Q4 2023 Sangamo Therapeutics Inc Earnings Call

Participants

Louise Wilkie; Investor Relations; Sangamo Therapeutics Inc

Sandy Macrae; CEO; Sangamo Therapeutics Inc

Amy Pooler; Head of Research; Sangamo Therapeutics Inc

Nathalie Dubois- Stringfellow; Senior Vice President, Chief Development Officer; Sangamo Therapeutics Inc

Luis Santos; Analyst; H.C. Wainwritght & Co., LLC

Maury Raycroft; Analyst; Jefferies LLC

Anvita Gupta; Analyst; Cowen & Co., LLC

Presentation

Operator

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 speakers' presentation, there will be a question and answer session to ask a question. During the session, you'll need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one. Once again, please be advised that today's conference is being recorded. I'd now like to hand the conference over to your speaker today with Wilkie Vice President of Investor Relations, Corporate Communications. Please go ahead.

Louise Wilkie

Good afternoon and thank you for joining us. On the call today will 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 screened shared through the live webcast link can be found on our website, Angamos.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. Engineered capsids. We anticipated plans and time lines 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 our interactions with regulatory agencies about the preclinical programs to the clinic, our strategic reprioritization and reallocation of resources on 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 2020 for operating expenses, upcoming catalysts and milestones and other statements that are not historical facts. Actual results may differ materially from what we discuss today. These statements are subject to certain risks and uncertainties that are discussed in our filings with the SEC specifically and our annual form annual report on Form 10 K for the fiscal year ended December 31st, 2023 filed with the SEC forward looking statements dated 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 or adequate additional funding.
On today's call, I'm joined by Sandy Macrae Chief Executive Officer, Patricia Dewar, Barber, Chief Financial Officer, Amy Pooler, hell of repetitive research, Greg Davis, Head of Technology, and Natalie de Boer, Stringfellow Chief Development Officer.
Now I'll turn the call over to our CEO, Sandy Macrae.

Sandy Macrae

Thank you, Luis, 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 her 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 will prioritize our resources to focus on our neurology pipeline. We implement these changes because we believe that Sangamo 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 announced that we have engineered such capsid, which demonstrated industry leading blood-brain barrier penetration and bring construction in nonhuman primates. This validates our conviction in such an important area of potentially taking us one step closer to helping patients who are suffering from devastating conditions. Sangamo 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 industry partner determined to help patients in need as preclinical data from our new stack BBB. delivery Capsugel demonstrate in this presentation, our view epigenetic regulation capsid delivery capability showed the ability to cross the blood-brain barrier, which we believe is critically important, developing therapies to potentially treat prior disease, tauopathies and other neurological conditions. These data further support further advancement of our premium and tau programs, which are on track for directly submissions to enter the clinic by the end of 2025.
Meanwhile, we continue to advance our lead candidate in chronic neuropathic pain, Nav 1.7, which uses And interestingly, administered capsule towards an investigator to investigational new drug submission with the U.S. Food and Drug Administration expected in the future fourth quarter this year, it is also important to recognize the significance of our recent Fabry disease advancements. We recently presented compelling Phase one two data at the 20th Annual WORLDSymposium, 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 Israel.
Good, Jim Suva part of it. 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 than we ever had originally anticipated. In addition, the European Medicines Agency granted Priority medicine eligibility for the program, which could potentially further accelerate activities in Europe. We are thrilled with this progress and are in active discussions to partner this program, which, if successful, we anticipate could form of a 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 deals in both the innovative genome targeting cargo and the required delivery capsids. We believe Sangamo is well positioned positioned to potentially usher in the future of neurology genomic medicines.
Amy, we shared this in detail by first wanted to show you four quarters. So excited our single finger epigenetic Rig two liters have demonstrated potency and selectivity across a variety of different indications. This is clearly seen in the left panels showing heavy expression of the zinc finger refreshers 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 endpoint in this case tau panel to the right gives you a first glimpse of our new intravenously administered AAV capsid variant that we're calling ST BBB for stack, stands for Sangamo Therapeutics, AAV capsids pitcher can tell a thousand words, and we were excited to see the dark purple stream, the brain damage to them on the right of this slide, which shows that stack BVB. media to deficient blood-brain barrier Crossing and widespread cargo delivery through the brain of nonhuman primates in important new preclinical studies, we're extremely encouraged that stat BBB, which we engineered through our sister capsid engineering platform significantly outperformed other known published capsids evaluated in our study. It achieved widespread brain delivery and transgene expression as well as the targeting 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, I want to spend a moment highlighting our choice for newness in our lead neurology programs for Nav 1.7 and prion disease. We are particularly pursuing these targets because one, they're validated by human genetics to have a well defined patient population three at the 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 is imaginable unimaginable to the most diverse impact. 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 are well known. Interestingly, administered capsid for delivery. Brian disease is a truly devastating condition with more than 1,500 patients diagnosed per year across use. Us and Europe 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 a repression of prior and in our preclinical models significantly extended survival in mice. They lived a normal most lifetime. We anticipate filing a clinical trial authorization submission, the UUK. because thanks to mad cow disease. They have an excellent infrastructure for identifying and caring for prime 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 regulatory submissions, we believe that the exciting stacked 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 state BPB. first, the thesis, the repression of the gene that produces TOMAPT. to address tail off these such as Alzheimer's disease. With the identification of state BBB., we intend to resume the development of our tau program with an IND submission expected as early as the fourth quarter of 2025. In addition, stack BVB. 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, myotonic dystrophy type one. Sangamo is exploring avenues to resume development of these programs with new potential collaborators with a reinvigorated neurology focus and our momentum already underway in 2024, we anticipate multiple potential near term milestones between now and the end of 2025 we also anticipate milestones for later-stage non-Euro due programs that could provide additional important non-dilutive funding as we plan to partner Fabry disease program. We expect to complete dosing in the Phase one twos STAR study in the first half of this year for our partner TMA program, Pfizer expects to present Phase three 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, investments to that vision and advance multiple reductions in force to significantly limit our spend. As a result, we have reduced our operating expenses by approximately 50% year over year. Whilst difficult these were the right decisions to make, as I am 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 million to $145 million as we complete our strategic transformation, fulfill our responsibilities and we anticipate our operating expenses to further decrease to under $105 million in 2025 as we transition our legacy clinical program. 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 capsule data, along with other updates from our pipeline Amy?

