Q4 2023 Sangamo Therapeutics Inc Earnings Call
Operator: Good day, and thank you for standing by, and welcome to Sangamo fourth quarter 2023 telecom telecom telecom telecom telecom telecom telecom. 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 star 11 on your telephone. You will then hear an automated message advising that your hand is raised.
Good day, and thank you for standing by and welcome to the Sangamo fourth quarter 2023 teleconference. At this time all participants are in a listen only mode. After the speaker's presentation there'll be a question and answer session to ask a question. During the session you will need to press star one on your <unk>.
Allophone, you will then hear an automated message a box in your hand is raised.
Operator: 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. Good afternoon.
Draw your question please.
Speaker Change: Star won't want again, please be advised that today's conference is being recorded I would now like to hand, the conference over to your speaker today.
Speaker Change: Louise Wilkie, Vice President of Investor Relations Corporate Communications. Please go ahead.
Louise Wilkie: 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 reinforces our decision to become a neurology-focused genomic medicine company. Slides from today's presentation, which can be 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.
Louise Wilkie: Good afternoon. Thank you for joining us on the call today, but it will be not any sharing our progress across the business, but also sharing exciting new data that we believe reinforced our decision to become a neurology focused medicines company.
Speaker Change: Slides from today's presentation, which are being screenshot. It through the live webcast link can be found on our website <unk> com under the investors and media sections at the events and presentations page.
Speaker Change: This call includes forward looking statements regarding <unk> current expectations.
Louise Wilkie: 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 the 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.
Speaker Change: Statements include but are not limited to statements relating to the therapeutics and commercial potential of our product candidates engineered capsid.
Speaker Change: Just to put the plans and time lines of Sangamo, and our collaborators for regulatory submissions and initiating and conducting clinical trials screening and dosing patients.
Speaker Change: <unk> clinical data advancement of our product candidates.
Speaker Change: Anticipated submission feedback from our interactions with regulatory agencies advancement of preclinical programs through the clinic, a strategic re prioritization 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.
Speaker Change: Our initial financial guidance for 2020 for an estimate for 2020 full operating expenses upcoming catalysts and milestones and other statements that are not historical facts actual results may differ materially from what we discuss today.
Louise Wilkie: 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 with 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 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.
Speaker Change: These statements are subject to certain risks and uncertainties that are discussed in our filings with the SEC specifically in our annual form annual report on Form 10-K for the fiscal year ended December 31, 2023 filed with the SEC.
Speaker Change: Forward looking statements stated today are made as of the states. We undertake no duty to update such information, except as required by law.
Speaker Change: On this call we discuss a 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.
Alexander D. Macrae: 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 Macrae, Chief Executive Officer, Prathyusha Duraibabu, Chief Financial Officer, Amy Pooler, Head of Research, Greg Davis, Head of Technology, and Nathalie Dubois, String Fellow, Chief Development Officer. Now, I'll turn the call over to our CEO, Sandy Macrae.
Speaker Change: 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.
Speaker Change: On today's call I'm joined by Sandy Macrae, Chief Executive Officer, Patricia do or Bobby Chief Financial Officer, Amy Poehler head of research Great data set of technology, and Luckily bar Stringfellow Chief Development Officer.
Speaker Change: Now I'll turn the call over twice a year Sandy Macrae.
Alexander D. Macrae: Thank you, Louise, and good afternoon to everyone joining the call. Today we are 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 discuss 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 program. 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.
Alexander D. Macrae: Thank you Luis and good afternoon to everyone joining the call.
Alexander D. Macrae: Today, we're pleased to discuss <unk> recent pipeline advancements that solidify our sharpen 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 her 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.
Alexander D. Macrae: We will then outline how we plan to progress our neurology assets into the clinic.
Alexander D. Macrae: 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.
Alexander D. Macrae: Due to this obstacle many devastating conditions affecting millions of patients go untreated.
Alexander D. Macrae: 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 CATFID, that we would prioritise our resources to focus on our neurology pipeline. We implemented 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 engineered such a 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.
Alexander D. Macrae: With conviction and our science and the promise that it holds we noticed in the third quarter of 2023, having seen initial results from the capsid.
Alexander D. Macrae: We prioritize our resources to focus on our neurology pipeline.
Alexander D. Macrae: We implement these changes because we believe that single holds great potential to unlock new treatments for patients with neurological diseases by pairing our highly potent epigenetic regularly search with an additional key requisite for success and then your logical space a capsid capable of crossing the blood brain barrier to <unk>.
