief Corporate Affairs Officer. Please go ahead.
spk01: Good morning and welcome to Tayshia's fourth quarter and full year 2021 financial results and corporate update conference call. Joining me on today's call are Ari Session II, Tayshia's president, founder, and CEO, 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. Earlier today, Tayshia issued a press release announcing financial results for the fourth quarter and full year ended December 31st, 2021. A copy of this press release is available on the company's website and through our SEC filings. Please note that on today's call, we will be making forward-looking statements, including statements relating to the safety and efficacy and the therapeutic and commercial potential of our investigational product candidates. These statements may include the effects of timing and results of clinical trials for our product candidates, our expectations regarding the data necessary to support regulatory approval of TASHA 120, the regulatory status and market opportunity for our clinical programs, as well as Tayshia's manufacturing plans. This call may also contain forward-looking statements relating to Tayshia's growth and future operating results, discovery and development of product candidates, strategic alliances, intellectual property, cash runway, and implementation and potential impacts of our strategic pipeline prioritization initiatives, 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 requirement 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, March 31, 2022. TASHA 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. With that, I'd now like to turn the call over to our president, founder, and CEO, R.A. Session II. R.A.?
spk06: Thank you, Kim. Good morning, and welcome, everyone, to our call. 2021 was a year of accomplishment that included positive data from three clinical programs, including GAN, GM2 gangliosidosis, and CLN7 disease. We are sharpening our strategic focus to prioritize key value-driving registration-directed programs in GAN, which has an estimated addressable patient population of 5,000 worldwide, and Rett Syndrome, which affects over 350,000 patients worldwide. To increase operational efficiency, activities for other ongoing clinical programs will be minimized and all other research and development will be paused. As a result, we have reduced our workforce by approximately 35%. Our strategic pipeline prioritization, along with existing cash and financing under our current debt facility, is expected to extend cash runway into the fourth quarter of 2023. We look forward to our continued execution across our clinical and regulatory strategies, and we'll update you on progress throughout the remainder of the year. I will now turn the call over to Suyesh to provide a more detailed update on our clinical program.
spk07: Suyesh, please go ahead. Thanks, RA. Recently, we reported positive initial clinical data for GAN, GM2 gangliosidosis, and CLN7 disease, further validating the therapeutic potential of our platform in multiple diseases of the central nervous system. Let's begin with TASHA 120 for the treatment of GAN. TASC-120 is the first gene therapy to be intrathecally dosed and is currently being evaluated as part of a groundbreaking historic dose escalation clinical trial at the NIH under the leadership of the principal investigator, Karsten Bonneman. We recently reported positive clinical efficacy and safety data for the high-dose cohort of 3.5E14 total VGs. as well as long-term safety and durability data across all therapeutic doses. Treatment with TASHA 120 achieved a clinically meaningful and statistically significant slowing or halting of disease progression seen in the highest-dose cohort of 3.5E14 total VG across all therapeutic-dose cohorts. At the highest dose, TASHA 120 demonstrated clinically meaningful and statistically significant improvements in the MFM32 score by year one compared to natural history. Additionally, long-term durability data across all therapeutic doses demonstrated a 10-point improvement in the mean change from baseline in MFM32 score by year three compared to the estimated natural history decline of 24 points. These long-term data confirmed the disease-modifying effect and sustained durability of TASHA-120. Notably, nerve biopsy data pre- and post-treatment with TASHA-120 provided evidence of active regeneration of nerve fibers, thereby demonstrating pathological improvement to complement the clinical benefits seen. In addition, preservation of visual acuity, as measured by the log-mass scale, was observed. And this was in conjunction with improvements in the retinal nerve fiber layer thickness as assessed by optical coherence tomography. There were no significant safety issues and no increase in adverse events at high doses. All adverse events related to immunosuppression or study procedures were comparable to other gene therapies and transient in nature. There were no dose-limiting toxicities reported following treatment with TASHA 120. no evidence of dorsal root ganglion inflammation, and no evidence of thrombocytopenia. Overall, this dataset is the most comprehensive gene therapy dataset in GAN, offering TASHA 120 a potentially de-risked regulatory path. We believe this program currently meets the most registration requirements based on FDA and EMA's guidance for gene therapy for neurodegenerative diseases. We look forward to our continued discussions with major regulatory agencies on potential registration pathways for TASHA 120 and anticipate a regulatory update by mid-2022. As a reminder, TASHA 120 has already received orphan drug and rare pediatric disease designations from the FDA. We also have partnerships in place to help raise awareness and facilitate early diagnosis of GAM. This includes a partnership with GeneDx the global leader in genetic testing, to include a genetic marker to test for GAN in the GeneDx routine hereditary neuropathy screening panel, which is free of charge to individuals at risk of or suspected of having GAN. It also includes collaborations with the Hereditary Neuropathy Foundation and the Charcot-Marie-Tooth Association Centers of Excellence, as well as healthcare professionals and patient advocacy groups to increase access to genetic testing. Turning to Rett Syndrome, TASHA-102 is the first and only gene therapy in clinical development for Rett Syndrome and is designed to deliver a MeCP2 transgene using a novel MiRare platform or a microRNA responsive auto-regulatory element platform. This technology is exclusively licensed to TASHA and developed by Drs. Sarah Sinnott and Stephen Gray of UT Southwestern Medical Center. MRI is designed to provide sophisticated regulation of transgene expression genotypically on a cell-by-cell basis, delivering controlled expression that prevents toxicity associated with excessive levels of MEKP2. We were very pleased to announce earlier this week initiation of clinical development for TASHA-102 with the acceptance of our CTA by Health Canada in March. St. Justine Mother and Child University Hospital Centre in Montreal, Quebec, Canada, has been selected as the initial clinical site under the direction of Dr. Elsa Rossignol, principal investigator. We also announced positive preclinical data that supported the CTA acceptance, including a pharmacology study in rat knockout mice, assessing the efficacy of TASIA-102, and a six-month GLP toxicology study in non-human primates exploring the biodistribution and mechanism of action of TASHA-102. TASHA-102 has a robust preclinical data package that supports and validates the ability of miRAIR to safely regulate transgene expression. Data from the IND CTA-enabled pharmacology study in mouse models of Rett syndrome demonstrated that MI-RAIR-regulated transgenic excretion improves survival, respiratory function, and motor function assessments across multiple dose levels. A one-time intrathecal injection of TASHA-102 significantly increased survival at all dose levels, with the mid-to-high doses improving survival across all age groups compared to vehicle-treated controls. Treatment with TASHA-102 significantly improved body weight, motor function, and respiratory assessments in MECP2 knockout mice. An additional study in neonatal mice is currently ongoing with preliminary data suggesting normalization of