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.
spk13: Good day, and thank you for standing by. And welcome to Sangamo fourth quarter 2023 teleconference. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press R11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I'd now like to hand the conference over to your speaker today, Louise Wilkie, Vice President of Investor Relations, Corporate Communications. Please go ahead.
spk01: Good afternoon.
spk12: Thank you for joining us on the call today, where we'll be not only sharing our progress across the business, but also sharing exciting new data that we believe reinforce our decision to become a neurology-focused genomic medicine company. Slides from today's presentation, which are being screen shared through the live webcast link, can be found on our website, sangamo.com, under the Investors and Media sections of the Events and Presentations page. This call includes forward-looking statements regarding Sangamo's current expectations. These statements include, but are not limited to, statements relating to the therapeutic and commercial potential of our product candidates and engineered capsids, the anticipated plans and timelines of Sangamo and our collaborators for regulatory submissions, initiating and conducting clinical trials, screening and dosing patients, and presenting clinical data, advancement of our product candidates, anticipated submissions, feedback from, and interactions with regulatory agencies, advancement of preclinical programs to the clinic, our strategic reprioritization and reallocation of resources and the anticipated benefits thereof, plans to partner certain of our programs, the sufficiency of our resources, cash runway, and plans to seek additional capital, and the timing of related updates. Our initial financial guidance for 2024 and estimates of 2024 operating expenses, upcoming catalysts and milestones, and other statements that are not historical facts. Actual results may differ materially from what we discussed today. These statements are subject to certain risks and uncertainties that are discussed in our filings of the SEC, specifically in our annual report on Form 10-K for the fiscal year ended December 31, 2023 filed with the SEC. The forward-looking statements stated today are made as of this date, and we undertake no duty to update such information except as required by law. On this call, we discuss our non-GAAP operating expenses. Reconciliation of this measure to our GAAP operating expenses can be found in our press release, which is available on our website. Please note that all forward-looking statements about our future plans and expectations, including our financial guidance, are subject to our ability to secure adequate additional funding. On today's call, I'm joined by Sandy McRae, Chief Executive Officer, Patricia Durababu, Chief Financial Officer, Amy Pooler, Head of Research, Greg Davis, Head of Technology, and Natalie Dubar-Stringfellow, Chief Development Officer. Now, I'll turn the call over to our CEO, Sandy McRae.
spk02: Thank you, Louise, and good afternoon to everyone joining the call. Today we're pleased to discuss Sangamo's recent pipeline advancements that solidify our sharpened strategic focus in neurology and help contextualize why we made this important decision to dedicate ourselves to addressing neurological disorders. On this call, we will explore our most recent announcement, highlighting the remarkable preclinical data from our new intravenously administered capsid that demonstrated an ability to cross the blood brain barrier and how our technology could potentially unlock value across our next generation neurology programs. We will then outline how we plan to progress our neurology assets into the clinic. The advancement of neurological medicines has long been limited by the inability to achieve widespread central nervous system delivery, particularly across the blood-brain barrier. Due to this obstacle, many devastating conditions affecting millions of patients go untreated. With conviction in our science and the promise that it holds, we announced in the third quarter of 2023 having seen initial results from the CAPSID, that we would prioritize our resources to focus on our neurology pipeline. We implement these changes because we believe that SANGMO holds great potential to unlock new treatments for patients with neurological diseases by pairing our highly potent epigenetic regulators with an additional key requisite for success in the neurological space, a capsid capable of crossing the blood brain barrier to successfully deliver the drug where it needs to go. Today's announcement that we have engineered such capsid, which demonstrated industry leading blood brain barrier penetration and brain transduction in non-human primates. This validates our conviction in such an important area, potentially taking us one step closer to helping patients who are suffering from devastating conditions. Sango is proud to be developing both epigenetic regulation cargo and advanced capsid delivery capabilities that could finally lead to new treatments for many neurological conditions. This differentiated approach underpins our wholly owned neurology pipeline. Our purpose is clear as we strive to unlock value as a strategic, highly focused company and an industry partner determined to help patients in need. As preclinical data from our new STAC BVB delivery capsule will demonstrate in this presentation, Our dual epigenetic regulation and capsid delivery capability showed the ability to cross the blood-brain barrier, which we believe is critically important to developing therapies to potentially treat prion disease, tauopathies, and other neurological conditions. These data support further advancement of our prion and tau programs, which are on track for regular submissions to enter the clinic by the end of 2025. Meanwhile, we continue to advance our lead candidate in chronic neuropathic pain, NAV1.7, which uses an intrathecally administered capsid towards an investigational new drug submission with the U.S. Food and Drug Administration expected in the fourth quarter of this year. It is also important to recognize the significance of our recent Fabry disease advancements. We recently presented compelling Phase 1-2 data at the 20th Annual World Symposium, showing enormous promise across many important biomarkers and measures of efficacy. Importantly, we also recently announced alignment with the Agency on a remarkable abbreviated clinical pathway to potential approval. The FDA advised that a single study with up to 25 patients in combination with confirmatory evidence is an acceptable pathway to BLA submission for Isogagine Sivaparvovic. This is a significant development as conducting a single study of this nature would enable a potentially abbreviated and most cost effective pathway to potential approval than was ever originally anticipated. In addition, the European Medicines Agency granted priority medicine eligibility for the programme, which could potentially further accelerate activities in Europe. We are thrilled with this progress and are in active discussions to partner this programme, which, if successful, we anticipate could form another key source of non-dilutive funding. I continue to strongly believe that our Fabry disease program could be transformative for patients and the compelling clinical data presented at World coupled with these highly encouraging regulatory updates underpin that belief. As the only biopharmaceutical company known to be internally delving both the innovative genome targeting cargo and the required delivery capsids, we believe that Syngamo is well positioned to potentially usher in the future of neurology genomic medicines. Amy will share this in detail, but I first wanted to show you what got us so excited. Our zinc finger epigenetic regulators have demonstrated potency and selectivity across a variety of different indications. This is clearly seen in the left panel's showing how expression of the zinc finger repressors in vivo in non-human primates, which are shown in green on the left, demonstrated nearly complete elimination of RNA expression in neurons from the targeted gene shown in white, in this case tau. The panel to the right gives you a first glimpse of our new intravenously administered AAV capsid variant that we're calling STAC-BBB, where STAC stands for Sangamo Therapeutics AAV Capsid. A picture can tell a thousand words, and we were excited to see the dark purple stain in the brain image on the right of the slide, which shows that STAC BBB mediated efficient blood-brain barrier crossing and widespread cargo delivery throughout the brain of non-human privates in important new preclinical studies. We're extremely encouraged that STAC BBB, which we engineered through our sifter capsid engineering platform, significantly outperformed other known published capsids evaluated in our study. It achieved widespread brain delivery and transient expression, as well as detargeting of the liver and other peripheral tissues, and was generally well tolerated. We look forward to telling you more about these remarkable findings today. First, though, I want to spend a moment highlighting our choicefulness in our lead neurology programs for NAV1.7 and prion disease. We are particularly pursuing these targets because one, they're validated by human genetics. Two, they have a well-defined patient population. Three, they have a delivery we believe to be achievable using AAV capsids. And four, could lead to quantifiable quicker patient outcomes. Importantly, they represent a significant medical need and commercial opportunity. NAV 1.7 addresses a significant unmet need, with over 43,000 patients in the US alone who face intractable pain resulting from small fibre neuropathy. These people live with constant debilitating pain that is imaginable, unimaginable to the most of us. In fact, these conditions have a higher suicide rate than in the broader population. With promising preclinical data for our NAV 1.7 programme, We believe we have a clear route to clinical proof of concept. We expect an IND submission in Q4 of this year and hope to be in the clinic next year with initial clinical data anticipated by the end of 2025. Importantly, NAF 1.7 uses a well-known intrathecally administered capsid for delivery. Prion disease is a truly devastating condition with more than 1500 patients diagnosed per year across US and Europe. It is a disease that rapidly progresses and is always fatal, usually within 12 to 15 months of symptom onset, and there are no currently effective treatment options available. However, we are hopeful we can advance treatment of this disease as the repression of prion in our preclinical models significantly extended survival in mice. They lived a normal mouse lifetime. We anticipate filing a clinical trial authorization submission in the UK because, thanks to mad cow disease, they have an excellent infrastructure for identifying and caring for prion patients. Our CTA enabling studies are already underway, and we expect to submit the CTA in the fourth quarter of 2025. While we intend to progress our core programs towards regular submissions, we believe that the exciting STAC BBB data we will discuss today also potentially unlocks a number of potential additional programs that were paused pending the identification of a suitable blood brain barrier penetrant capsid. They were waiting for STAC BBB. The first of these is the repression of the gene that produces tau, MAPT, to address tauopathy such as Alzheimer's disease. With the identification of STAC BBB, we intend to resume the development of our TAO program with an IND submission expected as early as the fourth quarter of 2025. In addition, STAC BBB could also potentially unlock multiple other neurology epigenetic regulation programs that were paused by SANGMO pending the identification of such a capsid. Diseases such as Parkinson's disease, mitronic drosophete type 1, Sangamo is exploring avenues to resume development of these programmes with new potential collaborators. With our reinvigorated neurology focus and our momentum already underway in 2024, we anticipate multiple potential near-term milestones from now and the end of 2025. We also anticipate milestones for our later stage non-neurology programmes that could provide additional important non-dilutive funding. As we plan to partner our Fabry disease programme, we expect to complete dosing in the Phase 1-2 STAR study in the first half of this year. For our partnered HEMA programme, Pfizer expects to present Phase 3 results in the middle of this year, just a few months away, and anticipates potential regulatory submissions in the US and Europe in early 2025, assuming that the pivotal readout is supportive. We are then eligible to earn up to $220 million in milestone payments and up to 14 to 20% royalties on potential sales from this program. Before we show you the detailed data, it's important to take a moment to talk about our current financial position. Over the course of 2023, we proactively made difficult decisions to preserve our most valuable assets. We declared our intention to become a focused neurology genomic medicine company, carefully aligned our resources and investments to that vision, and advanced multiple reductions in force to significantly limit our spend. As a result, we've reduced our operating expenses by approximately 50% year over year. Whilst difficult, these were the right decisions to make, as I'm sure you'll see in great detail very shortly. We ended 2023 with approximately $81 million in available cash, cash equivalents and marketable securities. We believe that these resources, in combination with potential future cost reductions, will be sufficient to fund our planned operations into the third quarter of 2024, without factoring in any additional capital raises. Given our streamlined structure, we expect our 2024 non-GAAP operating expenses to be in the range of £125 to £145 million. As we complete our strategic transformation, fulfil our responsibilities, and we anticipate our operating expenses to further decrease to under £105 million in 2025 as we transition our legacy clinical programmes. In the meantime, we continue to actively pursue a number of different opportunities to raise additional capital. I'll now turn it over to Amy to discuss our latest Capsa data, along with other updates from our pipeline. Amy.