Alexander D. Macrae: Access to live for the drug quicker it needs to go.
Alexander D. Macrae: Today's announcement that we've been known that we have engineered such capsid, which demonstrated industry, leading blood brain barrier penetration and brings turns junction in nonhuman primates. This validates our conviction in such an important area of potentially taking us one step closer to helping patients who suffer.
Alexander D. Macrae: From devastating conditions.
Alexander D. Macrae: 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 an industry partner determined to help patients in need.
Alexander D. Macrae: Sangamo is proud to be developing booth that put your network regulation cargo and advance capsid delivery capabilities that could finally lead to new treatments for many neurological conditions.
Alexander D. Macrae: This differentiated approach underpins our wholly owned neurology pipeline.
Alexander D. Macrae: Our purpose is clear as we strive to unlock value strategic highly focused company and industry partner determined to help patients in need.
Alexander D. Macrae: As preclinical data from our new STAC BBB delivery capsid will demonstrate in this presentation, our dual epigenetic regulation and capsid delivery capabilities showed the ability to cross the blood-brain barrier, which we believe is critically important in developing therapies to potentially treat prion disease, tyopathies, and other neurological conditions. These data further 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 US 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 advancement.
Alexander D. Macrae: There's preclinical data from our new stack PPP delivery captured will demonstrate in this presentation are jus epigenetic regulation 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 type work that these and other neurological.
Alexander D. Macrae: These data further.
Alexander D. Macrae: Support further advancement of our prior anti programs, which are on track for breakthrough submissions to enter the clinic by the end of 2020 fives. Meanwhile, we continue to advance our lead candidate in chronic neuropathic pain NAV, one seven which uses an interest equally administered capsid towards and investigate two investigational new.
Alexander D. Macrae: Drug submission with the U S food and drug administration expected in the fourth quarter of this year.
Alexander D. Macrae: It is also important to recognize the significance of our recent fabry disease advancements. We recently presented compelling phase one two data the 20th annual World Symposium, showing enormous promise across many important biomarkers and measures of efficacy.
Alexander D. Macrae: We recently presented compelling Phase I-II 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 Isorogagene-Civaparvovec. This is a significant development as conducting a single study of this nature would enable a potentially abbreviated and cost-effective pathway to potential approval than was ever originally anticipated. In addition, the European Medicines Agency granted priority medicine eligibility for the program, which could potentially further accelerate activities in Europe.
Alexander D. Macrae: Unfortunately, we also recently announced alignment with the agency on a remarkable abbreviated clinical pathway to potential approval.
Alexander D. Macrae: The FDA advised a single study with up to 25 patients in combination with confirmatory evidence is an acceptable pathway to BLA submission for.
Alexander D. Macrae: Gauging Super powerful effect.
Alexander D. Macrae: This is a significant development is conducting a single study of this nature would enable a potentially appreciated and most cost effective pathway to potential approval than was ever hot originally anticipated.
In addition, the European Medicines agency granted priority medicine eligibility for the program, which could potentially further accelerate activities in Europe.
Alexander D. Macrae: We are thrilled with this progress and are in active discussions to partner this program, 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 dealing in 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 medicine. Amy will share this in detail, but I first wanted to show you what got us so excited.
Alexander D. Macrae: We are thrilled with this progress and are in active discussions to partner this program, which if successful we anticipate could form another key source of non dilutive funding.
Alexander D. Macrae: I continue to strongly believe the turf 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.
Alexander D. Macrae: Yeah.
Alexander D. Macrae: I see only biopharmaceutical company known to be internally telephone booth, the innovative genome targeting cargo and the required delivery cap suits. We believe that sangamo is well positioned to potentially usher in the future of neurology genomic medicines.
Alexander D. Macrae: Amy we shared the.
Alexander D. Macrae: Some detail, but I first wanted to show you forgot to soy excited.
Alexander D. Macrae: 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 the 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.
Alexander D. Macrae: I always think finger epigenetic regulators have demonstrated potency and selectivity across a variety of different indications. This is clearly seen in the left panels showing have expression of the zinc finger repressor just in people in nonhuman primates, which are shown in green on the left demonstrates it.
Alexander D. Macrae: Really complete elimination of RNA expression neurons from the targeted gene Shounen point in this case too.
The panel to the right gives you a first glimpse of her new intravenously administered AAV capsid variants that we're calling stack BBB, where stack stands for Sangamo therapeutics AAV capsid.