survival. Positive IND-CTA-enabling 600-GLP toxicology data in NHPs reinforced TASHA-102's favorable safety profile across all dose levels tested, including doses up to fourfold above the presumed clinical starting dose. These data are supported by distribution, as reflected by DNA copy number in multiple areas of the brain and sections of spinal cord. Perhaps most importantly, we observed correspondingly low levels of mRNA across multiple tissues. This indicates that the MI-RARE downregulation is appropriately minimizing the transgene expression from the construct in the presence of endogenous MeCP2 in these wild-type NHPs as expected. Let me repeat that. High levels of DNA in target tissues mean that there is good distribution of drug from an intrathecal injection, but low levels of mRNA mean that the downregulation by the MI-RARE platform is working well to minimize any toxicity. Indeed, no toxicity from transient expression was observed, which was confirmed by functional evaluations demonstrating no detrimental change in neurobehavioral assessments, and histopathologic evaluations demonstrating no adverse tissue findings on necropsy. Collectively, these data further support the therapeutic potential, safety, and tolerability of TASHA-102 to treat Rett syndrome across a broad dose range. These preclinical safety and efficacy data will be presented at the International Rett Syndrome Foundation Rett Syndrome Scientific Meeting, taking place April 26th to 27th, 2022, in Nashville, Tennessee. Currently, there are no disease-modifying therapies to treat over 350,000 patients estimated to suffer from Rett Syndrome worldwide. We're excited to advance TASIA-102 as the first gene therapy in clinical development for the treatment of this devastating neurodevelopmental disorder and look forward to reporting preliminary Phase 1-2 clinical data by the end of 2022. As a reminder, TASIA-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. For GM2 gangliosidosis, TASHA-101 is the first and only bisistronic vector in clinical development, representing an important first for the field of gene therapy. Driven by the same promoter, TASHA-101 expresses both the HEX-A gene, coding for the alpha subunit, and the HEX-B gene, coding for the beta subunit, in a one-to-one ratio, enabling the production of functional heterodimeric beta-hexosaminase A, and providing the ability to restore and normalize enzyme activity in GM2 gangliosidosis using one vector. We reported initial positive biomarker data in January for Tayshia 101, demonstrating normalization of beta-hexazomibase A, or HexA, enzyme activity in patients with multiple forms of GM2 gangliosidosis. We shared data for two patients, including month one and month three analyses for a patient with Sandoff disease and month one analysis for a patient with Tay-Sachs disease. Following one intrathecal administration, Tay-SHA-101 achieved hexaenzyme activity of 190% of normal at month one and 288% of normal at month three in patient one with Sandoff disease, representing 38-fold and 58-fold above the presumed asymptomatic level of 5% of normal identified by natural history at month one and month three respectively. Patient two with Tay-Sachs disease achieved hexaenzyme activity of 25% of normal at month one, which represented fivefold above the presumed asymptomatic level of 5% of normal identified by natural history. Preliminary data suggested that TASHA-101 was well tolerated with no significant drug-related events in both patients. The unfortunate death of patient one was attributed to pneumonia and pleural effusion with a concomitant hospital-acquired MRSA infection. The independent Data Safety Monitoring Board agreed with the initial assessment from the principal investigator and confirmed that the patient's death was unrelated to study drugs. Patient two continues to progress well, and we are continuing to monitor patients two and three. We do not intend to pursue further enrollment in the Phase 1-2 trial at this time due to prioritization of programs to increase operational efficiency, but we will continue to follow the patients who were previously dosed. For CLN7, we reported positive preliminary clinical safety data for the first-generation construct in CLN7 Besson disease from the ongoing clinical trial in collaboration with UT Southwestern Children's Health and Children's Medical Center Foundation. We recently dosed a fourth patient at 1E15 total VG, bringing the total to three out of the four patients dosed at 1E15 total VG, which is the highest dose ever safely administered intrathecally in humans for gene therapy. Dose escalation from 5E14 to 1E15 total VG was supported by the Data Safety Monitoring Board. Initial data from three patients supported a favorable tolerability and safety profile with no major adverse events across doses. Further development of the CLN7 program will focus solely on the first generation construct in collaboration with our existing partners. In 2022, we expect several potential value-creating catalysts, including regulatory feedback for TASIA-120 in GAM by mid-2022 and preliminary Phase I-II data for TASIA-102 in Rett syndrome by year-end. Clinical development of the first-generation construct for CLN7 remains ongoing with our existing partners. We will continue clinical development of TASHA 118 in CLN1 disease and expect to initiate clinical development of TASHA 105 in SLC13A5 deficiency this year. With that, I'll turn the call over to Cameron to review our financial results. Cameron?
spk04: Thank you, Suresh. This morning, I will discuss key aspects of our fourth quarter and full year-ended December 31st, 2021 financial results. More details can be found in our Form 10-K, which will be filed with the SEC shortly. As indicated in our press release today, research and development expenses were $37.9 million for the three months ended December 31, 2021, compared to $12.3 million for the same period in 2020. Research and development expenses were $131.9 million for the full year ended December 31, 2021, compared to $31.9 million for the full year ended December 31, 2020. The $100 million increase was primarily attributable to an increase of $38.3 million of expenses incurred in research and development, manufacturing, and other raw material purchases, which included CGMP batches produced by Catalan and UT Southwestern. We also incurred an increase in employee compensation expenses of $32.7 million, which included $7.1 million of non-cash stock-based compensation, due to an increase in the employee headcount and the research and development function. We also incurred an increase of $29 million of third-party research and development consulting fees, primarily related to GLP toxicology studies, clinical study CRO activities, and consulting for regulatory and clinical studies. General and administrative expenses were $11.8 million for the three months ended December 31, 2021, compared to $6.1 million for the three months ended December 31, 2020. General and administrative expenses were $41.3 million for the full year ended December 31, 2021, compared to $11.1 million for the full year ended December 31, 2020. The full year increase of approximately $30.2 million was primarily attributable to $16.3 million of incremental compensation expense, which included $7.7 million of non-cash stock-based compensation due to increases in employee headcount. We also incurred an increase of $13.9 million in professional fees related to legal, insurance, investor relations, communications, accounting, personnel recruiting, market research, and patient advocacy activities. Net loss for the three months ended December 31st, 2021 was $50.4 million or $1.32 per share as compared to a net loss of $18.3 million or 50 cents per share for the three months ended December 31st, 2020. Net loss for the full year ended December 31st, 2021 was $174.5 million or $4.64 per share compared to a net loss of $60 million or $3.40 per share for the full year end of December 31st, 2020. As of December 31st, 2021, Taysha had $149.1 million in cash and cash equivalents. Our strategic pipeline prioritization initiatives along with existing cash and financing under the current debt facility, is expected to extend cash runaway into the fourth quarter of 2023. And with that, I will hand the call back to RA.
