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spk05: financial results and corporate update conference call. At this time, all participants are in listen-only mode. Following management's prepared remarks, we'll hold a brief question-answer session. As a reminder, this call is being recorded today, May 11th, 2021. I'll now turn the call over to Dr. Kimberly Lee, Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.
spk00: Good morning and welcome to Tayshia's first quarter 2021 financial results and corporate update conference call. Joining me on today's call are Ari Session II, Tayshia's president, CEO, and founder, 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 first quarter ended March 31, 2021. A copy of this press release is available on the company's website and through our SEC filing. 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 drug candidates. These statements may include the expected timing and results of clinical trials for our drug candidates and the regulatory status and market opportunities for those programs, as well as patient manufacturing plans. This call may also contain forward-looking statements relating to patients' growth and future operating results, discovering development of drug candidates, strategic alliances and intellectual property, as well as matters that are not 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 insurgencies related to the timing and results of clinical trials and preclinical studies of our drug candidates, our dependence upon strategic alliances and other third-party relationships, our ability to obtain patent protections 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 filed with the Securities and Exchange Commission. This conference call contains time-sensitive information that is as accurate only as of date of this live broadcast, May 11th, 2021. Tisha undertakes no obligations 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, CEO, and Founder, R.A. Session II.
spk07: Thank you, Kim. Good morning and welcome, everyone, to our first quarter Corporate Update and Financial Results Conference Call. As always, we hope you and your families continue to remain safe and healthy. Keisha has made great progress in the first quarter and continues to execute on its corporate initiatives. I will elaborate on some of the key achievements made thus far this year and highlight the expected milestones for the remainder of 2021. Following this, I will turn the call over to Suyash and Cameron for updates on our pipeline development and financial results, respectively. TASHA has transformed into a pivotal stage gene therapy company with the recent acquisition of exclusive worldwide rights to a groundbreaking clinical program, TASHA 120, an AAV9 interfecally dosed gene therapy invented by our chief scientific advisor, Dr. Stephen Gray of UT Southwestern. The NIH is conducting an ongoing clinical trial of TASHA 120 for the treatment of giant axonal neuropathy, organa. Notably, The GAN program is the first interfecally dosed AAV gene therapy study in history and, as such, has had significant impact on the field. As the program has laid the foundation for our extensive pipeline, we believe this acquisition represents a clear strategic and value-accretive opportunity that will provide read-through across our entire portfolio and inform the development of our gene therapy product candidates. We are thrilled to carry on the work done by Dr. Gray's lab and the NIH. As Suyesh will discuss in more detail, TASHA 120 has a comprehensive preclinical and clinical package that we believe may support an expedited approval pathway. The clinical data for TASHA 120 in patients with GAN are statistically significant, clinically relevant, dose-dependent, and durable, with a clear halt in disease progression at therapeutic doses. We are very encouraged that this represents significant value as the first potentially disease-modifying treatment for an estimated 2,400 patients living with GAN in the U.S. and in Europe alone. As such, we intend to engage with major regulatory agencies as soon as possible and, in parallel, will be accelerating the build-out of our commercial infrastructure to support patient identification, payer engagement, and product distribution. We believe that TASIA 120, if approved, represents a near-term commercial opportunity for TASIA of more than $2 billion. Beyond further advancing our new clinical stage programs, we continue to achieve significant progress with our preclinical programs that we expect will provide the next wave of novel gene therapy. We are extremely excited to announce the recent publication of new preclinical data for TASIA 102 in Rett Syndrome, in a highly regarded scientific journal, Brain. For the first time, we have quantitative evidence of MI Rare's ability to demonstrate genotype-dependent regulation of MEKP2 gene expression across different brain regions in both wild-type and knockout mouse models of Rett syndrome. Various challenges such as phenotypic variability, mosaicism, and targeting a dose-sensitive gene like MEKP2 make development of a gene therapy difficult. MI Rare offers a solution by allowing for the regulation of MEXP2 gene expression on a cell-by-cell basis without causing overexpression-related toxicity. Importantly, treatment with TASHA-102 in 4- to 5-week-old knockout mice with Rett syndrome resulted in a statistically significant survival extension by 56%. which is a very impressive result as these mice had meaningful accumulated disease. In our view, the benefits in these adolescent knockout mice should be a more translatable model of the disorder in humans. We believe these data validate our novel approach to treating REC, help de-risk the clinical program, and support the advancement of TASHA-102 into Phase I-II clinical trials by end of the year. We remain on track to file an IND or CTA in the second half of this year. You will hear from Suya shortly, as he will review the robust data in greater detail. Our Chief Scientific Advisor, Dr. Steven Gray, initiated