spk16: Thank you, Sandy, and hello to everyone joining today's call. We know that widespread CNS delivery is challenging with conventional AAVs, which is why we have developed our Sifter platform, which is designed to enable the selection of neurotropic AAV Capsid variants. We do this by using a directed evolution process to create, refine, and select the best possible capsid from a library of millions of unique capsids. When we set out to develop an industry-leading novel IV-administered capsid, we outlined the key characteristics needed for success, one that could solve the challenges that many drug developers have historically faced. We knew that this capsid needed to have broad brain coverage in all the key areas integral to disease pathology. enhance enrichment in the brain compared to other published capsid, as well as robust neuronal transduction. We also needed it to express the zinc finger therapeutic cargo and repress the target gene, all while being easily manufacturable at scale. Although this may seem like a lot of boxes to check, we believe each of these qualities is essential for a truly effective capsid that could be deployed into humans. That is why we are so pleased with the preclinical data from our recent non-human primate studies, that demonstrate how well-placed STAC BBB is to potentially address these criteria. In these preclinical studies, we were encouraged to see that STAC BBB demonstrated robust penetration of the blood-brain barrier and widespread gene expression throughout the brain, primarily targeting neurons regardless of the promoter, and with results that were consistent across individual animals and groups. We saw extensive expression of zinc finger cargo throughout the brain, including key disease-relevant regions, a clear dose response curve for zinc finger expression, and a corresponding repression of the disease target. Vector genomes were enriched in the central nervous system while detargeted from the dorsal root ganglia and liver. And as Sandy mentioned, crucially, we believe the STAC-BBB is also manufacturable at scale. So how did we assess this performance? In our latest experiments, we started with 100 million capsid variants, which engineered with a specific peptide insertion and carefully barcoded to enable tracking. We then evaluated these capsid variants through progressive rounds of screening, enriching for the best performers through three rounds of selection, until we identified STACBB as the standout high performer. The visualization shown here is the final round of the sifter screening process, where 1,260 novel capsids were all evaluated simultaneously in cinnamologous macaques. On this graph, the y-axis shows the relative level of enrichment of the capsid throughout the brain, was zero representing capsids that exhibited no comparative enrichment in the brain. What we're looking for here is a high degree of neuronal RNA expression indicating successful BBB crossing and delivery to neurons. We see on the x-axis the overall coefficient of variation, or in other words, how consistent the full change enrichment is among the samples that were tested. We are looking for a capsid that is both highly enriched in the brain and that we are able to reliably detect across multiple tissues. showing that the results are reproducible and not a one-off chance outcome. The highest performing capsids will be found in the top left corner, so we were very encouraged to see the STAC BBB capsid coming out on top, outperforming all the others in the library on this assessment. The library assessment also included known published neurotrophic capsid variants that were evaluated head-to-head in addition to our own. We were very pleased that STAC BBB was the top performing capsid in this benchmarking study. Moreover, we also saw this performance was consistent across all three animals and multiple levels of the brain with STAC BBB illustrated here in green consistently outperforming the next best published capsid here shown in orange. In fact, we saw a 700-fold better enrichment in the brain for STAC BBB compared to the benchmark capsid AAV9 shown in blue on this graph, highlighting the superior neuronal expression needed by STAC BBB. On this next graphic, you can see how this superior performance continues to be demonstrated across all key areas of the brain, including the hippocampus and deep brain regions, which traditionally have been so difficult to reach with intrathecal administrations of antisense oligonucleotides, also called ASOs, or more traditional capsids. The liver can act as a primary sink for intravenously administered capsids. However, we saw there was significant detargeting of STAC BBB in the liver, with 100-fold lower expression compared to the benchmark AAV capsid when compared against historical sanguinal studies at the same dose. Low peripheral exposure in the liver is desired. We then conducted follow-on studies, taking our lead capsid, STAC BBB, and testing its individual performance. On the left of the slide, we see an image of a non-human primate brain. It is from an animal that was treated with a STAC BBB capsid administered intravenously at a dose of 2E13 vector genomes per kilogram, and packaged with both a nuclear localized green fluorescent protein, or GFP, as well as a zinc finger repressor targeting the prion gene. We then used antibody labeling to stain for the GFP cargo, as illustrated with the deep purple or almost black coloring you see on the left side. We are very pleased to see both a widespread and uniform expression of GFP mediated by STACBBB, throughout all the gray matter, which is where the cell bodies reside in the brain. Conversely, you see no GFP expression in the white matter as we would anticipate because it primarily consists of myelinated axons. On the right is a control animal that wasn't treated with AAV, but the tissue was processed in the same way to visualize GFP, and as you can see, there is no signal. If you dive deeper into some of the cortical regions, you can see there are two types of staining. You see the darker purple staining, which is the GFP cargo being expressed by the STAC BBB. And then the lighter blue is a nistle stain that labels all the cell nuclei in the brain. It's important to note that there are many different cell types in the brain with neurons making up roughly 19 to 40% of all cells dependent on the brain region. Here we clearly see that STAC BBB is neurotropic with pronounced staining of the cell nuclei and in some places even an overflow of GFP protein out into the cell body of the neuron. This transduction was consistent across the cortical regions shown, which are important to many different disease pathologies and appears largely localized to neurons. This transduction was consistent across 12 other brain regions we analyzed, with clear enrichment of STACBB observed in the neurons in each of these areas. Because of the observed neurotrophic nature of STACBB, the level of enrichment seemed to align with the number of corresponding neurons found in each brain region. The lateral geniculate nucleus, for example, is tightly packed with neurons, and we saw striking STAC BBB enrichment here. Extensive transduction is crucial because each area is linked to a whole range of diseases for which treatments are desperately needed. Based on this compelling data, we believe that diseases such as Huntington's disease, Parkinson's disease, ALS, or frugicataxia could all be potentially unlocked by STAC BBB and our think-finger cargo. If we dive a little deeper into some of these brain regions, for example, the dentate nucleus, This deep cerebellar region is particularly hard to reach with CSF routes of administration. However, using an intravenous approach where we're leveraging the intimate relationship between the brain vasculature and neurons, we are able to transduce almost all the neurons in this region. As you see here, 30 out of 31 neurons visible in this field were transduced. We were thrilled to see this robust level of brain transduction. Moreover, this consistent transduction was reproducible across animals. Here we show the dentate nucleus of three separate animals treated with STAC BBB, all of which exhibited similar levels of GFP expression. Finally, we believe STAC BBB is manufacturable at scale. Capsid manufacturability is critical to creating a successful commercial drug product for patients. We expect to leverage our long track record of AAV production and process development to manufacture STAC BBB at scale. Our tech ops team has manufactured the capsid at 50 liters and are currently scaling up to 500 liters. we have been able to produce the CAPSID using both the HEC293 and SF9 platforms. We believe STAC BBB is manufacturable at commercial scale using standard cell culture and purification processes, is soluble using known excipients, and can be characterized using available analytics, which we consider to be crucial factors in the potential long-term success as we seek to scale up to the levels needed for clinical trials for potential commercialization. I'll now turn it back to Sandy to discuss our ZincFinger platform. Sandy?
spk02: Thanks, Amy. As Amy emphasized, our latest stack BBB data demonstrate that we've engineered a capsid that exhibited brain-wide delivery in non-human primates. However, this is only one half of the effect of neurology genomic medicine. I will now tell you about the other half, our potent zinc finger cargo, which can be combined with our delivery capsids to potentially create truly innovative genomic medicines. Our neurology pipeline leverages Sangamo's proprietary Syncfinger gene targeting technology, a high precision genomic engineering platform. Think of Syncfingers as the landing mechanism which can identify the exact zip code within the genome to attach and to regulate. This is what they do in the bodies and brains of all of us. ThinkFingers are highly versatile, extremely customizable, and very compact, meaning they can be easily packaged into viral vectors. They're roughly one-eighth the size of other editing modalities, so we believe we can package up to three repressors if necessary into one AAB capsid and repress several genes at any one time if we wanted to. They're also derived from human proteins, which potentially avoids issues with immunogenicity that may arise with bacterial proteins. Think of our zinc finger platform as a Swiss Army knife, which is flexible and offers different tools based on your needs. Broadly, zinc fingers recognize an 18 base pair piece of DNA to induce a variety of actions, such as causing a double-stranded break via nucleus properties, activation, repression, base editing, epigenetic modification, and site-specific integration. Our base editing capabilities were highlighted last month in Nature Communications, showing that compact zinc finger architecture utilizes toxin-derived cytin deaminases for highly efficient base editing in human cells. We were pleased to read in Nature Communications that other groups believe zinc fingers are the most capable epigenetic regulation tool, and are delighted with our partnership with Chroma Medicine, who have licensed our zinc fingers exactly for this purpose. We are currently focusing on leveraging our epigenetic regulation capabilities in neurology, and the data that follows on prion, tau, and NAV1.7 will focus on that technology specifically. So Amy, can you now tell us a little more about how the zinc fingers are leveraged in our prion and tau programs?
spk16: Thanks, Sandy. Turning now to prion disease, which affects approximately 600 patients a year in the U.S. and Canada and around 900 in Europe, prion disease is an awful disease, typically fatal in 12 to 15 months. There are no approved disease-modifying therapies that currently exist. Prion is an excellent fit for zinc finger repression. We know that prion knockout animals do not get the disease prion reduction can delay or prevent disease, and neuronal prion production and protein reduction also prevents disease. We therefore believe that the repression of prion expression may slow or halt disease progression and neurodegeneration. We knew that we wanted to achieve widespread delivery to the brain for prion disease, given that misfolded prion protein spreads throughout the brain as the disease progresses. As mentioned earlier, we therefore packaged our prion-targeted zinc finger repressor into the newly identified stack BBB capsid and administered it intravenously to three separate non-human primates. In order to assess which regions of the brain stack BBB delivers to, we collected 220 punches from each animal and conducted RT-qPCR analyses to measure how much prion-targeted zinc finger was expressed. Each dot on these brain images illustrates the location of one of the punches we collected, and each row represents one of the three animals that was dosed. The color represents the level of pre-untargeted zinc finger expression that was measured. As you can see from the key in the top right, ZFR expression levels are indicated by the intensity of green for each one of the punches. These results confirmed the GFP protein expression data and support that STAC-BBB mediated consistent brain-wide expression of pre-untargeted zinc finger repressor in all three animals. We next wanted to quantify if expression correlated with an associated reduction in prion mRNA in these brain punches. We were happy to see a reduction of prion expression in all 35 brain regions that we analyzed. As a reminder, these brain punches do not solely consist of neurons, but additional brain cell types as well. Cells such as oligodendrocytes, astrocytes, and microglia. Because prion is expressed in multiple brain cell types, when we are seeing total prion reduction here at the bulk brain level of 20 to 30%, the percent reduction in individual neurons must be significantly higher. When looking at the single-cell analyses and similar studies in the past, including the tau data I will show you in a moment, we have seen upwards of 80% reduction at the individual neuron level. So how do we think the level of repression we saw in the green bar graph just now will impact disease progression? Based on this level of bulk repression observed in a mouse model of aggressive prion disease, we concluded that zinc finger repressors can significantly extend survival in prion-infected animals. In collaboration with the Broad Institute, we engineered zinc finger repressors to target the mouse prion gene and administered these as a single dose in mice either 60 or 122 days following prion infection. Without any intervention, you can see that clearly the untreated mice consistently die around 160 days post-infection. However, Mice treated with a single administration of a prion zinc finger repressor showed notable extended survival compared to those control animals living to beyond 400 or 500 days after infection, which is within the normal lifespan of a mouse. This is an incredible alteration in disease progression. In a separate published study, performance of ASOS, also illustrated on this graphic, was evaluated in the same mouse model. These data show that multiple treatments were required. starting from approximately 70 days post-infection, as shown in graph 2, to be able to induce an extension in lifespan. And when ACEs were administered at a later time point post-infection, as shown in graph 4, when the disease was further progressed, there was only minimal extension in lifespan. Conversely, even when administered 122 days post-infection, shown in graph 3, which is a timeline more aligned to what we believe we will see in the clinic, A single dose of the zinc finger repressor was still able to profoundly delay disease progression and extend survival in mice. These data reflect the 2E13 VGE per kilogram dose level, which is considered a mid-dose of AAV, showing that we have the potential to dose higher should we decide that that's appropriate. The pre-on program is progressing with our clinical lead zinc finger repressor that showed greater than 95% pre-on reduction per cell with no detectable off-targets and meaningful potency both in vitro and in vivo. We expect to begin clinical enabling toxicology studies in the second half of this year and anticipate submitting a