spk06: Thanks, Cameron. This year, we are focused on strategic pipeline prioritization initiatives for GAN and RET syndrome and our plans to conduct small proof-of-concept studies in CLN1 disease and SLC13A5 deficiencies. We anticipate several potentially value-creating catalysts this year, including a regulatory update for TASHA 120 in GAN by mid-year and preliminary clinical data for TASHA 102 in Rett Syndrome. I would like to give special thanks to the continued support and dedication of our TASHA employees, board of directors, scientific advisory board, collaborators, and the patients and advocates who remain our motivation every day to continue our mission to develop curative gene therapies to eradicate devastating monogenic CNS disease. I will now ask the operator to begin our Q&A session. Operator?
spk09: Thank you. At this time, we'll now be conducting a question and answer session. If you'd like to ask a question today, please press star 1 from your telephone keypad, and 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. So that we may address questions for as many participants as possible, we ask that you limit yourself to one question. One moment please while we poll for questions. Thank you. And our first question comes from the line of Salveen Richter with Goldman Sachs. Please proceed with your question.
spk10: Hey, good morning. This is Elizabeth on for Salveen. Just given the strong data that you had for GM2 this year, I guess why choose to deprioritize that program?
spk06: Hi Elizabeth, good morning. Hopefully you can hear me okay. I think it really boils down to really focusing on a couple of key value drivers this year. Just with the uncertainty in the capital markets from a fundraising perspective, I think it was really imperative to put the company in the best possible position for when red data would be available as that's a pretty large opportunity. We're talking about 350,000 patients worldwide and really the significant medical need there. What I would say is I think there's always the opportunity to take another look at prioritization once we see external factors stabilize somewhat, but I think this was extremely important to make sure that the company itself was put in the best possible position to preserve cash runway, but also value creation. Obviously, the focus on GAN is pretty evident because we're going to be embarking on regulatory pathway discussions. And then, you know, RET is just such a large opportunity and one that we're going to be the first and only gene therapy in development where a lot of other companies haven't made it that far. We thought it was just prudent for us to focus there. So hopefully that answers your question.
spk09: Thank you. Our next question is from the line of June Lee with Truist Securities.
spk08: Hi, thanks for taking our questions. In addition to restructuring, would you also consider monetization of some of non-core programs via out-licensing or partnering? And then also our understanding is that the term loans from SVB is contingent upon you having three active programs. So in addition to GANs,
spk06: or red do you plan to have a third program still active thank you hey jim good morning thanks for the question so i'll take the last question first so i think as we stated you know there will be a key focus on dan and red syndrome but we're also going to be continuing development on CLN 1, CLN 7, and XLC 1385. So in total, there's five active programs. I think what we've decided to do is essentially pause work on additional clinical programs as well as programs moving from pre-clinical uh into the clinic and and that's really where i think the prioritization came from so we significantly meet uh the requirements uh for that uh that loan facility and that was actually just validated um as we filed the the case um your your first question around um bd opportunities i think you know As the former head of BD in my former career, I think we are always open to having conversations around BD. I think for us, what would be important is to, if we were to do a deal, is to find a partner that either has an opportunity for us to reach markets that we don't necessarily have or to accelerate programs that we cannot. What I will say is there's active discussions around potentially looking at opportunities for ex-U.S. territory type of deals that could accelerate clinical development and speed to market in certain parts of the world. But I think this is something that we'll always kind of keep as dry powder. I think we will always look at ways to bring in non-diluted forms of capital while accelerating our programs. I think that's always a prudent thing to do. So really good question.
spk09: Our next question is from the line of Mike Ulms with Morgan Stanley. Please proceed with your question.
spk15: Hey, guys. Thanks for taking the question. Just with respect to GAN, maybe you can just give us an update on your current thinking on the path forward there in the U.S. And in the past, you had mentioned analytic comparability as one of the potential scenarios there. And I'm just curious if you've done that analysis yet. Or are you waiting to get feedback from the FDA before you move forward with that? Thanks.