Alexander D. Macrae: And we were excited to see the dark purple stain in the brain image on the right of the slide, which shows that STAC BVB mediated efficient blood-brain barrier crossing and widespread cargo delivery throughout the brain of non-human primates in important new preclinical studies. We're extremely encouraged that STAC-BBB, which we engineered through our SIFTR capsid engineering platform, significantly outperformed other known published capsids evaluated in our It achieved widespread brain delivery and transient expression as well as de-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.
Alexander D. Macrae: A pitcher can tell a thousand words, and we were excited to see the dark purple shading the brain damage too.
Alexander D. Macrae: On the right of the slide which shows that stack Bvb media deficient blood brain barrier crossing and widespread cargo delivery. So the brain of nonhuman primates in important new preclinical studies.
Alexander D. Macrae: We're extremely encouraged that stack BBB, which we engineered to our sister capsid engineering platform significantly outperformed other known publish cap suits evaluation in our study.
Alexander D. Macrae: It's achieved widespread print delivery and try and gene expression as well as D targeting up to deliver another peripheral tissues and was generally well tolerated.
Speaker Change: We look forward to telling you more about these remarkable findings today.
Alexander D. Macrae: First, though, I want to spend a moment highlighting our choicefulness in our lead neurology programs for NAF1.7 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, and three... They have a delivery system we believe to be achievable using AAV capsids.
Speaker Change: First of all I want to spend a moment, highlighting our choice fullness and our elite neurology programs for NAV one seven in prion disease, we are particularly pursuing these targets because one they are validated by human genetics to we have a well defined patient population.
Speaker Change: Three.
Speaker Change: The epic delivery, we believe to be achieved using AAV capsid and four could lead to quantifying pool quicker patient outcomes.
Alexander D. Macrae: And four, could lead to quantifiable quicker patient outcomes. Importantly, they represent a significant medical need and Commercial Opportunity. NAV1.7 addresses a significant unmet need with over 43,000 patients in the U.S. alone who face intractable pain resulting from small fiber neuropathy. These people live with constant debilitating pain that is imaginable, and unimaginable to most of us. These conditions have a higher suicide rate than in the broader population.
Speaker Change: Fortunately they represent a significant medical need.
Speaker Change: And commercial opportunity.
Speaker Change: Not one seven addresses a significant unmet need with over 43000 patients in the U S alone who piece intractable pain, resulting from small fiber neuropathy.
Speaker Change: These people live with constant debilitating pain imaginable unimaginable to most of us.
Speaker Change: In fact.
Speaker Change: These conditions have a higher suicide rate than in the broader population.
Alexander D. Macrae: 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, NAF 1.7 uses a well-known, intrathecally administered capsid fertiliser. Prion disease is a truly devastating condition with more than 1,500 patients diagnosed per year across the 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 to be a normal mouse lifetime.
Speaker Change: With promising preclinical data for NAV, one seven program. We believe we have a clear route to clinical proof of concept, we expect and I N T 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.
Speaker Change: Importantly, not 1.7 uses a well known interests equally administered capsid for delivery.
Speaker Change: Prion diseases are truly devastating condition with more than 500 patients diagnosed per year across shoes U S and Europe.
Speaker Change: It is a disease that rapidly progresses and as always phase two usually within 12 to 15 months of symptom onset.
Speaker Change: And there are no currently effective treatment options available.
Speaker Change: 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 mouse lifetime.
Alexander D. Macrae: We anticipate filing a clinical trial authorisation submission to 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.
Speaker Change: We anticipate filing a clinical trial authorization submission that UK, because thanks to mad cow disease, they have an excellent infrastructure for identifying and carrying for <unk> patients.
Speaker Change: Our Cta, enabling studies are already underway and we expect to submit the Cta in the fourth quarter of 2025.
Speaker Change: While we intend to progression or core programs toward frankly submissions, we believe that the exciting stacked ppb 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.
Speaker Change: Penetrant capsid.
Speaker Change: We're waiting for stacked P. P b.
Alexander D. Macrae: 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 StatBBB, 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, mitonic tricep type 1. Sangamo is exploring avenues to resume the development of these programs with new potential collaborators.
Speaker Change: The first a thesis a depression of the gene that produces tablet P.
Speaker Change: PT to address Taiwan cities, such as Alzheimer's disease with the identification of stack PPP, we intend to resume the development of our <unk> program with a 90 submission expected as early as the fourth quarter of 2025.