clinical trial application in the UK for prion in the fourth quarter of 2025. Moving now to tau, a well-known target for the treatment of neurodegenerative diseases called tauopathies. Recent data from Biogen's ASO study shows stabilization of cognitive function with regular injections of ASOs addressing tau, which seems to cement tau's implication in Alzheimer's disease. In addition, there are also a host of tauopathy disorders that span more than 12 distinct indications, including progressive supernuclear palsy and frontotemporal dementia, and account for a very large patient population with a high unmet medical need that we could potentially address with our zinc finger approach. Using a combination of STAC BBB delivery capabilities and a tau zinc finger repressor, we see a potential ability to halt disease progression with a one-time IV administration for various tauopathy indications, given the capsid's demonstrated ability to reach all the brain regions with a high specificity in non-human primates. Here, we packaged our clinical lead tau zinc finger repressor, which shows fantastic repression of tau, exceptionally specific expression, and no detectable off-targets in vitro, into our SAC-BBB capsid and tested it at three different intravenously administered doses, 5E12, 2E13, and 1E14 vector genomes per kilo. Similar to the slide we saw before on prion, here we were looking for widespread expression of the zinc finger repressor throughout the brain. Here we were also assessing the three dose levels and we're very pleased to see dose dependent expression with the intensity of green increasing as the dose increased, indicating a higher level of zinc finger expression. Importantly, and similarly to the prion study, we are not only looking at the level of zinc finger expression, but also the corresponding levels of tau repression. Here we show these data for the deep brain thalamic region, including the lateral geniculate nucleus. Like prion, tau is a gene that is expressed not only in neurons, but also in astrocytes and oligodendrocytes. We know that tau expression in neurons is the critical driver of disease pathology, which is why we are so focused on repressing it in these cells. In this case, the clinical lead construct uses a synapsin promoter, so we know that we are only targeting zinc finger expression to neurons. we were pleased to see a dose-dependent increase in finger expression that correlated with a dose-dependent decrease of tau expression. Like in the prion experiments, this is a bulk analysis of whole brain punches, which consists of many cell types, not just neurons. So to be able to achieve this level of tau repression at the bulk level, we must be achieving significantly higher repression at the single cell level in neurons. Here you'll see that we achieved an almost 50% reduction in tau at the bulk level and at the top dose in the lateral geniculate nucleus. which is likely correlated to the higher proportion of neurons we see in this region, as illustrated by the dark staining in the image above from the same brain region in the GFP arms of the study. Let's take a moment to look more closely at the pons, part of the brainstem and a key brain region in the tauopathy called progressive supernuclear palsy. On the left is the bulk tissue punch analysis for this region, and like what I showed you on the previous slide, we saw a correlation between increased sink finger expression and decreased tau expression in a dose-dependent manner. Because understanding the activity of the zinc finger at the single cell level is so important, in addition to the bulk brain tissue analyses, we also utilized a multiplexed RNA scope and immunohistochemistry approach to visualize ZFR expression and tau repression in neurons. This data is beautiful and shows a high level of detail that is only recently possible, allowing us to understand what's going on at the single cell level. On the top is a PONS image from a control animal, and the bottom is from an animal treated with the top dose of STAC BBB encoding the tau clinical lead zinc finger repressor. In purple are the neurons, which in the control animals robustly express tau mRNA, shown in white. Conversely, in the bottom row of images, you can clearly see that where the zinc finger was expressed in green, we saw a striking corresponding reduction of tau. We calculate that approximately 80% of the neurons express zinc fingers in this region, which resulted in almost complete repression of tau in those cells. Here we show more of this beautiful single cell data demonstrating the power of both STACPBB and our tau zinc finger repressor working together, in this instance in the motor cortex. On the top row, you see the vehicle control where tau mRNA was clearly expressed across the brain region, in particular within neurons in purple and glia in orange. Here, no zinc finger repressor was detected, and the tau mRNA levels remain consistent between the different images. Conversely, at the bottom, we see a potent repression of tau mRNA across the image on the left. Zooming into this a little more, in the middle image, and as indicated in green, we detected the zinc finger repressor, particularly in neurons. And importantly, where we saw the zinc finger repressor expression, we saw an almost complete elimination of tau mRNA, most visible in the bottom right panel. This is truly encouraging data that gives us great hope for the promise of a single administration of STACPBB and our TAO zinc finger repressor. For our TAO program, we have identified the clinical lead zinc finger and IND enabling activities are well advanced, making this program well suited to move into the clinic, either ourselves or with a potential partner. Toxicology studies could be initiated as early as the second quarter of this year with a potential IND submission as early as the fourth quarter of 2025. Finally, I'll outline our lead neurology indication, NAV1.7, and how we're using this program as a way to balance the portfolio through a diversified delivery approach. Our NAV1.7 program does not leverage STACBBB, but instead uses a known AAV delivery capsid that is already in the clinic. Our aim here was to develop a medicine capable of reaching the dorsal root ganglia, as NAV1.7 is a voltage-gated sodium channel expressed there. And mutations in this channel play a critical role in pain perception. By potently reducing NAV1.7 in the DRG, we believe we can prevent the transmission of nociceptive pain signals in order to treat chronic neuropathic pain and a host of other indications. There is an urgent need for new therapies in this space and a potentially very large patient population to address, so we are very motivated to be moving forward with our NAV1.7 program and plan to initially focus on patients with small fiber neuropathy. As you see here, preclinical data from our clinical lead zinc finger repressor targeting SCN9A, the gene that encodes NAV1.7, demonstrated a meaningful repression in vitro with exquisite levels of specificity, as we only saw repression of NAV1.7 without impacting any other sodium channels. It's difficult to use small molecules to treat these channels because NAV channels share a lot of structural similarities at the protein level. However, at the DNA level, they are distinct. which makes them well-suited to the zinc finger technology. Taking this into animal models on the left, you see a study targeting neurons in the DRG, which are groups of cells outside the spinal column in the blood-brain barrier. Using intrathecal injection of the zinc finger repressor in mice, we observed significant expression, which you see in red. This then resulted in an almost complete elimination of the SCN9A expression, shown by the absence of white, which indicated a potent knockdown of the NAV1.7 gene at the mRNA level. If you look at the middle pain, you can understand what this looks like in a mouse model. We used the gold standard mouse model of neuropathic pain called the spared nerve injury model and performed a single injection of the zinc finger repressor intrathecally after the nerves were cut to induce pain. The single administration of our zinc finger repressor resulted in a full reversal of pain perception in these animals as indicated by the orange and dark red bars in the bottom middle pain which are very similar to the results of those animals that had never received the surgery, as indicated in blue, which is very impressive. Finally, you see the non-human primate study on the far right, where we wanted to show that we can target the DRG and achieve potent repression of SCN9A. In this study, we administered three different doses of zinc fingers intrathecally, and we saw dose-dependent and potent repression of NAV1.7. Importantly, there's a lot of research emphasis on peer-reviewed publications about identifying any potential DRG toxicity, and we did not find anything in these studies that would be indicative of such toxicity, which is crucial as we seek to advance this program into the clinic. We are very encouraged by the NAV 1.7 program, and we look forward to completing these final toxicology studies. We expect to submit an IND for this program in the fourth quarter of this year. I will now hand back to Sandy to wrap this up before we open for Q&A.
spk02: Thank you, Amy. Really appreciate everyone joining us today as we look forward to answering your questions. And what we've outlined, we strongly believe in the power of our science to address devastating neurological conditions. We're advancing epigenetic regulation cargo and novel AAV capsid for a high value gateway neurological diseases like chronic neuropathic pain and prion disease. Today we have shown we have a capsid that demonstrated the ability to penetrate the blood-brain barrier and exhibited industry leading CNS tropism in non-human primates. The development of STAC BBB potentially unlocks multiple neurology programs that could be advanced ourselves or with partners as a potential source of non-dilutive funding. And we have the prion disease program which we believe could quickly validate STAC BBB and proteins in humans. In addition, our Fabry disease program has continued to generate compelling phase 1-2 data and is ready for a potential registration study with an abbreviated clinical pathway aligned with the FDA and multiple collaboration discussions in progress. We have transformed Sangamo into a focused neurology business with the potential to transform the lives of patients with debilitating neurological conditions. We have also made the necessary but very difficult decisions to focus our company and streamline our OPEX with the intention of reducing our burn but without impairing potential value. We believe these changes enable us to set forth an attractive opportunity to raise additional funds via additional potential collaborations. Alongside this, we have the Pfizer collaboration in Hime that brings revenue bearing opportunity with $220 million in potential milestones. As you can see, We believe our company is well positioned to change the lives of patients as a neurology, genomic medicine company. Operator, please open the lines for questions.
spk13: And thank you. As a reminder to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster and one moment for our first question. And our first question comes from Patrick Truccio from HC Wainwright. Your line is now open.
spk03: Hello, everyone. Hi, team. This is Luis Santos on for Patrick. Congratulations on this, as you said, beautiful and fantastic data. We are interested in knowing a little bit more what data do you still have left for completion of the package for the CTA on the prion disease? Also on the TAO program, did you release which epitope of TAO you are targeting? Maybe I'll have a follow-up question. Thank you.
spk27: Thank you, Patrick. These are really good questions.
spk02: It is beautiful data. And for the team that has been working on this for several years, it's a fulfillment of their scientific careers, truly. So I'm going to split into two. So the section on how do we get Prion into the clinic, we'll go to Natalie, the head of development.
spk22: Hi, everyone. So for the CTA for Prion, now that we have the STAG-BBV, we are going to do a GLP tox study, which will be required for the IND. In order to do this, we have to manufacture the product to put in the tox study, and we're going to do this this year. for filing an IND in the end of 2025. We also need to do a clinical manufacturing lot with the clinical candidate.
spk02: You've had great discussions already in the UK with people about the enthusiasm to take this forward.
spk22: Absolutely. There is a really good system here where the patient that has prion disease are going to a common center and we have linked to really the expert in prion disease in the UK and they have also direct communication with the regulatory authority in England. So we think that we're well positioned to really move quickly in the UK.
spk02: Thank you, Natalie. And then for types of tau, Amy, how do you think about that?
spk16: Sure, I'm happy to take that one. I think one of the advantages of the zinc finger platform is that we're targeting tau at the DNA level. We know that there's so much complexity for tau, the different splice variants at the RNA level, and then many, many different configurations of tau at the protein level. Because we're targeting upstream of all of that, we believe that we're able to address really all different tauopathies and all of these different possible forms of toxic tau.
spk02: Which would be a real competitive and patient advantage.
spk16: Absolutely.
spk03: Just a very quick follow-up. On the dose response, what level of reduction of tau do you expect will be enough to be promising and translational into humans? So what levels of tau reduction will we see what we need to see, not just from the beautiful RNA scope images, but at the pathological level, at the physiological level in mice and HP, so that we can be more confident in humans.
spk18: Yeah, that's a great question.
spk16: It depends on the different brain regions, really the level of repression that we're targeting. But we believe, especially when you look at the outstanding efficacy in the prion studies, that we're in the range that we would be expecting to see some clinical results. What's really important is that at the single cell level, we see an almost complete repression of tau. And this is important because we know that the tauopathies are spreading throughout the brain. So not only is it important to have that widespread brain delivery, like what we're seeing with STACPBB, but also at a single cell level that we see this really complete repression of tau.
spk02: Amy, when you speak to potential partners, what's the level of repression that interest people?
spk16: That's a great question, and I think it depends on the indication. For some telepathies, we think something between 10% to 30%, depending on the brain region, would be important.
spk15: Thank you. And thank you. And one moment for our next question.
spk11: And our next question comes from Maury Raycroft from Jefferies. Your line is now open.
spk00: Hi. Thanks for taking my questions, and congrats on the update today with the new capsid. I'm wondering with the new capsid, have you looked at the relative immunogenicity of it and how that would compare to AAV9 or other published capsids? And based on this, do you see any potential to have a redosing option?
spk02: Amy, can you cover that for us, please? And Natalie, maybe you want to say something?
spk16: That's a great question. Thank you. These novel engineered capsids are being engineered in order to improve the crossing of the blood-brain barrier and brain penetrance. We believe that they have a similar profile compared to other natural capsids with a similar range of neutralizing antibody prevalence. Of course, another frontier of capsid engineering could be to evade that, but that was not what we set out to do in the study. And we were really excited with the penetrance that we saw in the brain of these animals.
spk22: Yeah, I think we don't expect to be very different from other AAVs. Of course, patients in the trial will be screened for pre-existing antibody to novel AAV capsid.