spk06: Thanks, Mike. Really good question. So really, I think it boils down to three scenarios in the United States with GAN. And XUS is kind of slightly different. I think there's a clear pathway when you start to think about the EMA, which opens up the rest of the world who references the EMA. But particularly for the FDA, it boils down to three scenarios. I think two are higher probability. One is lesser probability, but certainly could always be a route that the FDA asks you to go. Scenario one would be if the FDA allows you to file with analytical comparability, essentially doing an analytical bridging study between the clinical material and the commercial grade material. In order to, what we would say, increase the probability of success of this option, what we decided to do was keep the manufacturer of this program at the same CDMO partner that manufactured the clinical program. We're using the same cell line, same media, same downstream purification. So essentially it's a life for life process and we wanted to make sure we held these things constant because we wanted to be able to increase that probability. This, I would probably say, would be, you know, probably not the FDA's preferred route. We haven't had that conversation with them. But if you just look at the comp and the closest comp to this would be the experience of Zolgensma, that would more align to option two. And I would say option two is probably our base case. And this is essentially what we're planning for internally. And this would be somewhat a bridge between filing on analytical comparability and doing a new study. This is essentially where you would dose a handful of patients under the current IND and protocol using the commercial-grade materials. The goal would ultimately be to propose to the FDA filing a rolling submission, essentially filing the preclinical data first. That's not changing. That's all there. Then starting to supplement the filing with the clinical data that's already been generated, which we now have seven years' worth of data, safety and efficacy data, that's been generated that we've seen long-term durability. dose response, good safety, efficacy across the board, and then supplementing that data with new data generated with the commercial-grade material. What I will say is the engineering run for the commercial-grade material just completed, and the yields are phenomenal. And we've just kicked off our GMP run for the validation batch, which is ultimately the commercial-grade material that will be released in Q3. So we're actually quite excited that we've made significant progress along with our CDMO partner there. The third scenario, which we think is somewhat unlikely and would be against the FDA's guidance that they issued last year for the development of gene therapy in neurodegenerative diseases, is for them to go back and ask for an additional study. Here, the natural history is pretty well elucidated. We have three sources of comparatives. Each patient in the interventional trial rolls over from the natural history study. So each patient acts as their own comparator. There's also using the full cohort, natural history cohort, as a comparative. And because the natural history data was so extensive, because the natural history data was so extensive, you could actually find age match controls within that natural history cohort to act as a comparator. So we're pretty fortunate that the level of robustness of the data, the long-term durability of the data, we now have pathological change where we actually see regeneration of nerve fibers, you know, from biopsies that were taken pre and post treatment. We feel pretty good about the data set that we're going to go in and talk to regulators about. This should be extremely compelling. But those would be the three scenarios in the U.S. XUS, we think this lines up perfectly for the conditional approval pathway based off the data set today, and that's going to be our conversation with the EMA regulators later this year.
spk09: Our next question is coming from the line of Jack Allen with Baird. Please receive your question.
spk02: Hi. Thank you so much for taking the questions, and congratulations on all the progress. I guess the first one, I wanted to stick in GAN and talk about TASHA 120. Maybe you can provide a little bit more context around the gating factors surrounding gating regulatory clarity here. Do you have a meeting on the calendar with FDA and any comments around when you may have clarity around the timeline in greater detail than mid-2022? And then I was just curious how the genetic testing program is going as well. Any comments you can make around early findings from that? And if you would consider presenting that data, I think it would be quite interesting to see a little bit more insight into the epidemiology of GAN as well.
spk06: Thanks, Jack, for the questions. I think the easy answer is the current guidance is for regulatory feedback is mid-year 2022. So I think we're going to probably just stop at that guidance without any further level of specificity. You know, obviously, as the agencies recover from, you know, COVID and Meeting requests associated with COVID approval. They're continuing to approve vaccines associated with that. Getting meetings on the books and having those meetings actually stay on the books has been somewhat of a challenge. somewhat of an issue. But what I will say, I think we're comfortable with the guidance of mid-2022. And so we'll essentially stop there with any further detail around guidance. And once we have more specificity, happy to give that to you. Or once we have that feedback in hand, happy to give that to you. As far as the genetic testing panel, this has actually gone quite well, and I think what was pretty interesting about some of the information that we've received is certainly there's more patients out there than I think the epidemiology that's in the literature actually lets on. Just anecdotally, we had a pretty interesting situation where we were speaking with an investor on a Friday afternoon. We get a call on Saturday, and essentially the investor's colleague, next-door neighbor, was diagnosed with GAN. So that kind of gives you a little bit of context that I think now that the data set is out there, And I think, you know, having the positive data set out there and the availability potentially of additional patients being dosed, you know, patients tend to find you. And this is just normal for rare disease, and this is what we're seeing.
spk09: Our next question is coming from the line of Kevin DeGieter with Oppenheimer.
spk05: Okay, great. Thanks for taking our questions. Maybe a two-part question with regard to manufacturing. You know, can you provide an update as to whether the strategic refocusing has any impact on the build out of in-house manufacturing capacity and then kind of, you know, within the cash runway assumption, you know, how should we think about CapEx and investment manufacturing?
spk06: Yeah, Kevin, thanks for the question. You know, obviously manufacturing is strategically important to the company, particularly as we're embarking on to, one, a validation run for commercial-grade materials, second, an extremely large an extremely large indication in Rett syndrome. So what I'll say is, again, manufacturing continues to stay strategically important to the company. We think it's one of the aspects that sets the company up and differentiates the company from some of our peers out there. And so that continues to remain a strategic focus. As far as – could you remind me of your second question?
spk00: Your second part was just –
spk05: Yeah, within the cash runway guidance, how should we think about maybe cumulative capex or some other metric across that timeframe?
spk06: Yeah, I think, Kevin, we're not going to provide additional guidance around what we've already provided around expense management and cash management, where cash extends until Q4 of 2023. But I think, again, to just answer your question, CMC For a gene therapy company, and it continued with our history, understanding where the bulk of the management team and board came from, you know, controlling your own destiny remains a key strategic focus to the organization. So I think that's where we'll probably stop from a guidance perspective.
spk09: Thank you. Our next question is from the line of Gil Bloom with Needham & Company.
spk03: Hello, everyone. Can you hear me?
spk06: Yep, we can hear you.
spk03: Okay, maybe just kind of a general question about RAS here. So, because it's a relatively larger indication, would you also expect the studies to be larger or more expensive to that account? Thank you.
spk06: Hi, Gil. That's a very insightful question. And I think as you can, you know, the larger the opportunity, obviously, the larger the study. I'll pause and let Suya answer, but I think the short answer to your question is yes. And I think when you start to look at the strategic prioritization, this is one of the reasons why, you know, we've done what we've done to put ourselves in the best position in order when we have RET data to position the organization broadly. Understanding the development cost for RET both on the clinical side but also on the CMC side are going to be quite extensive. But I'll stop there and let Suyash chime in. Sure.