Speaker Change: In addition, stack bvb oxo.
Speaker Change: Also potentially unlock multiple other neurology epigenetic regulation programs that were caused by Sangamo painting, the identification of such a capsid.
Diseases, such as Parkinson's disease, mitral electricity, Taiwan sang.
Speaker Change: Sangamo exploring avenues to resume development these programs with new potential collaborators.
Alexander D. Macrae: With our 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 our later stage non-neurology programs that could provide additional important non-dilutive funding. As we plan to partner with the FibroDisease Programme, we expect to complete dosing in the Phase 1-2 STAR study in the first half of this year. For our partnered HeMay program, Pfizer expects to present phase 3 results in the middle of this year, just a few months away, and anticipates potential regular submissions in the U.S. and Europe in early 2025, assuming that the pivotal readout is supported. We are then eligible to earn up to $220 million in milestone payments and up to 14-20% royalties on potential sales from this program.
Speaker Change: With a reinvigorated neurology focus.
Speaker Change: Momentum already underway in 2024, we anticipate multiple potential near term milestones.
Speaker Change: We enter 2025.
Speaker Change: We also anticipate milestones for later stage non neurology programs that could provide additional important non dilutive funding.
Speaker Change: As we plan to partner Fabry disease program, we expect to complete dosing in the phase <unk> Stomp study in the first half of this year.
For our partner he made program Pfizer expects to present phase III results in the middle of this year, just a few months away and anticipates potential regulatory submissions in the U S and Europe in early 2025, assuming that the pivotal readout is supportive.
Speaker Change: 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.
Alexander D. Macrae: 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 security. 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.
Speaker Change: Before we show you the detailed data it's important to take a moment to talk about our current financial position.
Speaker Change: Over the course of 2023, we proactively made difficult decisions to preserve our most valuable assets, we declared our intention to become a focus neurology genomic medicine company carefully aligned our resources and investments to that vision and advanced multiple reductions enforced to significant limits our spend.
Speaker Change: As a result, we have reduced our operating expenses by approximately 50% year over year.
Speaker Change: While it's difficult these were the right decisions to make.
Speaker Change: Im sure Youll see in great detail very shortly.
Speaker Change: We ended 2023 with approximately $81 million in available cash cash equivalents and marketable securities.
Speaker Change: 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.
Speaker Change: 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 2000.
Amy Pooler: 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 CAHPSA data, along with other updates from our pipeline. Amy.
Speaker Change: 25, as we transition our legacy clinical programs.
Speaker Change: In the meantime, we continue to actively pursue a number of different opportunities to raise additional capital.
Speaker Change: I'll now turn it over to Amy to discuss her latest capsid data along with other updates from our pipeline.
Amy Pooler: 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 SIFTR 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 capsids, as well as robust neuronal transduction. We also needed it to express the Zinkzinger 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 in humans.
Speaker Change: Hey.
Amy Poehler: Thank you Sandy and Hello to everyone joining today's call.
Amy Poehler: We know that widespread CNS delivery is challenging that conventional avis, which is why we have developed our sister platform, which is designed to enable the selection of narrow Tropic 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 capsid.
Amy Poehler: 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.
Amy Poehler: We knew that this capsid needed to have broad brain coverage in all the key areas integral to the disease pathology enhanced enrichment and the brand compared to other published capsid as well as robust neuro and all transaction.
Amy Poehler: We also needed to express the zinc finger therapeutic cargo and repressed the target gene all while being easily manufacturable at scale.
Amy Poehler: Although this may seem like a lot of boxes to check we believe each of these qualities as a central for truly effective capsid that could be deployed into humans.
Amy Pooler: That is why we are so pleased with the preclinical data from our recent non-human primate studies that demonstrate how well-placed StackPBB 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. Additionally, vector genomes were enriched in the central nervous system while de-targeted 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?
Amy Poehler: That is why we're so pleased with the preclinical data from our recent nonhuman primate studies that demonstrate how well play a stack BBB is to potentially adjust these criteria.
Amy Poehler: And 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 the results that were consistent across individual animals and groups.
Amy Poehler: We saw extensive expression of zinc finger cargo throughout the brain, including key disease relevant regions clear dose response curve for zinc finger expression and a corresponding repression of disease target.
Amy Poehler: Vector genomes are enriched in the central nervous system, while the targeted from the dorsal root ganglia in liver and Cindy mentioned crucially, we believe the stack BBB is auto manufacturer, but scale.