Amy Pooler

Thank you, Sandy, and hello to everyone joining today's call. We know that widespread CNS delivery is challenging with conventional AV.s, which is why we have developed our sister platform which is designed to enable the selection of neurotrophic AAV capsid variance. 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 capsids as well as robust neuronal transduction. We also needed 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 nonhuman primate studies that demonstrate how well-placed that PBB is to potentially address these criteria in these preclinical studies we are encouraged to see that stack 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 are enriched in the central nervous system will be targeted from the dorsal root ganglia and liver. And as Sandy mentioned, crucially, we believe the stack, the BBS. auto manufacturable at scale. So how did we assess this performance? And 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 this capsid variance through progressive rounds of screening enriching for the best performers through three rounds of selection until we identified stack BBB. as the standout high performer. The visualization shown here is the final round of the sister screening process where 1,260 novel capsids are all evaluated simultaneously and cynomolgus monkeys on this graph, the y-axis shows the relative level of enrichment of the capsid throughout the brain with 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, another one-off chance outcome. The highest-performing capsules will be found in the top left corner. So we were very encouraged to see the stack BBB capsid coming out on top of performing of others in the library on this assessment. The library assessment also included known published nature of the capsid variants that were evaluated head to head. In addition to our own, we are very pleased that stack 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 stack 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 stack BBB. compared to the benchmark capsid AAV nine shown in blue on this graph, highlighting the superior neuronal expression mediated by stack B BBP. 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 interest. The co-administration of antisense oligonucleotides also called ASOs or more traditional capsid, the liver can act as a primary sink for intravenously administered capsids. However, however, we saw there was significant the targeting and stacked BBB in the liver with a 100 fold lower expression compared to the benchmark AAV capsid when compared against historical Sangamo called studies at the same dose, no peripheral exposure in the liver is desired. We then conducted follow-on studies taking our lead capsids stack, BBB and testing its individual performance. On the left of the slide, we see an image of a nonhuman primate brain. It is from an animal that was treated with a stacked BBB capsid administered intravenously at a dose of two e. 13 vector genomes per kilogram and packets with both the nuclear localized green fluorescent protein or GFP, as well as the zinc finger presser targeting the prion gene with unused antibody labeling to stand for the GFP cargo is illustrated with the Deep Purple or almost black color. And 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 myelination and Exxon on the right is a control animal that wasn't treated with AAV, but the tissue is 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 stack PPP. And then the lighter blue is a Nestle stand 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 stack BBB. is neuro. Tropic was 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 transaction was consistent across the cortical regions shown, which are important to many different disease pathologies and appears largely localized turnaround. This transaction was consistent across 12 other brain regions. We analyze with clear enrichment of BBP observed in the neurons in each of these areas because of the observed neurotrophic, Nick narrow topic nature of stack PPP, the level of enrichment seems to align with and the number of corresponding around found in each brain region. The lateral genetic nucleus, for example, is tightly packed with neurons, and we saw striking fact, BBB enrichment here, extensive transaction is crucial because each area is linked to a whole range of diseases for which treatments are desperately needed. Based on these compelling data, we believe the diseases such as Huntington's disease, Parkinson's disease, ALS or Friedreich's ataxia, could all be potentially unlocked by stack BBB. And I think finger cargo, if we dive a little deeper into some of these brain regions. For example, the dental nucleus, the steep cerebellum region has 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 them of all the neurons in this region. As you see here, 30 out of 31 neurons visible in the 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 Dentale nucleus of three separate animals treated with stack BPB., all of which exhibited similar levels of GFP expression. Finally, we believe that 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 SEC BBB at scale. Our TechOps 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 ACT two nine three, and that's up nine platforms. We believe that PBBS. manufacturable commercial scale using standard cell culture and purification processes, 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 zinc-finger platform. Sandy? 2m