spk00: Got it. Okay, makes sense. And for your figure where you compared your capsid to other published capsids, Can you say which capsids these were, what the screening or inclusion criteria was, and were any excluded? For example, the Voyager capsid.
spk02: Thanks, Maury. There are a lot of capsids that people are talking about, which I think reflects the interest in the field in trying to find that magic capsid. We know now from talking to many pharma companies that they have capsid search groups in place because it feels like a next generation neurological disease set of medicines. So we just looked across the literature and identified the mutations that had been made in those capsids, and then recreated them in our laboratory, which is something that everyone can do. So we're pleased that ours turned out at the top of the pile. But what's more important is the characteristics of our capsid on its own, that it's widespread, that it's easily manufacturable, that it hits all the spots, that it transduces the zinc fingers, and it reduces both tau and prion.
spk00: Got it. That's helpful. And Last question, and then I'll hop back in the queue. I'm just wondering if you can say anything additional on partnering conversations around these capsid data yet, and if you can provide any more perspective around the terms that you would aim to get for partnering any of your wholly-owned CNS programs. Thanks, Mario.
spk02: So, we've known the penultimate screening around results since the end of last year. And so we've been gradually talking and socializing this with our friends and pharma companies. When we showed the latest data and some of it, the single cell data is only out in the last week or so. The word awesome was used often in this. So we continue to talk to them because we feel that both with the capsid itself and the capsid with our cargo, There is no way that Sangamal can advance all of the potential indications with this and that we can only do it through partnership with that kind of pharma ecosystem. Of course, the money is valuable, but it would be wrong for me to start talking about numbers here. And we look forward to finding ways to move this into as many indications as possible. Got it. Makes sense. Thank you for taking my questions.
spk10: And thank you.
spk11: And one moment for our next question. And our next question comes from Nicole Germino from Truist.
spk13: Your line is now open.
spk05: Hi, this is Alex. I'm from Nicole. Congrats on the data and all the progress.
spk06: A couple from us. Can you remind us for your stack, BBB, how would this fit into Alzheimer's given the current focus on the amyloid plaque? And could STAC BBB have any impact on existing plaque? Or do you think that this could be potentially used after approved antibodies? And then I have a follow-up.
spk02: So I think we heard your questions. It wasn't quite clear. Amy, can you repeat the quote you think we're answering and then take it from there?
spk16: Sure. I think I may have only caught the first part of your question, which is understanding how targeting tau fits in with the amyloid hypothesis for Alzheimer's disease.
spk23: Yeah.
spk16: Okay. Great. Great. I think that there's been accumulating evidence over the past years, which, again, the data that I showed today also from the Biogen trial with the ACEs targeting tau really have shown how important tau is in driving the pathology of the disease. There are patients or, let's say, people that have a lot of amyloid in their brains but actually don't have Alzheimer's disease. And it's only when you have this development of tau, the tauopathies, that's correlated with the cognitive decline that's associated with the disease. So we believe, like others actually, that tau is a critical step in that pathway and that its reduction will be really important for slowing or stopping the progression of the disease.
spk02: And particularly when compared to those ASOs, you can give it, hopefully, we expect you'll be able to give it once and it will have a long time effect.
spk16: That's right. Not only would it be a single administration, but also be able to target all of the different brain regions that we think are involved in the disease.
spk02: Which ASOs don't always do.
spk16: That's right.
spk02: Can you repeat your second question, please?
spk06: Do you think that in the treatment landscape, where this would play out, given the improved antibodies, and you see this as sort of before antibodies, afterwards, how do you think the community is doing it?
spk02: So perhaps I can take that. We're a preclinical stage and the data is very encouraging. We need to move it into humans and show its effect. While that's happening, I'm sure that we will, in this field, we'll collect a lot of data with other forms of tau antibodies or ASOs and understand the benefit. And gradually, the benefit that we show, I think, will be understood, particularly that it's a one one time treatment, which compare that to repeated intrathecal injections, I think is very appealing. It's very appealing for the patient, but it's also very appealing for dealing with a confused person. It's also very appealing for hopefully for society to be able to do this easily and in any hospital or clinic in the country. So this is why we're so excited about it. If tau is as important as we're all believing, having a single injection intravenously that crosses the blood-brain barrier and completely reduces the production of tau in cells offers an enormous opportunity for what is a devastating disease. Natalie?
spk22: Yeah, in addition, if you compare this treatment to antibody, as Amy was saying, we're targeting the expression of tau We're not targeting a specific epitope of a tau protein, which, you know, there is many forms of tau protein in isomer patients, and we don't know exactly which one is the most relevant for each patient. So we're going at the root with the gene epigenetic regulation approach.
spk14: Makes sense. Thanks for all the color.
spk11: And thank you. And one moment for our next question. And our next question comes from Luca Isi from RBC.
spk13: Your line is now open.
spk07: Oh, great. Thanks for taking our questions. This is Lisa on for Luca. Well, congrats on all the progress. I have a few questions on the cyber program. Just wondering if you can add any color on how your conversations with potential partners has changed since you have reached alignment with the FDA on a registrational path forward. And on the Faber-Pivotal study, can you share some more additional color on what the primary endpoint will be? Is it fair to assume the FDA will want to see reduction in GL3 inclusions by kidney biopsy, similar to what we've seen with Faberzyme? Any color here would be helpful. Thanks so much.
spk27: Natalie, you've been having a lot of these discussions recently.
spk22: Yes, so we're absolutely thrilled with our interaction with the FDA and to have aligned in a single well-controlled study with confirmatory evidence for the basis of a BLA submission and approval. At this point, we're not commenting on the endpoint for this trial. And of course, we've had, now let Sandy comment further, but we've This is very exciting for the potential partner we are in conversation with as it really accelerates the path to BLA approval and it's also reduced the cost. Sandy?
spk02: Yeah, I think an enormous credit is due to Peter Marks and his group at the agency. They have broken a logjam. They've made a public statement that they wanted more technology. gene therapies or genomic medicines for rare diseases to move forward. And that to do that, you have to look at studies that are manageable and at endpoints that are achievable. And that's why this study has then got the notice of lots of people who, frankly, were standing at the sidelines of Fabry disease, wondering how to get it to registration. This is a very manageable study. that not only we'll look at biopsy results, but we'll also look at the, and this is a direct quote from the agency, at the totality of the data and the benefit that it brings to patients. And I think that is such a healthy way to look at medicine approval. And we look for getting to this, into the hands of the partner and to patients and registration as quickly as possible.
spk15: Thanks so much. And thank you.
spk11: And one moment for our next question. And our next question comes from Yanen Zhu from Wells Fargo.
spk13: Your line is now open.
spk04: Hi, thanks for taking our question. This is Quan for Yanen. So just a follow-up on the prior fabric questions. Can you share what the potential partners might be looking for? And can we expect to see additional kidney biopsy data from the STAR study? And I have a follow-up.
spk02: So the partners are looking, we're very simply looking for compelling clinical data, real benefit that would make patients move from ERT. And we now have 13 patients that are off ERT. over a year in some cases, and no desire to go back onto ERT. I think that's really important. And some of them had been on ERT for a significant time. And in those patients, their SF-36 is significant, and they are moving, changing category of FOSS-MSSI, which is the investigator rating. So as they are now, even though they were treated with the ERT, they're now even better with the gene therapy. And finally, in seven of them that came in with antibodies, five of them, the antibodies have completely disappeared, completely disappeared, and in two of them, significantly reduced. And those are the kind of antibodies that eventually limit the effectiveness of the treatment. That's what the partners see and think, wow, this is the medicine that we will be able to take forward. But until we had the second part, which was the regulatory pathway that was manageable, they were cautious. And now that we're the only clinical stage asset for Fabry disease, where we have the best in class data and we have a way forward with the regulatory authorities, this is a natural place for any pharma company that's looking for a phase three asset to come.
spk04: Got it. Thank you so much. And my second question is on your capsid. So on the Stag BBB capsid, can you share how you achieved the 100-fold detargeting on the liver? Thank you.
spk02: Amy, Amy, can you explain that?
spk17: Yeah, I'm happy to take that.
spk16: Leslie, you saw from the slides that I just presented, we started with a library of 100 million different novel capsids. And we went through a whole screening process using non-human primates in order to select for capsids that were enriched in the brain. Although we didn't design specifically the capsids to be detargeted to the liver, we do believe that there's some relationship between that liver detargeting and the really improved targeting of the brain that we saw in those studies. And that's possibly what enabled us to find a capsid that was so well transducing the non-human primate brain.
spk26: And why is that important, Amy?
spk16: Well, it's important because the liver is such a sink for intravenously administered AAVs, actually by any route. We know that the AV can go to the liver and it can be potentially an issue for some patients. It's better if we can find a capsid that targets the tissue that we want to transduce to treat these diseases, which in this case is the central nervous system, and limits that exposure to the peripheral tissue for safety.
spk04: Got it.
spk14: Thank you so much for all the callers.
spk11: And thank you. And one moment for our next question. And our next question comes from Ambita Gupta from TD Cowan.
spk13: Your line is now open.
spk21: Hi, guys. This is Anvita Anpal with you today. Congrats on all the progress and the fantastic data presented today. What are your early thoughts on the potential clinical trial design for the first study with the NAV1.7 in chronic neuropathic pain? And then if you could also provide some color on maybe who would be the ideal patient for this program would be super helpful. Thank you.
spk27: Natalie, can you comment on the route forward for NAV 1.7?
spk22: Yes, thank you. Yes, we are planning to file an IND for NAV 1.7 by the end of this year, and we are finishing our GLP-TUCH study and our clinical manufacturing, so we will also finalize our clinical protocol. At this point, we are not commenting on the design of the trial or the endpoints, but we are well underway in planning those studies.
spk02: I agree, Natalie. I read the protocol last week, or the version that's being circulated, and the bit that struck me is in one study, 17% of patients with intractable pain described their life as being worse than death. This is not toothache or a bunionectomy that has been described for NAV1.8. This is the kind of intractable pain that dominates your life and makes these patients consider suicide and that their life is just awful. We need to get this into patients as soon as possible. So we've got that protocol ready to go. We've had discussions with the agency about how to move forward. And once we get that IND done and we're heading to the clinic, we will share that with you because I think it's important that patients get to hear that there's this opportunity coming that will replace, hopefully, all of these anti-epileptics and opiates that are used in this dreadful condition.
spk15: And thank you. And one moment for our next question. And our next question comes from Gina Wang from Barclays.
spk13: Your line is now open.
spk09: Hi, good afternoon. This is Hershita on for Gina.
spk08: Thank you so much for the detailed call this afternoon, and thank you for taking our questions. Most of them have been answered, but I just had a quick follow-up on Fabi. Given your recent update, I was curious, can you help categorize the importance of improvement in health scores, specifically for the SF36 survey? Could you provide color on how the general health and physical component scores are rated? Are they equally rated, or is there a higher rate to one of the components? Thank you so much.
spk25: Natalie, can you cover that?
spk22: Yes, so in our Phase I-II study, you know, it's primarily initially a safety study, but we're also collecting a lot of data in the patient. And really, we are looking, as you know, Fabry is a multifaceted disease, and we're looking at many different parameters, including kidney function, heart function, pain score, GI score, and general health. So at this point, we're collecting all those points, and what is remarkable is that the body of this data all point in the same direction of improvement in the patient. Of course, we're following those patients and the numbers of patients with more and more time since treatment is increasing every month, and we're collecting this data. But the data at World really show that we have maintenance of EGR for our slope. We have improvement in EGR score in FOSM SSI, in SF36, in pain. So everything is tracking in the right direction. So at this point, there is not one that is, you know, necessarily more important than the other in the Phase I-II trial.
spk15: And thank you.
spk11: And I am showing no further questions.
spk13: I would now like to turn the call back over to Louise Wilkie for closing remarks.
spk12: Thank you once again for joining us today, and thank you for all your questions. As a reminder, you'll be able to access the presentation that we gave today on the investor relations section of the Sangamo website after this call. We look forward to keeping you updated on our future developments. Thank you.