spk07: Great question, Gil. Essentially, you're right. I wouldn't say that the study is going to be bigger. What I will say is that the central trial program as a whole is going to be bigger. And it's bigger for two reasons, really. First of all, it is a huge market opportunity, as you've already heard. And There's also a little bit more focus on the safety matters with regard to RAP, given the fact that there's a risk of overexpression of METC2. And so you've got to be a little bit more cautious and safe. That's why, as a whole, we're going to start our clinical trial, as you will have heard from Eddie this week. We now have an open CTA in Canada, which we're very excited about and ready to start focusing on patients. As a whole, we're going to start with an adult study, primarily safety, looking at some preliminary efficacy. After we've dosed a handful of adults, we'll then move into a pediatric girl study, where the bulk of the patients with RET are, and where we think that the greatest opportunity for improvement will be, although we think all patients with RET will improve, regardless of age. And then, shortly after that, we will also start a pediatric boys' study, which is a somewhat unusual thing to do, given that there are only a small number of boys around. But the boys, you'll probably remember, have no metastasis or slumps. They're very severely affected. But the vast majority of them die in utero. A handful of them survive. So there may be only 200 or 300 boys in the world with it. But we can do some kind of rescue study there and demonstrate an improvement. And of course, because I've known that too, you're not so worried about overexpression toxicity in these boys. It could actually provide a potentially expedited path to conditional approval. So that's how we're approaching the RET situation as a whole.
spk06: The only thing that I would add to what Sush just mentioned, when you start to think about the Rett boys, not only do they offer an accelerated pathway to an approval just because of the nature of the phenotype, the biology of the boys are quite similar to the biology of the animal models that we have for Rett. The industry standard animal model for RET is the knockout mouse model. Essentially, that model has no MeCP2. And that's basically what we're seeing in the boys in the biology for their disease. And so, as Suresh mentioned, there really is less of a concern around overexpression. But I think when you start to look and correlate the IMD-enabling pharmacology studies one-to-one, You know, we're seeing at multiple age groups a significant improvement across a number of hosts of functional outcomes, respiratory outcomes, motor function, and a number of other functional assessments. And again, when you even dose earlier in the neonates, we're seeing a normalization of survival, or preliminary data suggests a normalization of survival. This gives us a lot of confidence that, you know, the opportunity and really our goal is to not leave a patient behind here in this population. It's a large indication. Just associated with the girls, we're talking about 350,000 patients worldwide. So it's a massive indication. It's a massive indication. But for us, I think it's more important to make sure that all patients are addressed.
spk09: Our next question comes from the line of Laura Chico with Wedbush Securities. Please receive your question.
spk17: Hey, good morning, guys. Thanks very much for taking the question. I guess I wanted to circle back on the cash runway. And with the changes, I just wanted to clarify how long the cash runway was extended. And as it relates to the GAN program, I just want to understand the base case scenario You have around 120, and you walked through the options there, RA, but I guess how would cash runway change if we had to go through kind of that extreme scenario where there was an additional study requested? Thanks very much.
spk06: Thanks, Laura. I'll take your second question first because it's top of mind. So when you start to think about if the FDA came back with an option of doing a pivotal study in GANs, Um, just because of the patient population, it's be a pretty small study. Um, we would essentially, uh, roll over patients that are currently in the natural history study. There's about 50 plus patients in the current natural history study of which about 40 of them haven't been dosed. So the patients are there. So there is no kind of need to go search for patients, but you wouldn't have to do some type of big patient finding opportunity. Um, so, but ultimately, ultimately, um, the cash runway would be really minimally impacted. I think, you know, when you start to think of clinical development for gene therapy trials, these trials are relatively small and the cost associated with conducting these trials are relatively small. The big cost is associated with the production of GMP manufacturing, right? And the use of external third parties to do that, which is what makes having your own manufacturing facility so strategically important because just one, being able to get a slot at a high-quality manufacturer and the cost to do that are pretty high. The difference between scenario one, which would be to do analytical comparability, the base case, which would be to dose a few more patients under the current protocol with commercial-grade material once it's available, and the third scenario, which if you had to do another complete study, the costs are, I would say, from scenario two to scenario three are pretty much the same. because you've already embarked on the production of GMP material that's commercially validated, so your commercial-grade material. That's where the big costs are. So it really would have minimal to no impact on cash runway, the difference between, honestly, scenario one, two, or three, because you're already doing the big cost impact, which is manufacture of commercial-grade GMP material. So that was your second question. Your first question was around the extension of cash runway. I think we previously guided to cash being into the second half of 2023. We essentially have been fortunate to extend cash runway by a quarter into Q4 of 2023.
spk09: Our next question comes from the line of Yun Zhang with BTIG. Please proceed with your question.
spk12: Hi, good morning. Thank you very much for taking the question. So on the Rett syndrome, I assume it's a dose-finding study. So I was curious, how are you going to, or what kind of markers will allow you to decide that you are getting close to the optimal dose? And also on the efficacy readout, any potential signal for efficacy? And I think we previously talked about this potential biomarkers and the EEG being one of them. And just curious, would that be included in the data readout by year and any additional markers?
spk07: Sure. Let me make a couple of comments. The two doses, you're right, the dose installation study in adults, females as well. The initial start of those is a 5E14 total VEG dose. And there is provision to escalate up to the 1E15 total QG. Now, I think the most important thing here is that we have an incredibly robust preclinical package. It's what allowed us to have the CTA open. And we've had a lot of back and forth with the regulators on some of the details. And the preclinical package, the idea enabling preclinical package was designed around three studies that built on many, many years of work that Stephen Gray and Sarah Sennett were involved in. So the most important study from a dose-finding perspective is our pharmacology study, which we ran in 252 mice with Rex and Joe, wild-type mice. There were 12 cohorts, sorry, 21 cohorts, and we looked at a number of different doses, a number of different age-time points of dose in mice, and the whole spectrum of parameters, all of this translate nicely to clinical action measures. For example, looks at the gait of these mice, importantly performed practice, multiple physical breathing, and a whole host of other assessments. From that particular study, we're able to elucidate the minimally-affected dose. And then on top of that, we also ran our toxicology studies, both in rats and NH teams. And the important data was, of course, the NHP data, the biodistribution data. And importantly, we found that with an elevated dose, fourfold over the clinical starting dose, we actually had perfectly clean tox. And our toxicology was no adverse findings. And we have very high levels of DNA showing good biodistribution, but correspondingly low levels of mRNA. So mechanistically showing that our regulation is working. We take the MED from the pharmacology study and the toxicology study, the non-observable adverse event level. You can actually hone in on a very good starting dose. And as I said, the starting dose is 5E14 and we've got to 1E15. Neither of those showed any appreciable toxicity and we expect both to be efficacious. That's how we selected those. In terms of outcome measures, we looked at a whole host of different outcome measures. You do know, of course, that there are no official well-known, well-understood biomarkers in serum or in the CSF. We are looking at a whole host of biomarkers. We are looking at EEG as a potential biomarker as well. And a whole host of different clinical influence, the RSPQ, the CGI, the score, as well as broader efficacy measures, such as the brainstem function, restoration, seizure frequency, how many seizures, what's the frequency, what triggers them. So we'll really be guiding our dose selection on the absence of a safety signal and just in general progress from a clinical perspective. As I say, EEG will be using the ultimate sports biomarker. We're not making any decisions around the biomarkers. It's not a well understood yet.