Sandy Macrae

Thanks, Romy. As Jimmy emphasized, early to state BVB. data demonstrate that we've engineered capsid, the Exubera to bring white delivery in nonhuman primates. However, this is only one half of the effect of neurology genomic medicine. I will now tell you that the other half are potent 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 zinc finger gene targeting technology, a high precision genomic engineering platform think of zinc fingers as a lending 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. Zinc fingers 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 reprocessors if necessary, into one AAV capsid and repress several genes at any one time if we wanted to there 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 recognized 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. Citing deaminase is for highly efficient base editing in human cells. We were pleased to read nature, communications and other groups believe zinc fingers are the most capable epigenetic regulation to 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, neurology and the data that follows on prior tower Nav 1.7 or focus on that technology specifically. So you may, can you notice a little more about how the zinc fingers are leveraged in our prior internal programs?

Amy Pooler

Thanks, Sandy.
Turning now to prevent disease, which affects approximately 600 patients a year in the US and Canada and around 900 in Europe. Prion disease is an awful disease typically fatal and 12 to 15 months. There are no approved disease-modifying therapies that currently exist. Pre-and has an excellent fit for zinc finger repression. We know that pre-and knockout animals do not get the diseased prion reduction can delay or prevent disease and neuronal pre on production of protein reduction also prevents disease. We therefore believe that the repression of pre-owned expression may slow or halt disease progression and nerve degeneration. We knew that we wanted to achieve widespread delivery for the brain for prion disease. Given that misfolded prion protein spreads throughout the brain as the disease progresses. As mentioned earlier, we therefore packaged or pre untargeted zinc-finger repress or into the newly identified stacked PVP capsid and administered intravenously to three separate nonhuman primates in order to assess what regions of the brain to be delivered to. We collected 220 punches from each animal and conducted our T. qPCR analysis to measure how much free untargeted zinc-finger was expressed each.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 color represents a level of that pre untargeted zinc-finger expression that was measured as you can see from the key in the top right, the FR 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 stack BBB Myriad mediated consistent brain white expression of pre untargeted zinc finger repress or in all three animals. We next wanted to quantify if expression correlated with an associated reduction in pre-owned mRNA and these brain punches, we were happy to see a reduction of prion expression and 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 pre-owned is Express multiple brain cell types, what we are seeing total premium 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 analysis and similar studies in the past, including the tower 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 the mouse model of aggressive prion disease, we concluded that zinc-finger suppressors can significantly extend survival and pre uninfected animals. In collaboration with the Broad Institute, we engineered zinc finger compressors to target the mouse, Tianjin and administered these as a single dose in mice, either 60 or 122 days following pre on 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 pre-and zinc finger presser 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 the 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 are required starting from approximately 70 days post infection, as shown in graph two to be able to induce an extension of lifespan and when assets are administered at a later time point post infection, as shown in graph four, when the disease has further progressed, there was only minimal extension of lifespan conversely, even when administered 122 days post infection shown on graph three, which has a timeline more aligned to what we believe we will see in the clinic a single dose of the zinc finger presser was still able to profoundly delay disease progression and extend survival in mice. These data reflect the two e. 13 VG. 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. Prion program is progressing with our clinical lead zinc finger presser that showed greater than 95% premium 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 application in the UK for prion in the fourth quarter of 2025 Moving now to tout a well-known target for the treatment of neurodegenerative diseases called tell up at these recent data from Biogen's. A So study shows stabilization of cognitive function with regular injections of ASOs addressing tau, which seems to cement thousand application and Alzheimer's disease. In addition, there are also a host of tauopathy disorders that span more than 12 distinct indications, including progressive super nuclear 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 stack BBB delivery capabilities and a tower zinc finger repress, or we see a potential ability to halt disease progression with a onetime IV administration for various tauopathy indications given the capsids ability demonstrated ability to reach all the brain regions at a high specificity in non-human primates.