spk13: This concludes today's conference call. Thank you for participating. You may now disconnect. Music Playing you Thank you. Thank you. Thank you. Good day, and thank you for standing by. And welcome to Sangamo fourth quarter 2023 teleconference. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press R11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I'd now like to hand the conference over to your speaker today, Louise Wilkie, Vice President of Investor Relations, Corporate Communications. Please go ahead.
spk01: Good afternoon.
spk12: Thank you for joining us on the call today, where we'll be not only sharing our progress across the business, but also sharing exciting new data that we believe reinforce our decision to become a neurology-focused genomic medicine company. Slides from today's presentation, which are being screen shared through the live webcast link, can be found on our website, sangamo.com, under the Investors and Media sections of the Events and Presentations page. This call includes forward-looking statements regarding Sangamo's current expectations. These statements include, but are not limited to, statements relating to the therapeutic and commercial potential of our product candidates and engineered capsids, the anticipated plans and timelines of Sangamo and our collaborators for regulatory submissions, initiating and conducting clinical trials, screening and dosing patients, and presenting clinical data, advancement of our product candidates, anticipated submissions, feedback from, and interactions with regulatory agencies, advancement of preclinical programs to the clinic, our strategic reprioritization and reallocation of resources and the anticipated benefits thereof, plans to partner certain of our programs, the sufficiency of our resources, cash runway, and plans to seek additional capital, and the timing of related updates. Our initial financial guidance for 2024 and estimates of 2024 operating expenses, upcoming catalysts and milestones, and other statements that are not historical facts. Actual results may differ materially from what we discussed today. These statements are subject to certain risks and uncertainties that are discussed in our filings of the SEC, specifically in our annual report on Form 10-K for the fiscal year ended December 31, 2023 filed with the SEC. The forward-looking statements stated today are made as of this date, and we undertake no duty to update such information except as required by law. On this call, we discuss our non-GAAP operating expenses. Reconciliation of this measure to our GAAP operating expenses can be found in our press release, which is available on our website. Please note that all forward-looking statements about our future plans and expectations, including our financial guidance, are subject to our ability to secure adequate additional funding. On today's call, I'm joined by Sandy McRae, Chief Executive Officer, Patricia Durababu, Chief Financial Officer, Amy Pooler, Head of Research, Greg Davis, Head of Technology, and Natalie Dubar-Stringfellow, Chief Development Officer. Now, I'll turn the call over to our CEO, Sandy McRae.
spk02: Thank you, Louise, and good afternoon to everyone joining the call. Today we're pleased to discuss Sangamo's recent pipeline advancements that solidify our sharpened strategic focus in neurology and help contextualize why we made this important decision to dedicate ourselves to addressing neurological disorders. On this call, we will explore our most recent announcement highlighting the remarkable preclinical data from our new intravenously administered capsid that demonstrated an ability to cross the blood brain barrier and how our technology could potentially unlock value across our next generation neurology programs. We will then outline how we plan to progress our neurology assets into the clinic. The advancement of neurological medicines has long been limited by the inability to achieve widespread central nervous system delivery, particularly across the blood brain barrier. Due to this obstacle, many devastating conditions affecting millions of patients go untreated. With conviction in our science and the promise that it holds, we announced in the third quarter of 2023 having seen initial results from the CAPSID, that we would prioritize our resources to focus on our neurology pipeline. We implement these changes because we believe that SANGMO holds great potential to unlock new treatments for patients with neurological diseases by pairing our highly potent epigenetic regulators with an additional key requisite for success in the neurological space, a capsid capable of crossing the blood brain barrier to successfully deliver the drug where it needs to go. Today's announcement that we have engineered such capsid, which demonstrated industry leading blood brain barrier penetration and brain transduction in non-human primates. This validates our conviction in such an important area, potentially taking us one step closer to helping patients who are suffering from devastating conditions. Sango is proud to be developing both epigenetic regulation cargo and advanced capsid delivery capabilities that could finally lead to new treatments for many neurological conditions. This differentiated approach underpins our wholly owned neurology pipeline. Our purpose is clear as we strive to unlock value as a strategic, highly focused company and an industry partner determined to help patients in need. As preclinical data from our new STAC BBB delivery capsule will demonstrate in this presentation, Our dual epigenetic regulation and capsid delivery capability showed the ability to cross the blood-brain barrier, which we believe is critically important to developing therapies to potentially treat prion disease, tauopathies, and other neurological conditions. These data support further advancement of our prion and tau programs, which are on track for regular submissions to enter the clinic by the end of 2025. Meanwhile, we continue to advance our lead candidate in chronic neuropathic pain, NAV1.7, which uses an intrathecally administered capsid towards an investigational new drug submission with the U.S. Food and Drug Administration expected in the fourth quarter of this year. It is also important to recognize the significance of our recent Fabry disease advancements. We recently presented compelling Phase 1-2 data at the 20th Annual World Symposium, showing enormous promise across many important biomarkers and measures of efficacy. Importantly, we also recently announced alignment with the Agency on a remarkable abbreviated clinical pathway to potential approval. The FDA advised that a single study with up to 25 patients in combination with confirmatory evidence is an acceptable pathway to BLA submission for Isogagine Sivaparvovic. This is a significant development as conducting a single study of this nature would enable a potentially abbreviated and most cost effective pathway to potential approval than was ever originally anticipated. In addition, the European Medicines Agency granted priority medicine eligibility for the programme, which could potentially further accelerate activities in Europe. We are thrilled with this progress and are in active discussions to partner this programme, which, if successful, we anticipate could form another key source of non-dilutive funding. I continue to strongly believe that our Fabry disease program could be transformative for patients and the compelling clinical data presented at World coupled with these highly encouraging regulatory updates underpin that belief. As the only biopharmaceutical company known to be internally delving both the innovative genome targeting cargo and the required delivery capsids, We believe that Sangamo is well positioned to potentially usher in the future of neurology genomic medicines. Amy will share this in detail, but I first wanted to show you what got us so excited. Our zinc finger epigenetic regulators have demonstrated potency and selectivity across a variety of different indications. This is clearly seen in the left panels. showing how expression of the zinc finger repressors in vivo in non-human primates, which are shown in green on the left, demonstrated nearly complete elimination of RNA expression in neurons from the targeted gene shown in white, in this case tau. The panel to the right gives you a first glimpse of our new intravenously administered AAV capsid variant that we're calling STAC BBB, where STAC stands for Sangamo Therapeutics AAV Capsid. A picture can tell a thousand words, and we were excited to see the dark purple staining the brain image to the on the right of the slide, which shows that STAC BBB mediated efficient blood-brain barrier crossing and widespread cargo delivery throughout the brain of non-human privates in important new preclinical studies. We're extremely encouraged that STAC BBB, which we engineered through our sifter capsid engineering platform, significantly outperformed other known published capsids evaluated in our study. It achieved widespread brain delivery and transient expression, as well as detargeting of the liver and other peripheral tissues, and was generally well tolerated. We look forward to telling you more about these remarkable findings today. First, though, I want to spend a moment highlighting our choicefulness in our lead neurology programs for NAV1.7 and prion disease. We are particularly pursuing these targets because one, they're validated by human genetics. Two, they have a well-defined patient population. Three, they have a delivery we believe to be achievable using AAV capsids. And four, could lead to quantifiable quicker patient outcomes. Importantly, they represent a significant medical need and commercial opportunity. NAV 1.7 addresses a significant unmet need, with over 43,000 patients in the US alone who face intractable pain resulting from small fiber neuropathy. These people live with constant debilitating pain that is imaginable, unimaginable to the most of us. In fact, these conditions have a higher suicide rate than in the broader population. With promising preclinical data for our NAV 1.7 program, We believe we have a clear route to clinical proof of concept. We expect an IND submission in Q4 of this year and hope to be in the clinic next year with initial clinical data anticipated by the end of 2025. Importantly, NAV 1.7 uses a well-known intrathecally administered capsid for delivery. Prion disease is a truly devastating condition with more than 1500 patients diagnosed per year across US and Europe. It is a disease that rapidly progresses and is always fatal, usually within 12 to 15 months of symptom onset, and there are no currently effective treatment options available. However, we are hopeful we can advance treatment of this disease as the repression of prion in our preclinical models significantly extended survival in mice. They lived a normal mouse lifetime. We anticipate filing a clinical trial authorization submission in the UK because, thanks to mad cow disease, they have an excellent infrastructure for identifying and caring for prion patients. Our CTA enabling studies are already underway, and we expect to submit the CTA in the fourth quarter of 2025. While we intend to progress our core programs toward regular submissions, we believe that the exciting STAC BBB data we will discuss today also potentially unlocks a number of potential additional programs that were paused pending the identification of a suitable blood brain barrier penetrant capsid. They were waiting for STAC BBB. The first of these is the repression of the gene that produces tau, MAPT, to address tauopathies such as Alzheimer's disease. With the identification of STAC BBB, we intend to resume the development of our TAO program with an IND submission expected as early as the fourth quarter of 2025. In addition, STAC BBB could also potentially unlock multiple other neurology epigenetic regulation programs that were paused by Sangamo pending the identification of such a capsid. Diseases such as Parkinson's disease, myotronic drosophie type 1, Sangamo is exploring avenues to resume development of these programmes with new potential collaborators. With our reinvigorated neurology focus and our momentum already underway in 2024, we anticipate multiple potential near-term milestones from now and the end of 2025. We also anticipate milestones for our later stage non-neurology programmes that could provide additional important non-dilutive funding. As we plan to partner our Fabry disease program, we expect to complete dosing in the Phase 1-2 STAR study in the first half of this year. For our partnered HEMA program, Pfizer expects to present Phase 3 results in the middle of this year, just a few months away, and anticipates potential regulatory submissions in the US and Europe in early 2025, assuming that the pivotal readout is supportive. We are then eligible to earn up to $220 million in milestone payments and up to 14 to 20% royalties on potential sales from this program. Before we show you the detailed data, it's important to take a moment to talk about our current financial position. Over the course of 2023, we proactively made difficult decisions to preserve our most valuable assets. We declared our intention to become a focused neurology genomic medicine company, carefully aligned our resources and investments to that vision, and advanced multiple reductions in force to significantly limit our spend. As a result, we've reduced our operating expenses by approximately 50% year over year. Whilst difficult, these were the right decisions to make, as I'm sure you'll see in great detail very shortly. We ended 2023 with approximately $81 million in available cash, cash equivalents and marketable securities. We believe that these resources, in combination with potential future cost reductions, will be sufficient to fund our planned operations into the third quarter of 2024, without factoring in any additional capital raises. Given our streamlined structure, we expect our 2024 non-GAAP operating expenses to be in the range of £125 to £145 million. As we complete our strategic transformation, fulfil our responsibilities, and we anticipate our operating expenses to further decrease to under £105 million in 2025 as we transition our legacy clinical programmes. In the meantime, we continue to actively pursue a number of different opportunities to raise additional capital. I'll now turn it over to Amy to discuss our latest Capsa data, along with other updates from our pipeline. Amy.