his work on MI Rare and TASHA-102 in 2007. We are very pleased that his team's efforts are being realized and recognized. Amongst other compelling preclinical data packages, we are particularly excited about HACIA-113, which has demonstrated successful AAV-mediated gene knockdown, resulting in reduced tau expression in mouse models of human tauopathy. These data may have significant implications for certain neurodegenerative diseases, including Alzheimer's disease. We are also pleased with preclinical results for TASHA 105 and SLC13A5 deficiency that demonstrate a reduction in plasma citrate levels, normalized EEG activity, and reduced number of seizures and seizure susceptibility in SLC13A5 knockout mice. In SLC6A1 haploid insufficiency, TASHA 103 improved nesting and EEG activity in the SLC6A1 knockout mouse model and reduced spike train activity in both the SLC6A1 knockout and heterozygous mouse models. In lefora disease, TASHA111 leforin and TASHA111 malin have achieved effective knockdowns of GYS1 expression in its soluble glycogen and decreased lefora body formation in the appropriate lefora disease mouse model. In APBD, TASHA 112 has generated significant reduction in GYS1 protein, abnormal glycogen accumulation, and polyglucosome body formation in the APBD knockout mouse model. In Angelman disease, TASHA 106 increased UBE3A expression through shRNA-mediated knockdown of UBE3A-ATF, an in vitro cell line. We believe that this promising result demonstrated by our preclinical candidates validates our scientific approach and underscore our ability to drive a sustainable development engine for innovative gene therapy with the potential to impact meaningful patient populations. We are working diligently to advance our other preclinical programs in IMD-CTA-enabling studies and to date have already advanced six programs into IND-CTA-enabling studies with an IND or CTA plan for at least one of these programs by the end of 2021. We look forward to providing further updates on our key programs at our R&D event, which will take place over two days on June 28th and 29th. To support our programs, we have developed several key partnerships, Notably, we have established collaborations with Yale University, Cleveland Clinic, and the UT Southwestern Gene Therapy Program to support the creation of a novel next-generation mini-gene platform that is designed to overcome key challenges in gene therapy. These mini-gene payloads for AAV gene therapy will be targeted for the treatment of genetic epilepsy, neurodevelopmental disorders, and other CNS diseases. We are excited to leverage each partner's unique capabilities to expand the boundary of AAV vector engineering and potentially open the door to treating genetic CNS diseases that have been traditionally precluded from treatment with gene therapies. Foundational to our success is our team, which remains focused on advancing the development of our portfolio of innovative gene therapy candidates. We intend to continue this momentum by further growing our experience team Since becoming a public company, we have expanded our team more than 10 times and have now surpassed 120 employees. We expect to grow the team to approximately 150 employees by year-end. As noted, we are complementing the efforts of our internal team with our collaborators at UT Southwestern. With the collective expertise and dedication of these teams, our seasoned board of directors, an independent, internationally renowned scientific advisory board, We believe we are uniquely positioned to expedite the development of our gene therapy candidates and our technology platform. I will now turn the call over to Suyesh to provide a more detailed update on our R&D initiative. Suyesh, please go ahead.
spk04: Thanks, R.A. As R.A. mentioned, Tayshia has a robust portfolio of 26 gene therapy product candidates for monogenic diseases of the CNS. Our candidates target broad therapeutic categories of immense unmet medical needs including neurodegenerative diseases, neurodevelopmental disorders, and genetic epilepsies. We have recently added TASIA-120 for the treatment of giant axonal neuropathy, or GAN, to our pipeline, making it our most advanced program. We believe the preclinical and clinical data generated to date holds significant promise for GAN patients. Preclinical studies have demonstrated strong proof-of-concept data for both the construct and the delivery modalities. TASHA 120 performed well in preclinical studies, demonstrating improved motor function and nerve pathology and long-term safety across several animal models. Preclinical data also demonstrated that TASHA 120 showed a significant improvement in the pathological appearance of the dorsal root ganglia, a key component of disease progression. DRG inflammation is a topic that has been the focus of much discussion within gene therapy circles in recent months. This is because it has been observed as a histopathological finding in some non-human primate gene therapy studies, although the NHPs exhibited no functional compromise. Interestingly, in GAN and in the majority of diseases in our neurodegenerative franchise, the DLG have a significantly abnormal histological appearance and function as a consequence of underlying disease pathophysiology. Thus, it was not surprising that when treated with TASIA-120, we saw considerable improvements in the pathological appearance of the DRG in the GAN knockout mice. We are fortunate that in addition to robust preclinical results, there is considerable natural history that provides us with patient data to identify optimal markers and endpoints for a clinical trial. To date, there are data in 45 GAN patients that demonstrate an average eight point decline per year in the MFM32 scores that are consistent across patients of all ages. Recall that the four-point decline per year in the MFM32 is considered clinically meaningful. Notably, and in line with recently published FDA guidance, regulatory agencies appreciate the availability of a well-controlled and high-quality prospective