Cindy: So how did we assessed this performance and.
Amy Pooler: In our latest experiments, we started with 100 million capsid variants, which were 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 StachBBB as the standout high performer. The visualization shown here is the final round of the SIFTR screening process, where 1,260 novel capsids were all evaluated simultaneously in Cynomolgus macaque. 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 fold change enrichment is among the samples that were tested.
Cindy: And our latest experiments, we started with 100 billion capsid variants, which engineered with a specific peptide in session.
Our fleet Barcoded to enable tracking with.
Cindy: We then evaluated these capsid variants to progressive rounds of screening enriching for the best performers. There are three rounds of selection until we identified stack BBB is the standout high performer.
Cindy: The visualization shown here is the final round of the sister screening process.
Cindy: We're at 1260 novel capsid, or all evaluated simultaneously and cinema like its macaques.
Cindy: This graph the Y axis shows the relative level of enrichment of the capsid throughout the brain with zero, representing capsid that exhibited no comparative enrichment in the brain.
Cindy: What we're looking for here is a high degree of neuronal RNA expression, indicating successful BBB crossing and deliberate to neurons, we see on the X axis. The overall coefficient of variation or in other words, how consistent the fourth change enrichment is among the samples that were tested.
Amy Pooler: 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-PVB 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, shown here in orange.
Cindy: 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 another one off chance outcome. The highest performing capsid there'll be found in the top left corner. So we were very encouraged to see the stock BBB capsid coming out on top performing all the others in the library on the South.
Cindy: Mint.
Cindy: The Library assessment also included known published nurture epic capsid variants that were evaluated head to head. In addition to our own we are very pleased that stack BBB with a top performing capsid and the benchmarking study.
Cindy: Moreover, we also saw this performance was consistent across all three animals and multiple levels of the brain with fact Pvp illustrated here in Green consistently outperforming the next best published capsid here shown in Orange.
Amy Pooler: 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. In 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 intracecal administrations of endosense oligonucleotides, also called ASOs, or more traditional CAPs. The liver can act as a primary sink for intravenously administered capsids.
Cindy: In fact, we saw a 700 fold better enrichment in the brain for stack BBB compared to the benchmark caps at 89 shown in blue on this graph highlighting the superior neuronal expression needed it they stack BBB.
Cindy: On the next graphic you can see how the superior performance continues to be demonstrated across all key areas of the brain, including the hippocampus in deep brain regions, which traditionally have been so difficult to reach with interest equal administrations of antisense oligonucleotides auto called asos or more traditional cap sets.
Cindy: The liver can act as a primary think for intravenously administered capsid.
Amy Pooler: However, however, we saw significant de-targeting of StacBBB in the liver with a hundred fold lower expression compared to the benchmark AAV capsid when compared against historical sangamo 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 side 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 by the deep purple or almost black coloring you see on the left side.
Cindy: However, we saw there was significant D targeting in fact, maybe being a lever with a 100 fold lower expression compared to the benchmark AAV capsid.
Cindy: When compared against historical Sangamo studies at the same dose.
Cindy: <unk> peripheral exposure in the liver as desired.
We then conducted follow on study is taking our lead capsid stack BBB and testing at the individual performance.
Cindy: On the left of the slide we see an image of a nonhuman primate brain. It is from an animal that was treated with affect ABB capsid administered intravenously at a dose of <unk> 13 vector genomes per kilogram and package with both the nuclear localized green fluorescent protein or G. S. P as well as the zinc finger repressor targeting the prion gene.
Cindy: With unused antibody labeling sustained for the F. B cargo is illustrated with the deep purple or almost black color and you see on the left side.
Amy Pooler: We are very pleased to see both a widespread and uniform expression of GFP mediated by STACBBB throughout all the grey 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.
Cindy: We are very pleased to see both a widespread and uniform expression of G. F. P mediated by stack BBB throughout all the grey matter, but just where the cell bodies resided in the brain.
Cindy: Conversely, you see no GFP expression in the white matter. So we would anticipate because it primarily consists of myelinated axons.
Cindy: On the right is the control animals that wasn't treated with AAV, but the tissue was processed in the same way to visualize J F. P and as you can see there is no signal.
Amy Pooler: 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 STACBBB. And then the lighter blue is a Nissl 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.