spk16: Thank you, Sandy, and hello to everyone joining today's call. We know that widespread CNS delivery is challenging with conventional AAVs, which is why we've developed our Sifter platform, which is designed to enable the selection of neurotropic AAV Capsid variants. We do this by using a directed evolution process to create, refine, and select the best possible capsid from a library of millions of unique capsids. When we set out to develop an industry-leading novel IV-administered capsid, we outlined the key characteristics needed for success, one that could solve the challenges that many drug developers have historically faced. We knew that this capsid needed to have broad brain coverage in all the key areas integral to disease pathology. enhanced enrichment in the brain compared to other published capsid, as well as robust neuronal transduction. We also needed it to express the zinc finger therapeutic cargo and repress the target gene, all while being easily manufacturable at scale. Although this may seem like a lot of boxes to check, we believe each of these qualities is essential for a truly effective capsid that could be deployed into humans. That is why we are so pleased with the preclinical data from our recent non-human primate studies. that demonstrate how well-placed STAC BBB is to potentially address these criteria. In these preclinical studies, we were encouraged to see that STAC BBB demonstrated robust penetration of the blood-brain barrier and widespread gene expression throughout the brain, primarily targeting neurons regardless of the promoter, and with results that were consistent across individual animals and groups. We saw extensive expression of zinc finger cargo throughout the brain, including key disease-relevant regions, a clear dose response curve for zinc finger expression, and a corresponding repression of the disease target. Vector genomes were enriched in the central nervous system while detargeted from the dorsal root ganglia and liver. And as Sandy mentioned, crucially, we believe the STAC-BBB is also manufacturable at scale. So how did we assess this performance? In our latest experiments, we started with 100 million capsid variants, which engineered with a specific peptide insertion and carefully barcoded to enable tracking. We then evaluated these capsid variants through progressive rounds of screening, enriching for the best performers through three rounds of selection, until we identified STACBB as the standout high performer. The visualization shown here is the final round of the sifter screening process, where 1,260 novel capsids were all evaluated simultaneously in cinnamologous macaques. On this graph, the y-axis shows the relative level of enrichment of the capsid throughout the brain, was zero representing capsids that exhibited no comparative enrichment in the brain. What we're looking for here is a high degree of neuronal RNA expression, indicating successful BBB crossing and delivery to neurons. We see on the x-axis the overall coefficient of variation, or in other words, how consistent the full change enrichment is among the samples that were tested. We are looking for a capsid that is both highly enriched in the brain and that we are able to reliably detect across multiple tissues. showing that the results are reproducible and not a one-off chance outcome. The highest performing capsids will be found in the top left corner, so we are very encouraged to see the STAC BBB capsid coming out on top, outperforming all the others in the library on this assessment. The library assessment also included known published neurotrophic capsid variants that were evaluated head-to-head in addition to our own. We are very pleased that STAC BBB was the top performing capsid in this benchmarking study. Moreover, we also saw this performance was consistent across all three animals and multiple levels of the brain, with STAC-BBB illustrated here in green consistently outperforming the next best published capsid, here shown in orange. In fact, we saw a 700-fold better enrichment in the brain for STAC-BBB compared to the benchmark capsid, AAV9, shown in blue on this graph, highlighting the superior neuronal expression needed by STAC-BBB. On this next graphic, you can see how this superior performance continues to be demonstrated across all key areas of the brain, including the hippocampus and deep brain regions, which traditionally have been so difficult to reach with intrathecal administrations of antisense oligonucleotides, also called ASOs, or more traditional capsids. The liver can act as a primary sink for intravenously administered capsids. However, we saw there was significant detargeting of STAC BBB in the liver, with 100-fold lower expression compared to the benchmark AAV capsid when compared against historical sanguinal studies at the same dose. Low peripheral exposure in the liver is desired. We then conducted follow-on studies taking our lead capsid, STAC BBB, and testing its individual performance. On the left of the slide, we see an image of a non-human primate brain. It is from an animal that was treated with a stack BBB capsid administered intravenously at a dose of 2E13 vector genomes per kilogram and packaged with both a nuclear localized green fluorescent protein, or GFP, as well as a zinc finger repressor targeting the prion gene. We then used antibody labeling to stain for the GFP cargo, as illustrated with the deep purple or almost black coloring you see on the left side. We are very pleased to see both a widespread and uniform expression of GFP mediated by stack BBB throughout all the gray matter, which is where the cell bodies reside in the brain. Conversely, you see no GFP expression in the white matter as we would anticipate because it primarily consists of myelinated axons. On the right is a control animal that wasn't treated with AAV, but the tissue was processed in the same way to visualize GFP, and as you can see, there is no signal. If you dive deeper into some of the cortical regions, you can see there are two types of staining. You see the darker purple staining, which is the GFP cargo being expressed by the STAC BBB. And then the lighter blue is a nistle stain that labels all the cell nuclei in the brain. It's important to note that there are many different cell types in the brain with neurons making up roughly 19 to 40% of all cells dependent on the brain region. Here we clearly see that STAC BBB is neurotropic with pronounced staining of the cell nuclei and in some places even an overflow of GFP protein out into the cell body of the neuron. This transduction was consistent across the cortical regions shown, which are important to many different disease pathologies and appears largely localized to neurons. This transduction was consistent across 12 other brain regions we analyzed, with clear enrichment of STACBB observed in the neurons in each of these areas. Because of the observed neurotrophic nature of STACBB, the level of enrichment seems to align with the number of corresponding neurons found in each brain region. The lateral geniculate nucleus, for example, is tightly packed with neurons, and we saw striking STAC-BBB enrichment here. Extensive transduction is crucial because each area is linked to a whole range of diseases for which treatments are desperately needed. Based on this compelling data, we believe that diseases such as Huntington's disease, Parkinson's disease, ALS, or frugicotaxia could all be potentially unlocked by STAC-BBB and our think-finger cargo. If we dive a little deeper into some of these brain regions, for example, the dentate nucleus, This deep cerebellar region is particularly hard to reach with CSF routes of administration. However, using an intravenous approach where we're leveraging the intimate relationship between the brain vasculature and neurons, we are able to transduce almost all the neurons in this region. As you see here, 30 out of 31 neurons visible in this field were transduced. We were thrilled to see this robust level of brain transduction. Moreover, this consistent transduction was reproducible across animals. Here we show the dentate nucleus of three separate animals treated with STAC BBB, all of which exhibited similar levels of GFP expression. Finally, we believe STAC BBB is manufacturable at scale. Capsid manufacturability is critical to creating a successful commercial drug product for patients. We expect to leverage our long track record of AAV production and process development to manufacture STAC BBB at scale. Our tech ops team has manufactured the capsid at 50 liters and are currently scaling up to 500 liters. we have been able to produce the CAPSID using both the HEC293 and SF9 platforms. We believe STAC BBB is manufacturable at commercial scale using standard cell culture and purification processes, is soluble using known excipients, and can be characterized using available analytics, which we consider to be crucial factors in the potential long-term success as we seek to scale up to the levels needed for clinical trials for potential commercialization. I'll now turn it back to Sandy to discuss our ZincFinger platform. Sandy?
spk02: Thanks, Amy. As Amy emphasized, our latest STAC BBB data demonstrate that we've engineered a capsid that exhibited brain-wide delivery in non-human primates. However, this is only one half of the effect of neurology genomic medicine. I will now tell you about the other half, our potent zinc finger cargo, which can be combined with our delivery capsids to potentially create truly innovative genomic medicines. Our neurology pipeline leverages Sangamo's proprietary Syncfinger gene targeting technology, a high precision genomic engineering platform. Think of Syncfingers as the landing mechanism which can identify the exact zip code within the genome to attach and to regulate. This is what they do in the bodies and brains of all of us. ThinkFingers are highly versatile, extremely customizable, and very compact, meaning they can be easily packaged into viral vectors. They're roughly one-eighth the size of other editing modalities, so we believe we can package up to three repressors if necessary into one AAB capsid and repress several genes at any one time if we wanted to. They're also derived from human proteins, which potentially avoids issues with immunogenicity that may arise with bacterial proteins. Think of our zinc finger platform as a Swiss Army knife, which is flexible and offers different tools based on your needs. Broadly, zinc fingers recognize an 18 base pair piece of DNA to induce a variety of actions, such as causing a double-stranded break via nucleus properties, activation, repression, base editing, epigenetic modification, and site-specific integration. Our base editing capabilities were highlighted last month in Nature Communications, showing that compact zinc finger architecture utilizes toxin-derived cytin deaminases for highly efficient base editing in human cells. We were pleased to read in Nature Communications that other groups believe zinc fingers are the most capable epigenetic regulation tool, and are delighted with our partnership with Chroma Medicine, who have licensed our zinc fingers exactly for this purpose. We are currently focusing on leveraging our epigenetic regulation capabilities in neurology, and the data that follows on prion, tau, and NAV1.7 will focus on that technology specifically. So Amy, can you now tell us a little more about how the zinc fingers are leveraged in our prion and tau programs?
spk16: Thanks, Sandy. Turning now to prion disease, which affects approximately 600 patients a year in the U.S. and Canada and around 900 in Europe, prion disease is an awful disease, typically fatal in 12 to 15 months. There are no approved disease-modifying therapies that currently exist. Prion is an excellent fit for zinc finger repression. We know that prion knockout animals do not get the disease prion reduction can delay or prevent disease, and neuronal prion production and protein reduction also prevents disease. We therefore believe that the repression of prion expression may slow or halt disease progression and neurodegeneration. We knew that we wanted to achieve widespread delivery to the brain for prion disease, given that misfolded prion protein spreads throughout the brain as the disease progresses. As mentioned earlier, we therefore packaged our prion-targeted zinc finger repressor into the newly identified STAC BBB capsid and administered it intravenously to three separate non-human primates. In order to assess which regions of the brain STAC BBB delivers to, we collected 220 punches from each animal and conducted RT-QPCR analyses to measure how much prion-targeted zinc finger was expressed. Each dot on these brain images illustrates the location of one of the punches we collected, and each row represents one of the three animals that was dosed. The color represents the level of pre-untargeted zinc finger expression that was measured. As you can see from the key in the top right, ZFR expression levels are indicated by the intensity of green for each one of the punches. These results confirmed the GFP protein expression data and support that STAC-BBB mediated consistent brain-wide expression of pre-untargeted zinc finger repressor in all three animals. We next wanted to quantify if expression correlated with an associated reduction in prion mRNA in these brain punches. We were happy to see a reduction of prion expression in all 35 brain regions that we analyzed. As a reminder, these brain punches do not solely consist of neurons, but additional brain cell types as well. Cells such as oligodendrocytes, astrocytes, and microglia. Because prion is expressed in multiple brain cell types, when we are seeing total prion reduction here at the bulk brain level of 20 to 30%, the percent reduction in individual neurons must be significantly higher. When looking at the single-cell analyses and similar studies in the past, including the tau data I will show you in a moment, we have seen upwards of 80% reduction at the individual neuron level. So how do we think the level of repression we saw in the green bar graph just now will impact disease progression? Based on this level of bulk repression observed in a mouse model of aggressive prion disease, we concluded that zinc finger repressors can significantly extend survival in prion-infected animals. In collaboration with the Broad Institute, we engineered zinc finger repressors to target the mouse prion gene and administered these as a single dose in mice, either 60 or 122 days following prion infection. Without any intervention, you can see that clearly the untreated mice consistently die around 160 days post-infection. However, Mice treated with a single administration of a prion zinc finger repressor showed notable extended survival compared to those control animals living to beyond 400 or 500 days after infection, which is within the normal lifespan of a mouse. This is an incredible alteration in disease progression. In a separate published study, performance of ASOS, also illustrated on this graphic, was evaluated in the same mouse model. These data show that multiple treatments were required. starting from approximately 70 days post-infection, as shown in graph 2, to be able to induce an extension in lifespan. And when ACEs were administered at a later time point post-infection, as shown in graph 4, when the disease was further progressed, there was only minimal extension in lifespan. Conversely, even when administered 122 days post-infection, shown in graph 3, which is a timeline more aligned to what we believe we will see in the clinic, A single dose of the zinc finger repressor was still able to profoundly delay disease progression and extend survival in mice. These data reflect the 2E13 VGE per kilogram dose level, which is considered a mid-dose of AAV, showing that we have the potential to dose higher should we decide that that's appropriate. The pre-on program is progressing with our clinical lead zinc finger repressor that showed greater than 95% pre-on reduction per cell, with no detectable off-targets and meaningful potency, both in vitro and in vivo. We expect to begin clinical enabling toxicology studies in the second half of this year and anticipate submitting a clinical trial