natural history study as a comparator in clinical trials for rare diseases. In addition, we believe this natural history study provides us with a head start in identifying patients. Based on the positive preclinical results, an ID was opened, and TASHA 120 has been further evaluated in an ongoing clinical trial. The primary endpoint is to assess safety. The secondary endpoint is to measure efficacy using pathologic, physiologic, functional, and clinical markers. To date, 14 patients have been administered intrathecal TASHA 120, and six patients have at least three years' worth of long-term follow-up data. Patient 120 has shown a dose-response relationship with the rest of disease progression at the second highest dose level, 1.8 times 10 to the 14 total VG at one year post-treatment, affecting a statistically significant eight-point improvement on the MFM32 score in comparison to the predicted natural history trajectory. These results are very promising as a four-point change in the MFM32 score is considered clinically meaningful. Six of these patients treated at therapeutic dose levels have shown sustained dose-dependent improvements in MFM32 scores for more than three years. Long-term results demonstrated that treatment with TASHA 120 at multiple dose levels was well-tolerated with no severe drug-related adverse events. We look forward to reporting additional data later this year, including results from the highest dose cohort, 3.5 times 10 to the 14 total VG. The FDA has already granted Tayshia-120 orphan drug and rare pediatric disease designations, and we will continue to work closely with the regulatory authorities in the U.S. In the near term, we expect to have discussions with the FDA and engage with other major regulatory agencies by year-end to discuss the pathway to approval for Tayshia-120. I would also like to highlight some of the promising preclinical data coming from our earliest stage candidates that demonstrate the incredible breadth depth, and velocity of our development engine. It is important to note that there are no approved disease-modifying therapies for any of the programs in our portfolio. With such compelling data-to-date for our pipeline, we are very encouraged that our gene therapy candidates could offer significant value to meaningful patient populations. We are very excited to share new preclinical data for TASIA-102 in Rett syndrome that was recently published in BRAIN. As RA discussed earlier, Historically, it has been a challenge to find the right approach to safely regulate MEKB2 expression in this disease. The complexities are highlighted by phenotypic variability, mosaicism, and the need to regulate MEKB2 such that it does not cause overexpression-related toxicity. Today's data give us confidence that we can achieve appropriate MEKB2 expression in all cells in a genotype-dependent manner with no signs of toxicity. With the built-in regulatory element, MI-RARE, TASIA-102 provided a statistically significant survival extension in knockout RET mice by 56%, while the unregulated mini-MECP2 gene transfer failed to significantly extend knockout survival at either dose tested. Additionally, the unregulated full-length MECP2 construct did not demonstrate a significant extension in survival and was associated with unacceptable toxicity profile in wild-type mice. We believe that the 56% improvement in survival in TASHA-102 treated knockout mice is extremely impressive, as these adolescent mice have accumulated significant disease. Of note, since RET patients do not demonstrate symptoms until about one year of age, and therefore will not be treated until after this point, we believe these data are likely to be highly translatable for the clinical setting. In addition to survival, behavioral side effects were explored. TASHA-102 treated wild-type mice had a significantly lower, meaning better, mean aggregate behavioral score than those treated with unregulated full-length MeCP2 and unregulated mini-MeCP2. Importantly, MI-rare mediated genotype-dependent gene regulation was shown by analyzing tissue sectioners from wild-type and knockout mouse treated with AAV9 vectors given intrathecally. TASHA-102 demonstrated reduced levels of MeCP2 in different regions of the brain, suggesting that MIRA inhibited mean expression in a genotype-dependent manner. This demonstrates that TASER-102 achieved MECP2 expression levels within normal physiological parameters. In summary, these positive data demonstrated MIRA's ability to exhibit genotype-dependent regulation of MECP2 gene expression across different brain regions in both wild-type and knockout mouse models of Rett syndrome without overexpression toxicities. We are very encouraged by these results, I look forward to filing an IND or CTA in the second half of this year, followed by initiation of a Phase I-II trial by year end. TASIA-102 has the potential to address a significant unmet need for an estimated 25,000 patients with Rett syndrome across the United States and in Europe. Now I'd like to highlight some of our other preclinical programs that we've recently released data on. TASIA-104, which is currently in IND CCNA enabling studies, for the treatment of SIRF1-associated Lee syndrome has demonstrated increased COX-1 activity in brain and muscle and restored elevation of blood lactate on exhaustive exercise in a dose-dependent manner in SIRF1 knockout mice. Dr. Ching-Lan Ling of UT Southwestern will be presenting these compelling data this Thursday at ASGCT. We remain on track to file a nine-deal CTA in the second half of this year. TASHA 105, our gene therapy candidates, that is currently in IND CTA-naveling studies for the treatment of SLC13A5 deficiency cause a significant sustained decrease of plasma citrate levels up to three months post-injection compared to age-matched wild-type controls. TASHA 105 normalized EEG brain activity, reduced the number of seizures, and reduced seizure susceptibility compared to vehicle-treated controls. Dr. Rachel Bailey will be presenting these positive data this