Cindy: If you dive deeper into some of the critical regions. You can see there are two types of staining, you'll see the darker purple standing which is the G. S. P cargo being expressed by the stack BBB and then the lighter blue with a missile Stan that labels all of a sudden nuclei in the brain.
Cindy: 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 dependant on the brain region.
Amy Pooler: 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 appear largely localized to neurons. This transduction was consistent across 12 other brain regions we analyzed, with clear enrichment of SACBB observed in the neurons in each of these areas. Because of the observed neurotrophic nature of STAC-BBB, 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.
Cindy: Here, we clearly see that stack BBB is narrow tropic with pronounced standing of the cell nuclei and in some places even an overflow GFP protein out into the cell body at the neuron.
Cindy: This transaction was consistent across the critical region shown which are important to many different disease pathologies and appears largely localized to neurons.
Cindy: This transaction was consistent across 12 other brain regions, we analyzed with clear enrichment affect EVP observed in the neurons in each of these areas.
Cindy: Because of the observed neurotrophic, Nick neurotropic nature to that BBB the level of enrichment seem to align with the number of corresponding neurons found in each brain region. The lateral geniculate nucleus for example, as tightly packed with neurons, let me saw striking stack BBB enrichment here.
Amy Pooler: 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 phregix ataxia could all potentially be unlocked by SACBBB and our ThinkFinger cargo. If we dive a little deeper into some of these brain regions, for example, the dentate nucleus, the steep cerebellar region is particularly hard to reach with CSF routes of administration.
Cindy: Extensive transaction is crucial because each area is linked to a whole range of diseases for which treatments are desperately needed based on the compelling data, we believe that diseases, such as Huntington's disease Parkinson's disease.
Cindy: Laughs or predicts ataxia, it could all be potentially unlocked by stack BBB and are thinking of cargo.
Cindy: If we dive a little deeper into some of these brain regions. For example, the dentate nucleus. The steep cerebellar region is particularly hard to reach with CSF routes of administration.
Amy Pooler: 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 can 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 STACBPB, all of which exhibited similar levels of GFP expression. Finally, we believe STAC BBB is manufacturable at scale.
Cindy: However, using an intravenous approach, where we're leveraging the internet relationship between the brain vasculature neurons, we are able to transduce almost all the neurons in this region as you see here 30 out of 31 neurons visible in the field are transfused, we were thrilled to see this robust level of brain transduction.
Cindy: Moreover, this consistent transduction with reproducible across animals here, we show the dentate nucleus of three separate animals treated with stack PPP all of which exhibited similar levels of Jeff P expression.
Cindy: Finally, we believe stack BBB is manufacturable at scale kept admin affects your ability 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 effectively be at scale.
Amy Pooler: 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 is currently scaling up to 500 liters.
Cindy: Our tech ops team has manufactured the capsid that 50 leaders and are currently scaling up to 500 liters, we have been able to produce the caps that do you think both the Hector nine three and that's up nine platform.
We believe stack BBB as manufacturer of commercial scale using standard cell culture and purification processes.
Cindy: Available using known excipient and can be characterized using available analytics, which we consider to be crucial factor in the potential long term success as we seek to scale up to the levels needed for our clinical trials for potential commercialization.
Amy Pooler: We have been able to produce the capsid using both the HEK-293 and SF9 platform. 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 ThinkFinger platform. Thanks, Sandy.
Speaker Change: I'll now turn it back to send it to discuss our zinc finger platform Sandy Thanks Amy.
Alexander D. Macrae: As Amy emphasized early to start Pvp data demonstrate that we've engineered capsid exhibited greenway delivery in nonhuman primates.
Alexander D. Macrae: However, this is only one half of the effect of neurology genomic medicine I will now tell you about the other half are porton potent zinc finger cargo, which can be combined with our delivery capsid to potentially create truly innovative genomic medicines.
Alexander D. Macrae: Thanks, Amy. As Amy stressed, our latest StatBVB data demonstrate that we've engineered a capsid that exhibits brain-wide delivery in non-human primates. However, this is only one half of the effect of neurogenomics 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 medicine. Our neurology pipeline leverages Sangamo's proprietary ZincFinger gene targeting technology, a high-precision genomic engineering platform. Think of ZincFingers as the landing mechanism that can identify the exact zip code within the genome to attach to and 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.
Alexander D. Macrae: Our neurology pipeline leave reaches Sangamo proprietary zinc finger gene targeting technology, a high precision genomic engineering platform think of sync fingers as the lending mechanism, which can identify the exact ZIP code within the genome to attach and to regulate this is what they do in the in the body.