Here, we packaged our Clinical Lead Talos zinc-finger presser, which shows fantastic repression of tau exceptionally specific expression and no detectable off targets in vitro into our stack BBB capsid and tested at three different intravenously administered doses, [5, 12 to 13 one and one E. 14] vector genomes per kilo.
Similar to the slide we saw before on prion here, we were looking for widespread expression of the zinc finger repress or throughout the brain here we are 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 pre-owned 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 Telemark region, including the lateral genetic nucleus like Freon 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 pressing it in these cells. In this case, the clinical lead construct uses a Synapse and promoter. So we know that we are only targeting zinc-finger expression to neurons. We were pleased to see a dose-dependent increase in zinc finger expression correlated with a dose dependent decrease of tau expression like in the pre on experiments. This is a bulk analysis of whole brain punches with consistent many cell types, not just neurons. So to be able to achieve this level of power pressure at the bulk level, we must be achieving significantly higher repression of the single cell level and neuron here, you'll see that we achieved an almost 50% reduction in power at the bulk level and at the top top dose in the lateral to Nicola nucleus, which is likely correlated to the higher proportion of neurons we see in this region as illustrated by the dark staining and the image above from the same brain region and the GFP arms of the study.
Let's take a moment to look more closely at the ponds part of the brain stem and a key brain region. And the top is the called progressive super nuclear policy 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 increasing 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 analysis, we also utilized our multiplex RNA scope and immunohistochemistry approach to visualize ZFR. expression and tower expression in neurons. This data is beautiful and shows a high level of detail that has only recently possible, allowing us to understand what's going on at the single-cell level on the top of the ponds, I meant from a control animal and the bottom is from an animal treated with the top dose stacked BBB encoding. The tau clinical-based zinc-finger presser and purple are the neurons, which in the control animals robustly expressed 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 expressing fingers in this region, which resulted in almost complete repression of tau and ourselves. Here, we show more of this beautiful single cell data, demonstrating the power of both stack BBB and our tau zinc-finger repress or 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 and purple and clear and orange here, no zinc or was detected. And the tau mRNA levels remained 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, preferably repress or particularly of neurons and importantly, where result zinc finger presser 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 stack PBB. and RTR. tower zinc-finger Rhopressa for our tau 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, Nav 1.7 and how we're using this program as a way to balance the portfolio through a diversified delivery approach.
Our Nav 1.7 program does not leverage that PBB., but instead uses a known AAV delivery capsule that is already in the clinic. Our aim here was to develop a medicine capable of reaching the dorsal root ganglia as Nav 1.7 as a voltage gated sodium channel expressed there and mutations in this channel play a critical role in pain perception by potently reducing Nav 1.7 and IDRG. We believe we can prevent the transmission of nociceptive pain signals in order to treat chronic neuropathic pain and host of other indications. There is an urgent need for new therapies in the space and a potentially very large patent population to address. So we are very motivated to be moving forward with our Nav 1.7 program and plan to initially focus on patients with small fiber neuropathy. As you see here, preclinical data from our clinical lead zinc finger repress or targeting SCN. nine A., the gene that encodes Nav 1.7 demonstrated a meaningful repression in vitro with exquisite levels of specificity as we only saw repression of Nav 1.7 without impacting any other sodium channel. It's difficult to use small molecules to treat these channels because now the channel share a lot of structural similarities at the protein level. However, at the at the DNA level, they're 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 for groups of cells outside the spinal column and the blood-brain barrier using intrathecal injection of the zinc finger repress or in mice, we observed significant expression, which you see in red. This then resulted in an almost complete elimination of the SCN. nine A. expression, shown by the absence of light, which indicated a potent knockdown of the Nav 1.7 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 Spirit nerve injury model and performed a single injection of the zinc finger presser. Interestingly, after the nerves are cut to induce pain, single administration of our zinc finger Rhopressa 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 the those animals that have never received. Surgery is indicated in blue, which is very impressive.
Finally, you see the nonhuman primate study on the far right where we wanted to show that we can target the DRG. and achieve potent repression of SCN. nine A. In this study, we administered three different doses of zinc fingers interest equally, and we saw dose-dependent and potent repression of Nav 1.7. Importantly, there's a lot of research emphasis in 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.