Thursday at ASGCT. TASIA-103 is our gene therapy candidate that is in IND CTA-enabling studies for the treatment of SLC6A1 haploinsufficiency. In the SLC6A1 knockout mouse model, TASIA-103 improved nesting and EEG activity. In addition, in SLC6A1 knockout and heterozygous mouse models, TASHA-103 reduced spike train activity, which is a recording of abnormal neuronal activity associated with seizures. We believe the estimated prevalence is 17,000 patients in the US and in EU. TASHA-111-leforin and TASHA-111-malin are gene therapy candidates in IMD CTA-enabling studies for the treatment of both subtypes of lefora disease achieved effective knockdown of GYS1 expression in the Lefora disease Leforin and Malin mouse models, respectively. Both product candidates decreased Lefora body formation within the brain in their respective mouse models. TASIA112 is being tested in IND TTA-enabling studies for the treatment of adult polyglutazone body disease, or APBD. In preclinical studies, miRNA knockdown of GYS1 induced significant reductions in GYS1 mRNA GYS1 protein, abnormal glycogen accumulation, and polyglutazone bodies throughout the brain in an APBD knockout mouse model. For GM2AB variant in preclinical studies, TASIA-119 causes significant dose-dependent reduction of GM2 accumulation after 20 weeks in mice that were dosed intrathecally at postnatal day one or at six weeks of age. Long-term follow-up studies, which include bimonthly behavioral as well as biochemical and histological analyses, are currently ongoing. TASIA-106 is being developed for the treatment of Asian one syndrome. In vitro testing in the neuroplast cell line demonstrated consistent knockdown of UBE3A-ATS and a subsequent increase in UBE3A expression across 26 distinct SHRNA candidates. Selection of a development candidate is expected by mid-year, followed by interim expression and safety data from confirmatory non-human primate studies by the year end. TASIA-113, an AAV-mediated gene knockdown construct, has shown particular promise. TASIA-113's AAV-9 capsid package's microRNA shuffles are designed to target tau mRNA for all six isoforms found in the human and or mouse brains. Treatment with TASIA-113 has shown a significant reduction in tau mRNA and protein levels while demonstrating widespread expression in neurons and glia. This has potentially significant implications for patients with neurodegenerative disorders characterized by deposition of abnormal tau protein in the brain, including Alzheimer's disease, MACT-associated frontotemporal dementia, and progressive supranuclear palsy. As you can see, collectively, these preclinical data highlight our next wave of novel gene therapies that have the potential to impact patient populations affected by significant diseases in a meaningful way. With that, we intend to file 9D-CTA for one of the following programs by the end of 2021. SLC13A5 deficiency, Lephora disease, APBD, or GM2AB variants. We also remain on track to file 9D-CTA for TASIO1 and 2 in Rett syndrome, and Tayshia-104 in SIRF1-associated Lee syndrome, and a 9D for Tayshia-101 in GM2 gangliosidosis in the U.S. during the second half of this year. We expect to initiate a Phase I-II trial for Tayshia-118, which is under an already open IMD. We are excited to have six near-term Phase I-II trial initiations planned throughout our portfolio. We are making incredible progress advancing our product candidates into clinical developments, and we look forward to providing additional updates at our R&D day that will span two days in June. We will continue to advance our pipeline by leveraging our next-generation platform technologies. As part of this initiative, we have recently established collaborations with Dr. Dennis Lal at the Gene Novix Institute, Cleveland Clinic, and Dr. Yonghui Jiang at Yale University to further push the boundaries of AAP vector engineering by developing next-generation minigene payloads that have the potential to overcome current limitations of packaging capacity, which is a critical barrier to treating genetic diseases not addressable by conventional AAV gene therapy technologies. This may enable us to effectively treat a wider range of devastating CNS diseases. UT Southwestern will produce bar-vector constructs that incorporate the minigene payloads and evaluate the constructs in both in vitro and in vivo studies. Through collective efforts of Tayshia and our partners, we will continue to strive for innovations in our platform technologies that will enable us to treat a broad range of CNS diseases with novel gene therapies. With that, I'll turn the call over to Cameron to review our financial results.
spk06: Thank you, Suryash. This morning, I will discuss key aspects of our first quarter 2021 financial results. More details can be found in our Form 10-Q, which will be filed with the SEC shortly. As indicated in our press release today, R&D expenses were $23.9 million for the first quarter ended March 31, 2021, compared to $5.5 million for the first quarter ended March 31, 2020. The increase was primarily related to the company's development program as a result of increased manufacturing-related spend, clinical and preclinical activities, and headcount. G&A expenses were $8.2 million for the first quarter ended March 31, 2021 compared to $0.07 million for the first quarter ended March 31, 2020. The increase was primarily due to an increase in personnel costs resulting from increased headcount, professional services fees, and other corporate-related expenses. Net loss for the first quarter ended March 31st, 2021 was $32 million or 87 cents per share as compared to a net loss of $5.4 million or 50 cents per share for the first quarter ended March 31st, 2020. As of March 31st, 2021, HACIA had $228.7 million in cash and cash equivalent. We continue to expect that our working capital will be sufficient to fund our operation into 2023 inclusive of the development, regulatory, and operational milestones RA and Suyash have outlined today. And with that, I will hand the call back to RA.