spk09: Our next question comes from the line of Sylvain Turcan with JMP Securities. Excuse me, what's your question?
spk16: Good morning, and congrats on all the progress. I just had two quick questions, please. Could you run me maybe in more granularity through your GAN base case in terms of getting this into commercial material into a handful of patients? How much would be a handful, and when could this start? Would it make sense to start right now, or do you need to wait for your validation run in the third quarter? So how much time to filing? And then my second quick question will be on the CLN7 program. Now you're going ahead with the first gen construct. Do you think that's good enough or do you just want to get some clinical experience no matter what with this program? Thank you for taking my questions.
spk06: Good morning. Good question. So starting with the first around the availability of commercial GMP material, commercial grade GMP material on GAN. As I mentioned before, we've actually just completed our second engineering run. This was the The first was a small-scale engineering run at the CDMO partner that went beautifully. The second was the definitive engineering run at scale that also went extremely well. We're actually quite fortunate. Dan and Rhett are actually our two highest-producing, highest-yielding products. And so, you know, one being, you know, on a pathway for regulatory discussion around what the approval pathway looks like, and the second just being a massive indication. I think this just really lines up nicely with, you know, how we're thinking about prioritizing our efforts this year. So we're actually quite excited about that. Our GMP definitive, the definitive GMP run for the commercial grade material just kicked off. And we expect that material to be available in Q3. This would either be the material that would support if we're able to do analytical comparability and the agency agrees with that, that would be scenario one, which would be the best case scenario. this would be the material that would support that BLA. I still think, even in the best case, it would be more of a rolling submission because there would be still some additional work from an analytical perspective that would need to be completed. From a base case, which we consider scenario two kind of the base case, you would still need this material to be released in order to commence dosing a few more patients under the current protocol. And so kind of what you would do for scenario one, scenario two, and scenario three really are really the same activities. You need commercial-grade material. You're going to either under scenario two and three need to dose additional patients with commercial-grade material. Under scenario one, you need the commercial-grade material in order to support the BLA in order to eventually commercialize the product. So, you know, all the activities are the same, but from a timing perspective, we expect that material to be released in two, three of this year. But as I mentioned, the two engineering runs, small-scale and large-scale engineering runs, kicked off and completed quite nicely, and we've recently kicked off the commercial-grade GMP run. So we're pretty excited about the progress there and the prioritization.
spk09: Our next question is from the line of Kristen Klushka with Kantor. Please receive your question.
spk18: Good morning. This is Rick on for Kristen. Thank you for taking our question. In terms of the prioritized programs announced today, could you please talk a little bit about the potential for grants or other non-dilutive funding opportunities around these implications? For example, we understand that a federal funding bill was recently passed supporting funding for Rett Syndrome research. Thank you.
spk06: No, it's a really good question. I think, you know, for RET, obviously RET and GAN are squarely within the activities that we have prioritized, and that's where the bulk of our R&D investments are going but certainly we always look for additional opportunities for non-dilutive financing either that's through grants uh government grants advocacy grants we've done in our history we've just haven't spoken a lot about them but what we've done in the past is collaborate very closely with advocacy groups where they funded a lot of the early proof of concept work We've taken a program over once we've gotten to a definitive animal proof of concept in order to do the IND-enabling tox studies and the IND-enabling pharmacology studies and win the big dollars that you need associated with GMP manufacturing before you go into a clinical trial. So these things are always top of mind. And in our history, I think we've always looked for ways to bring in non-diluted forms of financing, particularly even more important in a situation where the market is from a macro perspective is a little bit uncertain, right? Geopolitical down sector and a number of other issues that are macro that aren't specific to the company. including looking at potential business development opportunities, particularly with programs that we see broad therapeutic potential, but unfortunately just haven't hit our level of prioritization. Now, again, we always have the opportunity to revisit that if and when situations change. But today, what I would say for clarity, the company is focused on the guidance that we've given you guys today. So that's where we are. But I think to your question, we always look for non-dilutive ways, along with our partners at Advocacy, along with our partners at UT Southwestern, for non-dilutive funding. I just wanted to answer Sylvan's second question and apologize, Sylvan, for skipping over it around CLN7. To clarify, the CLN7 program has actually gone quite well. As CS mentioned, we've recently dosed the fourth patient, which is the third patient dosed at 1E to the 15th, which is the highest dose ever given intersecally in a gene therapy trial. Patient safety was reported at World Symposium earlier this year. These patients continue to do well. And ultimately, I think you guys have heard me say this before, if it's not broke, don't fix it. And so we're going to continue to focus solely on the first-generation construct because ultimately that's going to allow for a faster pathway to registration. So that's really what's kind of led us there. But future development will be focused solely on the first-generation construct. Thank you both for the questions.
spk09: Thank you. Our next question is from the line of Yun Yang with Jefferies. Please just use your question.
spk14: Thank you. Thank you. Thank you for taking my question. So I have a question on GAN. So for the tool and the blusher, you mentioned that I think you're meeting with the ex-U.S. regulatory agencies scheduled in January. So have you met with them? I know you are not going to provide an update until maybe this year, but just wanted to check if you have met with them. And also in the U.S., you talked about three scenarios for some time, it sounds like option two could be a likely option when you meet with the FDA. If it is option two, what would be the timing for BLA filing? I think in the past you mentioned around mid-2023. So I want to get your updated view on that. And lastly, Ari, you mentioned that your cash runaway has been increased by one quarter. So should we really think about the reduction in workforce by 35% leads to one quarter extension in the cash runaway? Thank you.