Sandy Macrae

Thank you, and 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, the demonstrated ability to penetrate the blood-brain barrier and exhibited industry-leading CNS tropism and non-human primates. The development of PBB. 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 prior disease program, which we believe could quickly validate stock BBB. and proteins in humans inherited. In addition, our Fabry disease program has continued to generate compelling Phase one two 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 and he may 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 and thank you.

Question and Answer Session

Operator

As a reminder to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one. Again, please stand by while we compile the Q&A roster. And one moment, our first question and our first question comes from Patrick Toshiya from H.C. Wainwright. Your line is now open.

Luis Santos

Hello, everyone. Hi, Team. This is Louis centres 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 and the prion disease.
Also on the tau program, did you release which at the top of how you are targeting, maybe I'll have a follow-up question. Thank you.

Sandy Macrae

Thank you, Patrick. These are really good questions. It is beautiful Dayton and for the team has been working on this for several years as a fulfillment of their scientific careers truly. So I'm going to split into two. So the section on how do we get prior into the clinic, we'll go to Natalie Head of Development/

Nathalie Dubois- Stringfellow

Hi, everyone. So for the CTA were pre on now that we have the stack BBB, 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 put in the talk study, and we're going to do this this year for filing an IND in the end of 2025. We'll also need to do a clinical manufacturing with the clinical candidates.

Amy Pooler

You've had great discussions already in the UK with the with people, but about the enthusiasm to take this forward?

Nathalie Dubois- Stringfellow

Absolutely. And there's a really good system here where on the patient that have prion disease are going to a common center and have we have linked to really the expert in prion disease in the UK, and they have also direct communication with and the regulatory authority in England. So we think that we're well positioned to really move quickly in the UK.

Luis Santos

Thanks that way. And then for for types of tone, Amy, how do you think about that?

Amy Pooler

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 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.

Luis Santos

Which would be a real competitive and patient advantage.

Amy Pooler

Absolutely.

Luis Santos

Just a very quick follow up on the dose response and what level of reduction of tau do you expect will be enough to be promising and translational into into humans? So what levels of tau reduction will we see will we need to see not just from the beautiful line scope images, but adds at the pathological level at the physiological level in mice, NHP's so that we can be more confident in humans.

Amy Pooler

Yes, 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 pre-and studies that we are 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 tower, but these are spreading throughout the brain.
So not only is it important to have that widespread brain delivery like what we're seeing with stacked BPB, but also at a single cell level that we see this really complete repression of tau.

Luis Santos

Amy, can you make when you speak to potential partners, what's the level of repression, the interest people?

Amy Pooler

It's a great question, and I think it depends on the indication for some top of these, we think something between 10%, so 30% depending on the brain region would be important.

Luis Santos

Thank you.

Operator

Maury Raycroft from Jefferies. Your line is now open.

Sandy Macrae

Hi. Thanks for taking my questions and congrats on the update today with the new capsid, I'm wondering with the new capsid, if 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?
Yes, Amy, can you cover that for us, please. And Natalie, maybe you want to system?

Amy Pooler

That's a great question. Thank you. These novel engineered capsids are being engineered in order to improve the crossing of the blood brain blood-brain barrier and brain penetrants. 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 are really excited with the penetrants that we saw in the brain of these animals?

Nathalie Dubois- Stringfellow

Yes, Jack, we don't expect to to be very different from other AAVs. Of course, patient in the trial will be screened for pre-existing antibodies to our novel AAV capsids.

Maury Raycroft

Got it. Okay. Makes sense. And then you for your figure where you compared your capsid to other published capsids, can you say which capsid These were what the screening or inclusion criteria was on were any excluded, for example, the Voyager capsule? Thanks.