application in the UK for prion in the fourth quarter of 2025. Moving now to tau, a well-known target for the treatment of neurodegenerative diseases called tauopathies. Recent data from Biogen's ASO study shows stabilization of cognitive function with regular injections of ASOs addressing tau, which seems to cement tau's implication in Alzheimer's disease. In addition, there are also a host of tauopathy disorders that span more than 12 distinct indications, including progressive supranuclear palsy and frontotemporal dementia, and account for a very large patient population with a high unmet medical need that we could potentially address with our zinc finger approach. Using a combination of STAC BBB delivery capabilities and a tau zinc finger repressor, we see a potential ability to halt disease progression with a one-time IV administration for various tauopathy indications, given the capsid's demonstrated ability to reach all the brain regions with a high specificity in non-human primates. Here, we packaged our clinical lead tau zinc finger repressor, which shows fantastic repression of tau, exceptionally specific expression, and no detectable off-targets in vitro, into our SAC-BBB capsid and tested it at three different intravenously administered doses, 5E12, 2E13, and 1E14 vector genomes per kilo. Similar to the slide we saw before on prion, here we were looking for widespread expression of the zinc finger repressor throughout the brain. Here we were also assessing the three dose levels, and we're very pleased to see dose-dependent expression with the intensity of green increasing as the dose increased, indicating a higher level of zinc finger expression. Importantly, and similarly to the prion study, we are not only looking at the level of zinc finger expression, but also the corresponding levels of tau repression. Here we show these data for the deep brain thalamic region, including the lateral geniculate nucleus. Like prion, tau is a gene that is expressed not only in neurons, but also in astrocytes and oligodendrocytes. We know that tau expression in neurons is the critical driver of disease pathology, which is why we are so focused on repressing it in these cells. In this case, the clinical lead construct uses a synapsin promoter, so we know that we are only targeting zinc finger expression to neurons. we were pleased to see a dose-dependent increase in finger expression that correlated with a dose-dependent decrease of tau expression. Like in the prion experiments, this is a bulk analysis of whole brain punches, which consists of many cell types, not just neurons. So to be able to achieve this level of tau repression at the bulk level, we must be achieving significantly higher repression at the single cell level in neurons. Here you'll see that we achieved an almost 50% reduction in tau at the bulk level and at the top dose in the lateral geniculate nucleus. which is likely correlated to the higher proportion of neurons we see in this region, as illustrated by the dark staining in the image above from the same brain region in the GFP arms of the study. Let's take a moment to look more closely at the pons, part of the brainstem and a key brain region in the tauopathy called progressive supernuclear palsy. On the left is the bulk tissue punch analysis for this region, and like what I showed you on the previous slide, we saw a correlation between increased sink finger expression and decreased tau expression in a dose-dependent manner. Because understanding the activity of the zinc finger at the single cell level is so important, in addition to the bulk brain tissue analyses, we also utilized a multiplexed RNA scope and immunohistochemistry approach to visualize ZFR expression and tau repression in neurons. This data is beautiful and shows a high level of detail that is only recently possible, allowing us to understand what's going on at the single cell level. On the top is a PONS image from a control animal, and the bottom is from an animal treated with the top dose of STAC BBB encoding the tau clinical lead zinc finger repressor. In purple are the neurons, which in the control animals robustly express tau mRNA, shown in white. Conversely, in the bottom row of images, you can clearly see that where the zinc finger was expressed in green, we saw a striking corresponding reduction of tau. We calculate that approximately 80% of the neurons express zinc fingers in this region, which resulted in almost complete repression of tau in those cells. Here we show more of this beautiful single cell data demonstrating the power of both STACPBB and our tau zinc finger repressor working together, in this instance in the motor cortex. On the top row, you see the vehicle control where tau mRNA was clearly expressed across the brain region, in particular within neurons in purple and glia in orange. Here, no zinc finger repressor was detected, and the tau mRNA levels remain consistent between the different images. Conversely, at the bottom, we see a potent repression of tau mRNA across the image on the left. Zooming into this a little more, in the middle image, and as indicated in green, we detected the zinc finger repressor, particularly in neurons. And importantly, where we saw the zinc finger repressor expression, we saw an almost complete elimination of tau mRNA, most visible in the bottom right panel. This is truly encouraging data that gives us great hope for the promise of a single administration of STACPBB and our TAO zinc finger repressor. For our TAO program, we have identified the clinical lead zinc finger and IND enabling activities are well advanced, making this program well suited to move into the clinic, either ourselves or with a potential partner. Toxicology studies could be initiated as early as the second quarter of this year with a potential IND submission as early as the fourth quarter of 2025. Finally, I'll outline our lead neurology indication, NAV1.7, and how we're using this program as a way to balance the portfolio through a diversified delivery approach. Our NAV1.7 program does not leverage SacBBB, but instead uses a known AAV delivery capsid that is already in the clinic. Our aim here was to develop a medicine capable of reaching the dorsal root ganglia, as NAV1.7 is a voltage-gated sodium channel expressed there. And mutations in this channel play a critical role in pain perception. By potently reducing NAV1.7 in the DRG, we believe we can prevent the transmission of nociceptive pain signals in order to treat chronic neuropathic pain and a host of other indications. There is an urgent need for new therapies in this space and a potentially very large patient population to address, so we are very motivated to be moving forward with our NAV1.7 program and plan to initially focus on patients with small fiber neuropathy. As you see here, preclinical data from our clinical lead zinc finger repressor targeting SCN9A, the gene that encodes NAV1.7, demonstrated a meaningful repression in vitro with exquisite levels of specificity, as we only saw repression of NAV1.7 without impacting any other sodium channels. It's difficult to use small molecules to treat these channels because NAV channels share a lot of structural similarities at the protein level. However, at the DNA level, they are distinct. which makes them well-suited to the zinc finger technology. Taking this into animal models on the left, you see a study targeting neurons in the DRG, which are groups of cells outside the spinal column in the blood-brain barrier. Using intrathecal injection of the zinc finger repressor in mice, we observed significant expression, which you see in red. This then resulted in an almost complete elimination of the SCN9A expression, shown by the absence of white, which indicated a potent knockdown of the NAV1.7 gene at the mRNA level. If you look at the middle pain, you can understand what this looks like in a mouse model. We used the gold standard mouse model of neuropathic pain called the spared nerve injury model and performed a single injection of the zinc finger repressor intrathecally after the nerves were cut to induce pain. The single administration of our zinc finger repressor resulted in a full reversal of pain perception in these animals, as indicated by the orange and dark red bars in the bottom middle pain which are very similar to the results of those animals that had never received the surgery, as indicated in blue, which is very impressive. Finally, you see the non-human primate study on the far right, where we wanted to show that we can target the DRG and achieve potent repression of SCN9A. In this study, we administered three different doses of zinc fingers intrathecally, and we saw dose-dependent and potent repression of NAV1.7. Importantly, there's a lot of research emphasis on peer-reviewed publications about identifying any potential DRG toxicity, and we did not find anything in these studies that would be indicative of such toxicity, which is crucial as we seek to advance this program into the clinic. We are very encouraged by the NAV 1.7 program, and we look forward to completing these final toxicology studies. We expect to submit an IND for this program in the fourth quarter of this year. I will now hand back to Sandy to wrap this up before we open for Q&A.
spk02: Thank you, Amy. We really appreciate everyone joining us today as we look forward to answering your questions. And what we've outlined, we strongly believe in the power of our science to address devastating neurological conditions. We're advancing epigenetic regulation cargo and novel AAV capsid for a high value gateway neurological diseases like chronic neuropathic pain and prion disease. Today we have shown we have a capsid that demonstrated the ability to penetrate the blood-brain barrier and exhibited industry leading CNS tropism in non-human primates. The development of STAC BBB potentially unlocks multiple neurology programs that could be advanced ourselves or with partners as a potential source of non-dilutive funding. And we have the prion disease program, which we believe could quickly validate STAC BBB in proteins in humans. In addition, our Fabry disease program has continued to generate compelling Phase 1-2 data and is ready for a potential registration study with an abbreviated clinical pathway aligned with the FDA and multiple collaboration discussions in progress. We have transformed Sangamo into a focused neurology business with the potential to transform the lives of patients with debilitating neurological conditions. We have also made the necessary but very difficult decisions to focus our company and streamline our OPEX with the intention of reducing our burn, but without impairing potential value. We believe these changes enable us to set forth an attractive opportunity to raise additional funds via additional potential collaborations. Alongside this, we have the Pfizer collaboration in Hime that brings revenue bearing opportunity. with $220 million in potential milestones. As you can see, we believe our company is well positioned to change the lives of patients as a neurology genomic medicine company. Operator, please open the lines for questions.
spk13: And thank you. As a reminder to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again Please stand by while we compile the Q&A roster, and one moment for our first question. And our first question comes from Patrick Truccio from HC Wainwright. Your line is now open.
spk03: Hello, everyone. Hi, team. This is Luis Santos on for Patrick. Congratulations on this, as you said, beautiful and fantastic data. Interesting in knowing a little bit more what data do you still have left for completion of the package for the CTA on the prion disease. Also, on the tau program, did you release which epitope of tau you are targeting? Maybe I'll have a follow-up question. Thank you.
spk27: Thank you, Patrick. These are really good questions.
spk02: is beautiful data. And for the team that has been working on this for several years, it's a fulfillment of their scientific careers, truly. So I'm going to split into two. So the section on how do we get prion into the clinic will go to Natalie, the head of development.
spk22: Hi, everyone. So for the CTA of prion, Now that we have the STAC BBB, we are gearing to do a GLP tox study, which will be required for the IND. In order to do this, we have to manufacture the product to put in the tox study, and we're gearing to do this this year for filing an IND in the end of 2025. We also need to do a clinical manufacturing lot with the clinical candidates.
spk02: You've had great discussions already in the UK with people about the enthusiasm to take this forward.
spk22: Absolutely. There is a really good system here where the patients that have prion disease are going to a common center and we have linked to really the expert in prion disease in the UK And they have also direct communication with the regulatory authority in England. So we think that we're well positioned to really move quickly in the UK.
spk02: Thank you, Natalie. And then for types of tau, Amy, how do you think about that?
spk16: Sure, I'm happy to take that one. I think one of the advantages of the ZincFinger platform is that we're targeting tau at the DNA level. We know that there's so much complexity for tau with different splice variants at the RNA level. and then many, many different configurations of tau at the protein level. Because we're targeting upstream of all of that, we believe that we're able to address really all different tauopathies and all of these different possible forms of toxic tau.
spk02: Which would be a real competitive and patient advantage.
spk16: Absolutely.
spk03: Just a very quick follow-up. On the dose response, it What level of reduction of tau do you expect will be enough to be promising and translational into humans? So what levels of tau reduction will we need to see, not just from the beautiful RNA scope images, but at the pathological level, at the physiological level? in mice and HP so that we can be more confident in humans?
spk16: Yeah, that's a great question. It depends on the different brain regions, really the level of repression that we're targeting. But we believe, especially when you look at the outstanding efficacy in the prion studies, that we're in the range that we would be expecting to see some clinical results. What's really important is that at the single cell level, we see an almost complete repression of tau. And this is important because we know that the tauopathies are spreading throughout the brain. So not only is it important to have that widespread brain delivery like what we're seeing with STAC BBB, but also at a single cell level that we see this really complete repression of tau.
spk02: Amy, when you speak to potential partners, what's the level of repression that interests people?
spk16: That's a great question, and I think it depends on the indication. For some telepathies, we think something between 10% to 30%, depending on the brain region, would be important.
spk15: Thank you. And thank you. And one moment for our next question.
spk11: And our next question comes from Morrie Raycroft from Jefferies. Your line is now open.
spk00: Hi, thanks for taking my questions, and congrats on the update today with the new capsid. I'm wondering with the new capsid, have you looked at the relative immunogenicity of it and how that would compare to AAV9 or other published capsids? And based on this, do you see any potential to have a redosing option?
spk02: Amy, can you cover that for us, please? And Natalie, maybe you want to say something?
spk16: That's a great question. Thank you. These novel engineered capsids are being engineered in order to improve the crossing of the blood-brain barrier and brain penetrance. We believe that they have a similar profile compared to other natural capsids with a similar range of neutralizing antibody prevalence. Of course, another frontier of capsid engineering could be to evade that, but that was not what we set out to do in the study. And we were really excited with the penetrance that we saw in the brain of these animals.
spk22: Yeah, I think we don't expect to be very different from other AAVs. Of course, patients in the trial will be screened for pre-existing antibody to our novel AAV capsid.