spk07: Thanks, Cameron. We are pleased to have shared with you our success over the first quarter. Looking ahead, we will continue to focus on rapidly advancing our pipeline with many key milestones anticipated over the next 18 months. We have made a significant transition into a pivotal stage gene therapy company with our acquisition of TASHA 120, and we expect to provide both clinical and regulatory updates by year end. Further, we remain on track to report first in human clinical data for TASHA 101 and GM2 gangliosidosis, as well as initiate a phase one slash two trial for TASHA 118 and CLN1 disease that currently has an open IND. As you've heard today, we have an extensive pipeline of preclinical programs that are advancing quickly. We expect to open four INDs or CTAs and have a total of five programs in clinical development, including for Rett syndrome and SIRF1-associated Lee syndrome, by year-end, and have an additional six programs currently in IND or CTA-enabling studies. In parallel, we will continue to support our R&D initiatives by expanding our team to approximately 150 employees by year-end. completing the build-out of our Dallas corporate headquarters by mid-year, as well as continuing the construction on our internal GMP manufacturing facility in Durham, North Carolina. With numerous potentially value-creating near-term milestones, we expect this year to continue to be a transformational period, and we look forward to providing further updates on our progress at our upcoming R&D Day event next month. Lastly, 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 on 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?
spk05: We will now begin the question and answer session. To join the question queue, you may press star then one on your telephone keypad. You'll hear a tone acknowledging your request. If you're using a speakerphone, please pick up your handset before pressing any keys. To withdraw your question, please press star then two. We will pause for a moment as callers join the queue. The first question comes from Saldine Richter from Goldman Sachs. Please go ahead.
spk01: Good morning. Thanks for taking my questions. So one question here about... Good morning. Good morning. One question here about capital and resource allocation as you're, you know, running multiple trials, building out a GMP facility and hiring employees. So how should we think about that over time? And secondly, with regard to the RET program, Maybe if you could touch on the registration path here and what you'd like to see from that first clinical data set to inform, you know, the pivotal program.
spk07: No, I appreciate the question, Salveen. Good morning. So I'll take the first one, and Suyas, if you could address the question on RET. As far as capital allocation goes, we reaffirmed our guidance this morning that we still have the capital resources to take us into 2023. You know, As it pertains to gene therapy drug development, it's much different than kind of classic drug development from a time and cost of test because you're not doing kind of high throughput screening, you know, trying to identify a target, you already know the target. And so it's actually much more capital efficient to go after gene therapy versus other forms or other modalities. And so the way that we're thinking about this is, again, You know, because our portfolio is appropriately staged, we have some programs that are moving into the clinic, some programs that have just hit animal proof of concept and some early discovery programs. Most of our translational and discovery work is being done by our collaborators at UT Southwestern. And having that academic partner is a really capital efficient way to do kind of your early translational discovery work. As it pertains to the clinical development, again, this is a pretty capital-efficient modality because the number of patients you need to actually get a signal and to achieve human proof of concept is quite small compared to some other modalities. So, again, you know, I think we feel very strongly about this. Moving five programs into clinical development this year, already having a few programs in the clinic, we still feel strongly that our capital takes us into 2023. I'll stop there, and C.S., do you want to address the question around Rett syndrome and kind of what our thoughts are on the path in the clinic and our path to approval?
spk04: Absolutely. Thanks, Alray, and thanks for the question, Salvin. Yes, so for Rett syndrome, you know, I think we've been spending a lot of time thinking about the clinical development program and the pathway to approval. And we're going to take a slightly more cautious approach than for some of our other conditions, such as GM2, CLM1, GAN, where the diseases are a little less common and where there is an ongoing relatively high risk of mortality quite early on. So the way we think about RET is that the first study of a group of two will be more of a phase one to primarily safety study with some exploration of preliminary efficacy. Following on from that, we will then perform a phase 2-3 study, which focuses, you know, takes learnings from the initial phase 1-2 study, takes the learnings from that and applies it into a more extensive phase 2-3 pivotal efficacy study. Now, with regard to the first study, the phase 1-2 study, likely we will be doing it in older patients. As you know, the FDA tends to push you away from children towards adults first, and in this particular study, situation with REC, we actually tend to agree with that approach. You know, there are these risks of toxicity with over-expression of MeCP2, so we just have to be quite mindful when we design this initial study. So the first study will be Phase 1-2, clinical proof of concept, safety, preliminary efficacy in the adult population. In terms of endpoints, we'll be looking at the safety aspects of safety initially, and then we'll be looking at efficacy really in three different buckets. The efficacy will be looked at firstly with a number of the different RET specific clinically rated scales. For example, the RET syndrome motor behavior assessment, the RET syndrome behavior questionnaire. So the RET scales. We'll also be looking at seizures in some detail because children with RET syndrome have significant seizure activity. So we'll be looking at how frequent the seizures are, how many medications to charge on, what triggers the seizures, how durable the seizures are. And over time, hopefully we'll be able to see a reduction in seizure activity and bring them off medications and also see an improvement in the EEG. And then the third bucket of clinical assessments will include a general multisystemic, multi-organ type aspects of Rett syndrome disease characteristics, such as the respiratory assessments, which, as you know, you have respiratory rhythm abnormalities and Rett syndrome, sleep apnea issues, cardiac issues such as QT prolongation. So I think that the first study, once again, we'll look at safety initially and some of these areas of preliminary efficacy. We will build on that and design the phase 2-3 study subsequent to that. As we've already talked about, we'll be engaging with regulatory agencies during the course of this year to pressure test our thinking around these particular plans, and we'll be starting the clinical study towards the end of the year.