Sandy Macrae

hanks, 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 I know 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 them the mutations that we made in those capsids. And then we created them in our laboratory, which is something that everyone can do. So we're pleased that Irish turned out to the top of the pile. But what's more important is the characteristics of our capsid on it so that it's widespread that it's easily manufacturable that hits all the sports search and zinc fingers, and it really reduces both tau and prior.

Maury Raycroft

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 types of data yet and on if you can provide any more perspective around the terms that you would aim to get for partnering on any of your wholly owned CNS programs?

Sandy Macrae

Thanks, Roy. So we've known the and ultimate screening round results since the end of last year. And so we've been we've been gradually talking 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. That is the word awesome. We've 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 Sangamo Qinnan funds, 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.

Maury Raycroft

Got it makes sense. Thank you for taking my quarter.

Operator

Nicole Germano from Truist. Your line is now open.

And this is Alex on for the call, and congrats on the data and all the progress. And a couple from from us. Can you remind us for your stack EBB., how does fit into Alzheimer's given the current focus on the amyloid plaque and that could stack PBD have any impact on existing plaque? Or do you think that this could be potentially used after prove antibodies? And then I have a follow-up.

Sandy Macrae

So I think we and we heard your questions, it wasn't quite clear. Amy, can you repeat what you think we're answering and then take it from there.

Amy Pooler

So I think I may have only got the first part of your question, which is understanding how targeting tau fits in with the amyloid hypothesis for Alzheimer's disease?

Sandy Macrae

Yes, answer them.

Amy Pooler

Okay. Great, great. I think that there's been accumulating evidence over the past years, which at which again the data that I showed the data from the Biogen trial that is targeting tau really have shown how important tau is and driving the pathology of the disease. There are patients or let's say, people who admit that have a lot of amyloid in their brands but actually don't have Alzheimer's disease. It's only when you have this development of tau at the top of these that's correlated with the cognitive decline that's associated with the disease. So we believe and like others, actually that tau is a critical step in that pathway and its reduction will be really important for for slowing or stopping the progression of the disease.

Sandy Macrae

And particularly when compared to Lucy. So she can give you hopefully, we expect to be able to give it once and it will have a long time effect.

Amy Pooler

That's right. Not only would it be single administration, but also be able to target all of the different rate brain regions that we think are involved in the disease.

Sandy Macrae

Which you're supposed to know if that's right. Can you repeat your second question, please?

On where do you think the unit treatment landscape where this will play out, given the improved antibodies and you see this and sort of before antibodies afterwards, how it how do you think the community is doing it.

Sandy Macrae

Perhaps I can take that on and we are 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 who collect a lot of data with other forms of tau antibodies or air source and understand the benefit and gradually the benefit that we show, I think will be understood, particularly that it's on one onetime treatment, which compare that to repeated interest equal 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 we have towers is important as we're all believing having a single injection intravenously, the crosses the blood-brain barrier and completely reduces the production of Tobin cells offers an enormous opportunity for four is a devastating disease, Natalie?

Nathalie Dubois- Stringfellow

Yes. In addition, if you compare this treatment 20 body, as Amy was saying, we're targeting the expression of tau. We're not targeting a specific app top of the tau protein, which you know, there is many forms of tau protein in a zone or patient. And we don't know exactly which one is the most relevant for each patient. So we're going at the route with the gene gene epigenetic regulation approach.

Thanks, and thanks for all the color, and thank you.

Operator

And one moment by next question and our next question comes from Luca Issi from RBC. Your line is now open.

Great. Thanks for taking our questions. This is Lisa on for Luca. Congrats on all the progress I have a few questions on the Fed's cyber program, and 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 the registrational path forward.
And on the Favory 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 GL-3 inclusions by kidney biopsy, similar at what we've seen with Fabrazyme. Any color here would be helpful. Thanks so much.

Sandy Macrae

Natalie you've had been having a lot of these discussions recently?

Nathalie Dubois- Stringfellow

Yes. So we are absolutely thrilled with our interaction with the FDA and to have a line 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 have 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 accelerate the path to BLA approval, and it's also reduced the cost, Sandy?

Sandy Macrae

Yes, 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 gene therapies for our genomic medicines for rare diseases to move forward. And to do that, you have to look at studies that are manageable and endpoints 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 will look at biopsy results, but we'll also look at that. 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 it medicine approval, and we look for getting to this to fit into the hands of the partner and two patients in registration as quickly as possible.