Alexander D. Macrae: <unk> brings a all of us.
Alexander D. Macrae: Zinc fingers are highly versatile extremely customizable and very compact, meaning they can be easily packaged to viral vectors.
Alexander D. Macrae: They are roughly one eighth the size of other editing modality. So we believe we can package up to three repressor, if necessary into one AAV capsid and repressor proteins at any one time, if we wanted to.
Alexander D. Macrae: They're also derived from human proteins, which potentially avoids issues with immunogenicity the mirage with bacterial proteins.
Alexander D. Macrae: Think of everything finger platform as a Swiss army knife, which is flexible enough first different tools based on your needs broadly zinc fingers recognize an 18 based peer piece of DNA to induce a variety of actions such as causing.
Alexander D. Macrae: 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 want. 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 nuclear 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 cytidine deaminases for highly efficient base editing in human cells.
Alexander D. Macrae: Causing a double stranded break via nucleus properties activation repression base editing epigenetic modification and site specific integration.
Alexander D. Macrae: Our base editing capabilities were highlighted last month in nature communications, showing the compact zinc finger architecture utilizes toxin derived <unk> deaminase as for highly efficient base editing in human cells.
Alexander D. Macrae: We were pleased to reach in nature communications or other groups believe zinc fingers are the most capable epigenetic regulation too and are delighted with our partnership with chroma medicine, who have licensed or zinc fingers exactly for this purpose.
Alexander D. Macrae: We were pleased to read in Nature Communications that other groups believe zinc fingers are the most capable epigenetic regulation tool, and we are delighted with our partnership with Chroma Medicine, who have licensed our zinc fingers exactly for this purpose. We're currently focusing on leveraging our epigenetic regulation capabilities in urology. 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 ThinkFingers are leveraged in our PRION and TAU programs? Thanks, Sandy.
Alexander D. Macrae: We are currently focusing on leveraging our epigenetic regulation capabilities neurology and the data that photos and prior in childhood and iPhone seven and we'll focus on that technology specifically.
Alexander D. Macrae: Amy can you tell us a little more about how did the zinc fingers are leveraged in our prior in tow programs.
Amy Poehler: Thanks Sandy.
Amy Poehler: Now the prion disease, which affects approximately 600 patients a year in the U S and Canada and around 900 in Europe.
Amy Poehler: <unk> disease is an awful disease typically fatal in 12 to 15 months. There are no approved disease modifying therapies that currently exist.
Amy Pooler: Turning now to prion 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 in 12 to 15 months. There are no approved disease-modifying therapies that currently exist.
Amy Poehler: <unk> is an excellent fit for zinc finger repression, we know that pre owned knockout animals did not get the disease prion reduction could delay or prevent disease and Toronto prion production of protein reduction also prevents disease. We therefore believe that the repression of prion expression may slow or halt disease progression and her to generation.
Amy Pooler: 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, a 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 proteins spreads throughout the brain as the disease progresses.
Amy Poehler: As mentioned earlier, we therefore packets or prion targeted zinc finger repressor into the newly identified stack BBB capsid and administered intravenously to three separate nonhuman primates.
Amy Pooler: 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 pre-untargeted sink 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 sec BBB delivers to, we collected 220 punches from each animal and conducted RT-qPCR analyses to measure how much pre-untargeted 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 the pre-untargeted sink 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.
Amy Poehler: In order to assess which regions of the brain sect ABB delivers too we collected 220 punches from each animal and conducted RT keep you see our analyses the measure how much pre owned targeted zinc finger with expressed.
Amy Poehler: Each dot on these brain images illustrates the location of one of the punch as we collected and each row represents one of the three animals that was just the color.
Amy Poehler: It presents a level of the preamp targeted zinc finger expression that was measured.
Amy Poehler: 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 confirms the G. S. P protein expression data and support that stack BBB immediate mediated consistent brain white expression of prion targeted zinc finger repressor in all three animals.
Amy Poehler: We next wanted to quantify its expression correlated with an associated reduction in prion mrna in these brain punches we.
We were happy to see a reduction of prion expression and all thirty-five brain regions that we analyzed as a reminder, this brain contracts do not solely consists of neurons, but additional brain cell types as well sell such as illiquid Thunder sites astrocytes in microglia.
Amy Pooler: These results confirmed the GFP protein expression data and support that STACBB 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, such as oligodendrocytes, astrocytes, and microglia.