spk06: Thanks for the question. Starting with your first question around regulatory, we have previously guided that we did conduct a meeting in late January with an regulatory authority around scientific advice for our GAN program. We're still awaiting formal meeting minutes from that program. from that meeting and you know once we have all of the formal meeting minutes both from this regulatory meeting as well as the regulatory meetings that will be scheduled with the US agency and other agencies will make sure to summarize those and provide that guidance and update that guidance once we have the formal feedback but it would just be premature for me to speak kind of outside of school about meeting minutes certainly the tone was a good meeting It was a long meeting. They were quite interested. The data obviously, as we laid it out, is compelling. But again, I want to make sure that we have final meeting minutes in hand before we provide any additional feedback on that. Around GAN specifically, I think you're absolutely right. coalesced around scenario two as the base case, and that's kind of the case that we're planning for internally. What I would say is the difference between scenario two of dosing a handful of patients under the current protocol in scenario three, doing a second study, it's probably six to eight months. There's not much of a gap really between either one of those scenarios. The reason for that is because all the patients are identified. You're not going out to have to identify patients. This would essentially be a rollover from This would essentially be a rollover from the natural history study. As I mentioned, there's already 50 plus patients in the natural history study of which only 14 of those patients have been dosed. So you could think about 40 or so of those patients haven't been dosed and we continue, as I mentioned, to identify patients on an ongoing basis quite successfully. So from an enrollment perspective, you really won't have an issue from a timing around enrollment. More so, the timing is associated with the availability of commercial-grade material. And then, as I mentioned, that material would be available in Q3. So, if you would take scenario two, which is very similar to the Zolgensma scenario from our previous life, where essentially the FDA The FDA approved Zolgensma on the basis of the original nationwide children's study and then those original patients. I think it was close to about 10 patients that were dosed in that study. They then allowed Avexis, Novartis at the time, to supplement the data set with data from the pivotal study with their commercial material that was being delivered from Libertyville, which was the commercial manufacturing facility located up in Chicago. And so this would essentially be the pathway that we are kind of considering as the best case because it's the best that we have out there. This is a rare, pediatric, life-threatening, neurodegenerative disease where there's no therapeutic alternative. In the case of Zolgensma, there was actually a therapeutic alternative and an approval ahead of that in Spinraza. In the case of gynecoma neuropathy, there's nothing. And so, you know, certainly in our conversations with advocates, advocacy in our conversations with KOL, we pressure tested our thinking and we think this would be the optimal approach to potentially go into. Now, we're going to go in and do our best to convince the agency around scenario one, but I think realistically, I think what we're going to do is plan for somewhat of a mid-case, which would be scenario two. That would allow us to either initiate a rolling submission at the end of this year or the beginning of next year and ultimately lead to an approval either late, and when I say late, end of the year, 2023, or early 2024 in the U.S. Obviously the pathway in Europe is quite different. We feel strongly that we meet the guidance around the conditional approval pathway, and that's going to be our going in conversation with the EMA regulators is really how to accelerate registration options for this program under the conditional approval pathway. And so that's going to be our goal. And so we want to be in the position If the regulators agree, which, again, with the data set that we have in hand, we think there's a strong possibility to initiate a rolling submission by the end of this year.
spk09: Thank you. Our next question is from the line of Sammy Corwin with William Blair.
spk11: Hey, guys. Thanks for taking my questions. For the RET study, will there be different outcome measures for patients depending on their age or disease stage? And then can we expect any data this year from the CLN1 or CLN7 clinical trials? Thanks.
spk06: Hey, Sammy. Good morning. Thanks for the question. Could you repeat your first question? I'm sorry. We couldn't hear you.
spk11: Oh, yeah. Will there be different outcome measures for patients in the RET trial depending on their disease stage?
spk06: No, it's a really good question. So if you want to tackle that first. Yeah.
spk07: In general, yes and no, basically. We're going to be looking at similar board buckets of efficacy measurements regardless of age. So we'll be looking at specific REC assessments, such as the RFCQ, such as the motor behavior assessment, the Hand Day Practice Scale. We'll be looking at certain seizure measurements, EEGs, for example, and seizure values. We'll look at the respiratory assessments, the respiratory distress index, sleep apnea, et cetera, communication assessments, the AUCA, quality of life assessments, plus a whole host of different biomarkers, which
spk09: Thank you. Our next question is from the line of David Holm with SMBC.
spk19: Hey, thanks for providing the update and taking my questions. So I just had a few. Again, going back to the base case for GAN and the regulatory path there, do you have any sense about how many additional patients FDA might ask you to dose? And then in terms of the follow-up on those patients, So, you know, who received the commercial grade material? What do you exactly need to report? Is it just safety and PK data or do you need to follow them and get, you know, some efficacy data as well?
spk06: Yeah, I think it's a really good question. And, David, unfortunately, you guys cut out a little bit, so we'll go back and answer Sammy's question after we answer your question, David. But your question was really, I think it boils down to, what do you think you'll need to show from an efficacy perspective around the commercial grade material, and how long do you think the follow-up would be around what you would need comparability. What I'll tell you, the best comp in this, again, would be in Zolgensma. Zolgensma, the FDA allowed us previously to use the chopping tin as a really nice biomarker around activity and kind of comparability between the original clinical trial material and the commercial grade material because the chopping tin actually went up pretty uniformly within the first 30 days across all patients. So you know you're getting really good target engagement. I don't think that's too dissimilar here, where we're using the MSN32, which is similar in a sense as the CHOP and TEN for older patients. And I think when you look across the entire data set, you do see a really nice kind of stabilization and improvement in disease as compared to the natural history Pretty shortly thereafter dosing. And so, you know, I think using our previous experience in Volgensma, I don't think that that is, you know, far removed. Now, what I will say, this is speculation because we haven't had the discussion. The right thing to ask is what they're going to ask for. And certainly we're going to do what they ask us to do. But I think what we'll ultimately do is lean on the extensive safety database that we have.
spk09: Please stand by. We'll resume with your answer in a moment, Mr. Wong. Our speakers may continue with your answer. We're with Mr. Wong. Please stand by. We'll resume our question and answer session momentarily. Thank you. Please stand by for when our question and answer session will resume momentarily. Thank you. Ladies and gentlemen, thank you for standing by. We'll resume our question and answer session momentarily. Please remain on the line. Thank you.
spk06: I'm sorry, session. Hey, speakers. We'll get dialing in.
spk09: We can hear you now. Please continue.
spk00: You're calling in for a recall.
spk06: The tissue gene therapy is called. Hi, operator. So we're going to give this another go. We just dialed in. Just let us know when we dial out and we just have the phone line available and we'll just pass the phone around.