spk01: Thank you.
spk05: Thanks for the question. The next question comes from Matthew Harrison from Morgan Stanley. Please go ahead. Good morning. This is Thomas Stein from Matthew. Can you give an update on where you are with manufacturing for the GAN program? In particular, what sort of assay work do you still need to complete?
spk07: Thank you. Thanks, Thomas, for the question. I'll turn this question over to Fred Porter, our Chief Technical Officer, on the line to talk about our manufacturing. Fred?
spk02: Thanks, RA. Thanks for the question, Matthew. You know, obviously, we're in the process of onboarding the GAN program. So where we're really beginning is with the assays, reviewing the assays that were conducted by the NIH for the Phase I, Phase II clinical material. And what our intention is is to try to update those methods to qualify and then validate them to prepare for late-stage pivotal work. So we're actively engaging on all the critical quality attribute assays with our partners to move that forward with our CEMO. In addition, we're looking very deeply into the potency assay development work, and this is something that's happening jointly between Suyasha's group and my own to move forward a potency assay very quickly to kind of synchronize a fully developed and qualified potency assay with pivotal lot manufacturing. I'm happy to answer any questions about that.
spk04: No, I can add one more comment. I can add one more comment on top of Fred. And it's an important question to ask about that. The other aspect that we're spending some time thinking about and really pulling the trigger on with some considerable effort is more from the QPCR assay to the VDPCR, so we get a slightly more accurate assay. numbers in terms of titrate. So that's another arm of work in parallel with the potency of the other CMC characterization that Fred mentioned. Thank you.
spk07: Thanks, Tom.
spk05: Once again, if you have a question, please press star, then 1. The next question comes from Raju Prasad from William Blair. Please go ahead.
spk08: Hey, guys. Thanks for taking the question and congrats on the progress.
spk09: You know, I'm kind of looking down your pipeline and I see a lot of technologies that you're de-risking from a payload perspective. The MI Rare platform, the Bicestronic vector, I can see, you know, follow-on indications once those technologies are de-risked. But my question was more on the regulatory side. You know, as you're kind of dealing with regulators on these different indications, What types of aspects of the programs do you think will be de-risked by, you know, clinical data there? Is it on endpoints and dealing with endpoints with the FDA? Is it on the IT administration? Maybe some color there would be great. Thanks.
spk07: No, it's a great question, and it's kind of central to our scientific thesis and really our focus on the use of validated gene therapy technology kind of coupled with very targeted novel payload design and really trying to achieve an economy to scale that really allow us to go after, you know, this kind of large portfolio of product candidates. And we're able to do that because we hold a couple of things constant. The first thing is all of our programs are AAV9s, The second thing, they all use HEC 293 suspension manufacturing as a platform. And the third is really around this notion of inter-thecal delivery. And this really allows us to take learnings and achieve economies of scale from one program to the next. I'll pause there, and Suyash, I'll allow you to kind of talk about maybe some of the things that we plan to discuss with regulators and how we plan to, you know, apply those learnings from one program to the next.