Got it .Thanks, much.

Operator

and thank you and one moment by Next question. And our next question comes from Ian Xu from Wells Fargo. Your line is now open.

Hi. Thanks for taking our question. This is Kwan Kim on for Yaron. So just a follow up on the prior year on 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.

Sandy Macrae

So the partners are looking. We're very simply looking for compelling clinical data, real benefit that would make as patients move from ERT. and we now have 13 patients are off ERT or over a year in some cases and no desire to go back onto our team. That's really important. And some of them had been on a year to for a significant time and some and in those patients, their SF-36 is significant and they are moving changing catagory of force MSSIF., which is the investigator routing. So as there are no, even though the what they were and treated with the ERT. there know, even better with the gene therapy. And finally, certain of them buy in certain that came in with antibodies, mindful of them. The antibodies have completely disappeared, completely disappeared and in two of them significantly reduced. And those are the kind of antibodies that limit the effect eventually limit the effectiveness of the treatment path for 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. And they were cautious and know that we are 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.

Got it. Thank you so much. And my second question is on the KFC. So on the stack PBB, Pepsi, can you share how you achieved the 100 fold? Are you targeting that bigger? Thank you.

Sandy Macrae

Amy, can you explain that?

Amy Pooler

Yes. I'm happy to take that. Let's say 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 nonhuman primates order to select for capsids that were enriched in the brain, although we didn't design specifically the capsids to be targeted to the liver. We do believe that there is some relationship between that Liberty targeting and they 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 nonhuman primate brain endpoints are important to me what's important because delivery such as zinc for intravenously administered AAV is actually by any route. We know that the AAV can go to the liver and it can be potentially an issue for some patients. It's better if we can find the capsid that targets the tissue that we want to transduce to treat these diseases, which in this case as a central nervous system and limit that exposure to the peripheral tissue for safety.

Got it. Thank you so much for all comments.

Operator

And thank you and one moment by next question.
And our next question comes from Anvita Gupta, TD. Cowan. Your line is now open.

Anvita Gupta

Hi, guys are done with our on-site ready 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 Nav 1.7 in chronic neuropathic pain? And then if you could also provide some color on maybe who would be who would be the ideal patient for this program would be super helpful. Thank you.

Sandy Macrae

Natalie, can you comment on the route to forward for Nav 1.7 yes, yes, thank you.

Nathalie Dubois- Stringfellow

And yes, we are planning to file an IND for Nav 1.7 by the end of this year. And we are we are finishing our GLP tox study and our clinical manufacturing. So we will well, we'll 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.

Sandy Macrae

Agree, Natalie, I read the protocol last week or the version that is being circulated and it struck me is seventh in one study, 17% of patients with intractable pain described their life as being worse than death. This is not a tweak or a bunionectomy that has been described for NaV 1.8. This is the kind of intractable pain that dominates your life and makes these patients consider suicide and that their life is just awful on. We need to get this into patients as soon as possible. So we've got the protocol ready to go. We've had discussions with the agency about how to move forward. And once we get that IND. done and where 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 term antiepileptics and opiates are used in this dreadful condition.

Operator

And thank you, and one moment for our next question.
And our next question comes from Gena Wang from Barclays. Your line is now open.

Hi, good afternoon. This is Christina on for Gena. Thank you so much for the detailed color this afternoon, and thank you for taking our questions. Most of them have been answered, but I just had a quick follow up on Saturday. Given your recent update, I was curious, can you help categorize the importance of improvement in health scores? And specifically for the SF-36 survey on, could you provide color on how the general health and physical components caused by weighted? Are they equally weighted or is there highly to one of the components. Thank you so much.

Sandy Macrae

Natalie, can you cover that?

Nathalie Dubois- Stringfellow

Yes. So in our Phase one two study, 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 every what is remarkable is that the and 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 EGF far slope. We have improvement in I. score in first semester site in SF-36 in pain. So everything is tracking in the right direction. So at this point, there's not one that is it's more, let's say, more important than the other in the Phase one two trial.

Operator

And Thank you. And I'm showing no further questions. I would now like to turn the call back over to Luis Wilkie for closing remarks.

Louise Wilkie

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 presentations that we 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.

Operator

This concludes today's conference call. Thank you for participating. You may now disconnect.