spk09: Can we go out again? I can hear you. You can be heard into the conference again now. We still have Mr. Huang on the line with us for his question.
spk06: Perfect. Perfect. David, sorry about this. We're just having some technical issues in the room. But to your question, I was just basically correlating our experience with Zolgensma and the approval pathway to Zolgensma and what the FDA asked us to do as it compared to, you know, trying to use that experience for GAN. So the question was really around what was the extent of the follow-up. The extent of the follow-up in the Zolgensma was really using the CHOP in 10 as a form of comparator for clinical comparability of the commercial grade material. And so we're fortunate to have a similar assessment in the MSM32, which is essentially the chop and tin for the older kids. And, you know, what we're seeing is pretty early a nice separation between patients that are in the interventional trial compared to the natural history study. And so we think that that could be a useful example and a comparator to provide to the FDA because you actually see a nice separation relatively quickly. What I'll also say is when you start to look at the long-term safety and durability, the patients that we have the most efficacy data on receive the lowest middle doses with the dose of 1.2E to the 14. And I think this patient, if they didn't receive the intervention would have probably succumbed because where this patient started was actually one of the lower scores on the MSN32, and we've essentially seen a really nice stabilization of the disease now going out five years. So I think, you know, with that totality of data, along with the pathology data from the biopsies, along with having a validated instrument that's been used in regulatory approvals before in the MSM32, I think we have a really compelling argument to be able to go in and basically shoot for the minimum amount of follow-up that's possible really just to validate that we have active drugs. That could be somewhere between, you know,
spk09: Ladies and gentlemen, please stand by while we switch speakers' lines. Speakers, please continue on your second line. Hi, guys. Please go ahead.
spk00: You're on your second line.
spk09: I'm going to disconnect. I'm hearing another line. May I disconnect that this time?
spk06: Yeah, we have to disconnect the other line. So I think I answered the question ultimately. I think I was just providing some additional commentary. So I think I answered David's question. And again, sorry for the technical difficulties there.
spk09: Thank you. Please stand by while we resume with the line of Sammy Corwin. Sammy, please go ahead.
spk11: Oh, hey, guys. Yeah, I think you were just going to answer my question on if we can accept any data from CLN1 or CLN7.
spk06: Thanks, Sammy. Yeah, so we've already presented data earlier this year on the CLN7 program. That was on the first three patients that were dosed, the first being 5B to the 14th. The The next two that were presented was at the 1E to the 15 dose, and we've mentioned that an additional patient was treated at 1E to the 15. And so we've already reported data on that program, and we continue to follow those patients. On CLN7, what we've decided to do is to not guide to the availability of clinical data, but to say that we continue, we're kind of morphing this program into and limiting enrollment to a proof of concept study, kind of a little bit different of a strategy from kind of a fast pathway to registration type of strategy. And so we'll guide the data later this year on the CLN1 program. Thank you.
spk09: Our final question comes from the line of Yanan Zhu with Wells Fargo. Please proceed with your question.
spk13: Yanan Zhu Thanks for taking my question and congrats on the initiation of the Rett syndrome program clinical trial. So my first question is on the GAN program's data because I think RAU mentioned about age-matched controls. I think so far the MFM32 data you presented is mainly the overall natural history control cohort. So I was wondering, what does the age-matched controls look like? Because I think you mentioned you have enough patient data there to do the specific age-match And also, is that part of your conversation or a package with your regulatory interaction? Thank you.
spk06: Hey, Yan, and thanks for the question. So essentially what I'll say is those analysis are ongoing, but I think what's important here, we have previously showed data that from the previous doses of patients' pretreatment decline, and their post-treatment stabilization. That's data that we actually shared last year when we acquired the program. The data that we shared this year was essentially a comparison from the full cohort of natural history that basically shows an 8.07 decline compared to the cohort's experience, depending on that particular dose cohort. That's the data that we've we've shared recently, and now the analysis around age match controls, which is a little bit more extensive, is ongoing, but I think you're absolutely right. This just lends itself to the robustness of the data itself. The fact of the matter that we have access to natural history data that offers three levels of control is extremely compelling. So when you start to look at the data set that we're gonna go in and have conversations with the regulators, you'll have natural history data, three levels of control, biopsy data, functional data across a number of meaningful clinical functions, including MFN32, including visual acuity, pathology data from the biopsy, but also retinal nerve fiber thickness data, as well as a whole host of sensory endpoints that we haven't presented to the street yet. So we feel Honestly, I think if you would ask Suyesh, and I'm only answering this because of the technical difficulties that we had, if you ask Suyesh, he would probably tell you that he's never gone into a conversation with a regulator with this wealth of data before. And I think this gives us a lot of confidence around the conversation with regulators. You know, and so that's essentially what I'll say. You know, the level of comparison from the natural history is The wealth of endpoints that were collected, the pathology data that we have in hand and what that shows just really lends itself and is why we feel, you know, so confident about our conversations and, to be quite honest, why we made the decision around prioritization today.
spk09: Thank you. At this time, we've reached the end of the question and answer session, and I'll turn the call over to Mr. Sessions for closing remarks.
spk06: Yes, thank you, Operator. And first and foremost, we just want to apologize for any other technical difficulties. I think we got through probably about 80% of the questions before that started to kick in. So hopefully, you know, our colleagues from the analyst community found this helpful, as well as the broader community. But we really appreciate you guys joining us this morning. You know, I think the way we're thinking about 2022 is a year of focus. It's a year of operational efficiency, and it's a transformational year as we potentially transition the company from now, and I say this every year, which is actually quite nice, now from a clinical stage company to a late stage clinical company into a registration company preparing for our first commercial launch. And so that is an important level of transition. Obviously, we're doing this in uncertain times. from a capital markets perspective. But I think the changes that we've made today have, and announced today, has really set the company up to be in the best possible position for when we have both data in hand from our Rett Syndrome program and feedback from regulators around our GAN program. And it put us, again, in a position of strength. So we really want to thank you guys for joining us today and hope you all have a wonderful day and a wonderful rest of the week. So thank you.
spk09: Thank you to everyone who joined us today. This will conclude today's conference call and webcast. You may now disconnect your lines at this time. We thank you for your participation.
Disclaimer