spk04: Thanks, Sari, and thanks, Raju, for the question. Yeah, there's lots and lots of commonalities, I think, between our programs. Over and above the simple, you know, the trifecta of comments we often make about AP9H, UK293, and IT administration, there's many, many other commonalities that I think we shared. And, you know, we're really... ...as a platform more than anything. Let me touch on a couple of things. So you mentioned... ...one. I think we're going to learn a huge amount from just one program to inform the next. You know, there's a lot of debate in the field about, you know, IT versus ICM versus ICV and the subtle difference in distribution between them all. I keep coming back to the perspective that, you know, IT administration works, has worked for decades. I've given it myself in the world of, oncology and anesthesiology, and it's worked for decades there. And when you look at the clinical data from GAN, from CLN3, CLN6, and another, and Zolgesma, you see it works, and it works beautifully. And I think as we continue to build our portfolio of programs, we can really, I think the FDA and other regulators will just become increasingly comfortable with intrathecal administration. And there's many nuances around that that many details. For example, we spent some time yesterday talking about the different types of infusion kits you might use to give intrathecal drug and the compatibility testing you might need to do for some of these different methods of administration. So I think there's lots and lots of learning, in particular from GAN, that will inform the rest of our portfolio. Another piece of learning, I think, that's important from GAN and as our programs progress is just on the immunosuppression regime we like to use. So the whole world of immunology of gene therapy has evolved and evolved rapidly over the past few years. Initially, people didn't give any immunological therapy and just treated liver inflammation reactively with all the prednisolone. Then it was decided, okay, let's give the prednisolone first to try and prevent it. And then additional medications have been trialed and added And we've settled on this very nice regime of six months of oral prednisolone plus 12 months of rapamycin at specific doses that we have a lot of experience with now and learnings from the GAN program where a number of patients have been managed with this regime in this pressure therapy very, very successfully to the point where actually we're not seeing any evidence of any T-cell mediated hepatic inflammation in any of the patients who have received this regime from the GAN study. We're using that approach in GM2, in CLM1, in SIRF1, and I think once again we're going to build up this body of evidence for that particular regime. I think the third thing I'll mention, and you touched on it, is endpoints in the clinical trial and what we can learn from one to the other. You know, I think for a lot of our diseases, where there are these neurological features. There's a developmental regression and a lack of failure to gain milestones. And we've settled on a very nice group of developmental assessments, the Bayley Scale, the Vineland, the CHOP Intend, and there's one or two others that are more disease specific. We know how to train the raters that do these particular assessments. We know to video the assessments in a particular way. We know to upload the videos to a server where they can then be reviewed externally by a second rater or a second group of raters who are blinded to whether the patient has been treated or not. All these things add a lot of robustness to the clinical development program and learnings from one to the other. The other thing I mentioned when we were talking about RET a few minutes ago was just seizures, how we collect seizure information, seizure activity, EEG, the medications the patients are on, et cetera. So I think that in our discussions with regulators, there are many, many commonalities, in particular on the clinical development side, that I think are going to be applicable to all programs and will constitute additional learning from one to the other. I hope that answers your question, Raju.
spk09: Yeah, no, that's extremely helpful. Maybe just a quick follow-up on that last point as it relates to, you know, the upcoming FDA discussions on the GAN program. You know, how should we be looking at the results of those discussions as it relates to, you know, the potential requests from the FDA? I'm thinking particularly about natural history comparator versus having to, you know, run a, a placebo arm or a sham control treated arm. I mean, you know, is that something that you're looking to see kind of to extrapolate to the rest of the pipeline? Like if they do give you a natural history comparator for Pivotal, that's something that you might try for, you know, GM2 and some of these other diseases? Or do you think that the discussions on GAN are only going to be related to GAN and each individual indication will probably be a different – you know, kind of a different set of discussions with the agency. Thanks.
spk04: So it's a really important point, you know, how much data are already existing for a particular disease. And there are certainly commonalities here from program to program, but there are also some subtle differences, and we're doing things a little bit differently from program to program. What I will say at the higher level is there's some very nice guidance that was published by the FDA recently on gene therapy development for neurodegenerative disease and had a specific section on natural history studies and historical controls. And they said very clearly this may be appropriate for a gene therapy product to treat a rare and serious neurodegenerative disease if there's a clear medical need, which is absolutely the case for most of our programs, where the inclusion of a current control is not practical or ethical, which is also true, certainly for programs like GM2 or CLM1, where there's this ongoing high risk of mortality. They also talk about the disease course is well documented and the expected treatment effect is large. It may be very, very suitable to use a natural history comparator as a control. Now, for GAM specifically, we have 45 patients, in fact, more than that. We've presented data of 45 patients in the natural history study with data that patients were enrolled in 2013, so it's seven or eight years of data on some of these patients, and we've got very, very clear indication that there's a consistent drop in the primary FCM points, the MFM32 of eight points per year. I think because of that, it's also predictable. The disease course is predictable. And so for GAN, very rare disease, and we're seeing a very nice treatment effect in the study. So all those things really contribute to the fact that for GAN in particular, I think it's You don't know what the FDA is going to say, but I think it checks all their boxes for a natural history study being an appropriate comparator. So my guess is it's unlikely they will ask us to do any kind of more formal concurrent control. Once again, you don't know what the FDA is going to say, but it checks all their boxes from that perspective. GM2, there's a lot of already good natural history data out there in publications, and so we're making use of that. CLN1, there is a prospective natural history study ongoing currently with about 40 to 50 patients in it. This is international, so we'll be using that. So it's a little bit different from program to program. For Rett syndrome, there is huge natural history databases that are available, although for Rett, we were likely building a concurrent control for a randomized but non-blinded concurrent control to add a little more robustness to that clinical development plan. So let me stop there. I hope I've answered your question and given you some context, but I can stop. We can go into more detail if you'd like, Raju, but let me stop there.
spk08: No, that was extremely helpful. Thank you. Thank you for the question.
spk05: Thanks so much. The next question comes from Yun Yang from Jefferies. Please go ahead.
spk03: Thank you. So, you know, the Today, when we talk about address the patient population for your gene therapy programs, it's been kind of a focus on the U.S. and Europe. But now you look to potential approval of a 120 in 2023. What are you thinking about a market opportunity outside the U.S. and Europe?