spk00: Got it. Okay, makes sense. And for your figure where you compared your capsid to other published capsids, can you say which capsids these were or what the screening or inclusion criteria was? And were any excluded? For example, the Voyager capsid.
spk02: Thanks. Thanks, Maury. There are a lot of capsids that people are talking about, which I think reflects the interest in the field and trying to find that magic capsid. We know now from talking to many pharma companies that they have capsid search groups in place because it feels like a next generation neurological disease set of medicines. So we just looked across the literature and identified the mutations that had been made in those capsids and then recreated them in our laboratory, which is something that everyone can do. So we're pleased that ours turned out at the top of the pile. But what's more important is the characteristics of our capsid on its own, that it's widespread, that it's easily manufacturable, that it hits all the spots, that it transduces the zinc fingers, and it reduces both tau and prion.
spk00: Got it. That's helpful. And last question, and then I'll hop back in the queue. Just wondering if you can say anything additional on partnering conversations around these capsid data yet. and if you can provide any more perspective around the terms that you would aim to get for partnering any of your wholly owned CNS programs. Thanks, Mario.
spk02: So we've known the penultimate screening around results since the end of last year, and so we've been gradually talking and socializing this with our friends in pharma companies, when we showed the latest data and some of it, the single cell data is only out in the last week or so. The word awesome was used often in this. So we continue to talk to them because we feel that with both with the capsid itself and the capsid with our cargo, there is no way that Sangamal can advance all of the potential indications with this, and that we can only do it through partnership with that kind of pharma ecosystem. Of course, the money is valuable, but it would be wrong for me to start talking about numbers here, and we look forward to finding ways to move this into as many indications as possible. Got it. Makes sense. Thank you for taking my questions.
spk10: And thank you.
spk11: And one moment for our next question. And our next question comes from Nicole Germino from Truist. Your line is now open.
spk05: Hi, this is Alex on for Nicole. Congrats on the data and all the progress.
spk06: A couple from us. Can you remind us for your stack, BBB, how would this fit into Alzheimer's given the current focus on the amyloid plaque? And could STAC BBB have any impact on existing plaque? Or do you think that this could be potentially used after approved antibodies? And then I have a follow-up.
spk02: So I think we heard your questions. It wasn't quite clear. Amy, can you repeat the quote you think we're answering and then take it from there?
spk16: Sure. I think I may have only caught the first part of your question, which is understanding how targeting tau fits in with the amyloid hypothesis for Alzheimer's disease.
spk23: Yeah.
spk16: Okay. Great. Great. I think that there's been accumulating evidence over the past years, which again, the data that I showed today also from the Biogen trial with the ACEs targeting tau really have shown how important tau is in driving the pathology of the disease. There are patients or let's say people that have a lot of amyloid in their brains, but actually don't have Alzheimer's disease. And it's only when you have this development of tau, the tauopathies, that's correlated with the cognitive decline that's associated with the disease. So we believe, like others, actually, that tau is a critical step in that pathway and that its reduction will be really important for slowing or stopping the progression of the disease.
spk02: And particularly when compared to those ASOs, you can give it, hopefully, we expect you'll be able to give it once and it will have a long time effect.
spk16: That's right. Not only would it be a single administration, but also be able to target all of the different brain regions that we think are involved in the disease.
spk02: Which ASOs don't always do.
spk16: That's right. Can you repeat your second question, please?
spk06: Do you think that in the treatment landscape, where this would play out, given the improved antibodies, and you see this as sort of before antibodies afterwards, how do you think the community is doing it?
spk02: So perhaps I can take that. We're a preclinical stage and the data is very encouraging. We need to move it into humans and show its effect. While that's happening, I'm sure that we will, in this field, we'll collect a lot of data with other forms of tau antibodies or ASOs and understand the benefit. And gradually, the benefit that we show, I think, will be understood, particularly that it's a one one-time treatment which compare that to repeated intrathecal injections I think it's very appealing. It's very appealing for the patient, but it's also very appealing for dealing with a confused person. It's also very appealing for hopefully for society to be able to do this easily and in any hospital or clinic in the country. So this is why we're so excited about it. If TAO is as important as we're all believing, having a single injection intravenously that crosses the blood-brain barrier and completely reduces the production of tau in cells offers an enormous opportunity for what is a devastating disease. Natalie?
spk22: Yeah, in addition, if you compare this treatment to antibody, as Amy was saying, we're targeting the expression of tau. We're not targeting a specific epitope of a tau protein, which, you know, there is many forms of tau protein in isomer patients, and we don't know exactly which one is the most relevant for each patient. So, we're going at the root with the gene epigenetic regulation approach.
spk14: Makes sense. Thanks for all the color.
spk11: And thank you. And one moment for our next question. And our next question comes from Luca Easi from RBC.
spk13: Your line is now open.
spk07: Oh, great. Thanks for taking our questions. This is Lisa on for Luca. Well, congrats on all the progress. I have a few questions on the cyber program. Just wondering if you can add any color on how your conversations with potential partners has changed since you have reached alignment with the FDA on a registrational path forward. And on the Fabry pivotal study, can you share some more additional color on what the primary endpoint will be? Is it fair to assume the FDA will want to see reduction in GL3 inclusions by kidney biopsy similar to what we've seen with Fabrozyme? Any color here would be helpful. Thanks so much.
spk27: Natalie, you've been having a lot of these discussions recently.
spk22: Yes, so we're absolutely thrilled with our interaction with the FDA and to have aligned in a single well-controlled study with confirmatory evidence for the basis of a BLA submission and approval. At this point, we're not commenting on the endpoint for this trial. And of course, we've had, now let Sandy comment further, but we've This is very exciting for the potential partner we are in conversation with as it really accelerates the path to BLA approval and it's also reduced the cost. Sandy?
spk02: Yeah, I think an enormous credit is due to Peter Marks and his group at the agency. They have broken a logjam. They've made a public statement that they wanted more technology. gene therapies or genomic medicines for rare diseases to move forward. And that to do that, you have to look at studies that are manageable and at endpoints that are achievable. And that's why this study has then got the notice of lots of people who, frankly, were standing at the sidelines of Fabry disease, wondering how to get it to registration. This is a very manageable study. that not only we'll look at biopsy results, but we'll also look at the, and this is a direct quote from the agency, at the totality of the data and the benefit that it brings to patients. And I think that is such a healthy way to look at medicine approval. And we look for getting to this, into the hands of the partner and to patients and registration as quickly as possible.
spk15: Thanks so much. And thank you.
spk11: And one moment for our next question. And our next question comes from Yanen Zhu from Wells Fargo.
spk13: Your line is now open.
spk04: Hi, thanks for taking our question. This is Quan for Yanen. So just a follow-up on the prior fabric questions. Can you share what the potential partners might be looking for? And can we expect to see additional kidney biopsy data from the STAR study? And I have a follow-up.
spk02: So the partners are looking, we're very simply looking for compelling clinical data, real benefit that would make patients move from ERT. And we now have 13 patients that are off ERT. over a year in some cases, and no desire to go back on to ERT. I think that's really important. And some of them had been on ERT for a significant time. And in those patients, their SF36 is significant, and they are moving, changing category of FOSS MSSI, which is the investigator rating. So as they are now, even though they were treated with the ERT, they're now even better with the gene therapy. And finally, in seven of them that came in with antibodies, five of them, the antibodies have completely disappeared, completely disappeared, and in two of them, significantly reduced. And those are the kind of antibodies that eventually limit the effectiveness of the treatment. That's what the partners see and think, wow, this is the medicine that we will be able to take forward. But until we had the second part, which was the regulatory pathway that was manageable, they were cautious. And now that we're the only clinical stage asset for Fabry disease, where we have the best in class data and we have a way forward with the regulatory authorities, this is a natural place for any pharma company that's looking for a phase three asset to come.
spk04: Got it. Thank you so much. And my second question is on your capsid. So on the Stag BBB capsid, can you share how you achieved the 100-fold detargeting on the liver? Thank you.
spk02: Amy, Amy, can you explain that?
spk17: Yeah, I'm happy to take that.
spk16: As you saw from the slides that I just presented, we started with a library of 100 million different novel capsids. And we went through a whole screening process using non-human primates in order to select for capsids that were enriched in the brain. Although we didn't design specifically the capsids to be detargeted to the liver, we do believe that there's some relationship between that liver detargeting and the really improved targeting of the brain that we saw in those studies. And that's possibly what enabled us to find a capsid that was so well transducing the non-human primate brain.
spk26: And why is that important, Amy?
spk16: Well, it's important because the liver is such a sink for intravenously administered AAVs, actually by any route. We know that the AV can go to the liver and it can be potentially an issue for some patients. It's better if we can find a capsid that targets the tissue that we want to transduce to treat these diseases, which in this case is the central nervous system, and limits that exposure to the peripheral tissue for safety.
spk04: Got it.
spk14: Thank you so much for all the callers.
spk11: And thank you. And one moment for our next question. And our next question comes from Ambita Gupta from TD Cowan.
spk13: Your line is now open.
spk21: Hi, guys. This is Anvita Anwar with you today. Congrats on all the progress and the fantastic data presented today. What are your early thoughts on the potential clinical trial design for the first study with the NAV1.7 in chronic neuropathic pain? And then if you could also provide some color on maybe who would be the ideal patient for this program would be super helpful. Thank you.
spk27: Natalie, can you comment on the route to forward for NAV 1.7?
spk22: Yes, thank you. Yes, we are planning to file an IND for NAV 1.7 by the end of this year. And we are finishing our GLP-TUC study and our clinical manufacturing. So we will also finalize our clinical protocol. At this point, we are not commenting on the design of the trial or the endpoints, but we are well underway in planning those studies.
spk02: I agree, Natalie. I read the protocol last week or the version that's being circulated, and the bit that struck me is in one study, 17% of patients with intractable pain described their life as being worse than death. This is not toothache or a bunionectomy that has been described for NAV1.8. This is the kind of intractable pain that dominates your life and makes these patients consider suicide and that their life is just awful. We need to get this into patients as soon as possible. So we've got that protocol ready to go. We've had discussions with the agency about how to move forward. Once we get that IND done and we're heading to the clinic, we will share that with you because I think it's important that patients get to hear that there's this opportunity coming that will replace, hopefully, all of these antiepileptics and opiates that are used in this dreadful condition.
spk15: And thank you. And one moment for our next question. And our next question comes from Gina Wang from Barclays.
spk13: Your line is now open.
spk09: Hi, good afternoon. This is Hershita on for Gina.
spk08: Thank you so much for the detailed call this afternoon, and thank you for taking our questions. Most of them have been answered, but I just had a quick follow-up on Fabi. Given your recent update, I was curious, can you help categorize the importance of improvement in health scores, specifically for the SF36 survey? Could you provide color on how the general health and physical component scores are rated? Are they equally rated, or is there a higher rate to one of the components? Thank you so much.
spk25: Natalie, can you cover that?
spk22: Yes, so in our Phase I-II study, you know, it's primarily initially a safety study, but we're also collecting a lot of data in the patient. And really, we are looking, as you know, Fabry is a multifaceted disease, and we're looking at many different parameters, including kidney function, heart function, pain score, GI score, and general health. So at this point, we're collecting all those points, and what is remarkable is that the body of this data all point in the same direction of improvement in the patient. Of course, we're following those patients and the numbers of patients with more and more time since treatment is increasing every month, and we're collecting this data, but the data at World really show that we have maintenance of EGR for our slope. We have improvement in EGR score in FOSM SSI, in SF36, in pain. So everything is tracking in the right direction. So at this point, there is not one that is, you know, necessarily more important than the other in the Phase I-II trial.
spk15: And thank you.
spk11: And I am showing no further questions.
spk13: I would now like to turn the call back over to Louise Wilkie for closing remarks.
spk12: Thank you once again for joining us today, and thank you for all your questions. As a reminder, you'll be able to access the presentation that we gave today on the investor relations section of the Sangamo website after this call. We look forward to keeping you updated on our future developments. Thank you.
spk13: This concludes today's conference call. Thank you for participating. You may now disconnect.
Disclaimer