spk07: Thank you for the question. That's a great question. You know, what's interesting about rare disease commercialization is the fact that you're able to leverage a major market approval pretty much all over the world. And what I mean by that And approval in the U.S. or in the EU, you're able to initiate almost immediately reimbursed name patient or early access programs. And some of the more highly reimbursable markets where you also have an overexpression of genetic diseases. And so in some countries like the GCC region of the Middle East, Saudi Arabia, Israel, Turkey, some of the Latin American countries where reimbursement is actually quite good, Brazil, Colombia. These are areas that we would actually look to commercialize post a major market approval, either under a reimbursed main patient program or early access program, would eventually you would seek a marketing approval over time. So that's really the way that we're thinking about commercialization. We are looking globally. We would most likely do this through some of your more established distribution partners. There's a number of partners, particularly in Israel, the Middle East, Turkey, Brazil, that are highly skilled in achieving reimbursement for specialized products, gene therapies, high-priced products. And so we would probably most likely go this route. We most likely would not look to out-license. our product from a commercialization perspective early on, but really do our commercialization through distribution collaborations in some of these areas that I mentioned. So that's the way that we're thinking about things today. Obviously, as time goes on, you gain more information and you alter your thinking that way. But at least for now, that's the way that we're approaching our commercialization, our pre-commercialization plans.
spk03: Thank you. And I have one more question on RAP syndrome program. So I'm sure that you're familiar with Novartis program, and I don't know how much you can speak about it, but aside from your program potentially have a better regulation of the transgene expression, can you talk about kind of a differentiation compared to Novartis, and is Novartis actively pursuing their RAP program? Thank you.
spk07: No, thank you for the question. So what I'll just do is highlight the difference, kind of the main difference in the two approaches, and then I'll turn it over to Sviesh to kind of talk about the differences in more depth. So really the main difference in the two programs is our program, HL102, is a gene therapy product, AV9, with a self-regulatory feedback loop built into the transgene that caps gene expression on a cell-by-cell basis, or what was described in the paper that was recently published, that has a genotypic regulation of gene expression. That's the term that we're using. Essentially, what we're doing is having a safety valve to guard against overexpression associated toxicity. The Novartis-Vexis construct is essentially self-complementary AAV9 with full-length MeCP2 with no regulatory component. That, at least, is the last construct that was published that we are all publicly aware of. I'll stop there. So, yes, maybe you want to go through in a little bit more detail some of the nuances.
spk04: Yeah, thanks, Ari, and thanks for the question. I think it's an important question. As Ari mentioned, the major difference, really, is the fact that, you know, we include, we have the MiniMECP2 gene, which was developed by Professor Sir Adrian Bird, and a very esteemed and knowledgeable RET expert, from Edinburgh, who was actually the first person to demonstrate unequivocally that Rett syndrome is a highly reversible disease. So we use his design for the mini-MECP2 gene, and then we attach this strip of microRNA binding sites via my RET platform, which stands for microRNA responsive auto-regulatory element. So when MECP2 levels go up within the cell, as a consequence of the gene therapy, the down-regulatory microRNA binding sites were triggered. They bind to this OmalRare platform, which is in the untranslated region of the construct, and bring down levels of methamphetamine, as RA suggested, acting as a safety valve. Now, we're very excited to be able to say to you that the first quantitative data demonstrating this reduction in MECP2 expression to the point where you have enough so it's efficacious, but not too much that it's toxic, was published in Brain, which is a very prestigious neuroscience journal. It went online on Friday, and we issued a press release yesterday. And I would encourage you to look at the paper. The lead author is Sarah Spinnett, and the senior author is our good friend and colleague and chief scientific advisor, Stephen Gray. There's a particular diagram in that paper which I suggest you look at, which looks specifically at different levels of expression of MeCP2 in different parts of the brain and different parts of the spinal cord. And you can see very nicely the non-MIRAC construct overexpresses, whereas the MIRAC construct expresses enough so that it is efficacious but not toxic. So We're very excited about that particular paper. So I think that's the main difference, the fact that we can demonstrate this, the ability to express MeCP2 within these normal physiological parameters now, we've shown in different parts of the brain, and we've shown it quantitatively as well. My understanding is that Novartis is still moving forward with that program. The last I heard was they're planning to move forward as an IND, but I don't know exactly where they are with that. But I think that's the main difference, really, between our products and theirs.
spk03: Thank you for the details.
spk04: Thank you.
spk05: There are no further questions. I will now turn the call over to Mr. Sessions for his closing remarks.
spk07: So, again, we appreciate everyone joining us on the call this morning. As you can see, the company has made great strides during the first quarter, and we continue to make progress throughout the rest of this year. And so we hope that you guys join us at our R&D day, which will take place over two days in June, June 28th and June 29th, and we'll provide further updates as the year goes on. Thank you for joining. Have a good day.
spk05: Ladies and gentlemen, this concludes today's presentation. Thank you once again
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