Amy Poehler: Because pre owned is expressed in multiple brain cell types. What 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.
Amy Poehler: When looking at the single cell analysis in similar studies in the past, including the tower data I'll show you in a moment, we've seen upwards of 80% reduction at the individual neuron level.
Amy Poehler: So how do we think the level of depression, we saw in the Green bar graph, just now will impact disease progression based.
Amy Poehler: Based on this level of bulk repression observed in a mouse model of aggressive prion disease. We concluded that zinc finger process can significantly extended survival in prion infected animals.
Amy Pooler: 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 percent, the percent reduction in individual neurons must be significantly higher. When looking at the single cell analyses of 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 untreated mice consistently die around 160 days post-infection.
Amy Poehler: In collaboration with the broad Institute, we engineered zinc finger repressor is to target the mouth prion gene and administered as a single dose in mice, either 60 or 122 days following prion infection.
Amy Poehler: 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 preamp 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.
Amy Poehler: This is an incredible alteration and disease progression.
Amy Poehler: And 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 on graph to to be able to induce an extension and lifespan and when assets are administered at a later time point post infection.
Amy Poehler: As shown on graph before when the disease is further progressed, there was only minimal extension and lifespan.
Amy Poehler: Firstly, even when administered 122 days post infection shown on graph three which is the timeline more aligned to what we believe we will see in the clinic a single dose of the zinc finger repressor, we're still able to profoundly delay disease progression and extend survival in mice.
Amy Pooler: 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 in 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 two, to be able to induce an extension in lifespan. And when ASOS was administered at a later time point post-infection, as shown in graph four, when the disease was further advanced, there was only a minimal extension in lifespan.
Amy Poehler: These data reflect the two or 13 vg per kilogram dose level, which is considered a mid dose of AZ showing that we have the potential to dose higher should we decide that that's appropriate.
The premium program is progressing with our clinical lead zinc finger repressor that showed greater than 95% prion reduction per cell with no detectable off targets and meaningful potency both in vitro and in vivo.
Amy Poehler: 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 U K for pre on in the fourth quarter of 2025.
Amy Poehler: Moving now to tell and well known target for the treatment of Neurodegenerative diseases called telepathy is.
Amy Pooler: Conversely, even when administered 122 days post-infection, shown in graph three, 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 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. The PREON program is progressing with our clinical lead zinc finger repressor that showed greater than 95% PREON 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 PREON 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 role in Alzheimer's disease.
Amy Poehler: Recent data from Biogen's Asa studies show stabilization of cognitive function with regular injections of asos addressing town, which seems to cement towels implication in Alzheimer's disease and.
Amy Poehler: In addition, there are also a host of telepathy disorders that spend more than 12 distinct indications, including progressive Supranuclear palsy frontal temporal dementia and account for a very large patient population with high unmet medical need that we could potentially address with our zinc finger approach.
Amy Poehler: Using a combination of stack BBB delivery capabilities, and a towel zinc finger repressor, we see a potential ability to halt disease progression with a one time IV administration for various tail off at the indications given the caps its ability demonstrated ability to reach all the brain regions with high specificity in nonhuman primates.
Here, we packaged our clinical lead powered zinc finger repressor, which shows fantastic repression of Tau.
Amy Poehler: <unk> specific expression and no detectable off targets in vitro into our stack BBB capsid and tested it at three different intravenously administered doses five at 12 to 13, one and 114 vector genomes per kilo.
Amy Poehler: Similar to the slide we saw the foreign prion here, we were looking for widespread expression of the zinc finger repressor throughout the brain here. We're 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.
Amy Pooler: In addition, there are also a host of telepathy 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 brain regions with 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 SACBBB capsid and tested it at three different intravenously administered doses, 5E12, 2E13, and 1E14 vector genomes per kilo.
Amy Poehler: Importantly, and some relate to the prion study we are not only looking at the level of zinc finger expression, but also the corresponding levels of tower impression here. We show these data for the deep brand polemic region, including the lateral geniculate nucleus.
Amy Poehler: Prion talented team that is expressed not only in neurons, but also in astrocytes and I'll look at Thunder sites, we know that Pal expression of neurons is the critical driver of disease pathology, which is why we are still focused on repressing. It in these cells.
Amy Poehler: In this case the clinical lead construct he says a synapse and promoter. So we know that we are only targeting zinc finger expression to neurons.
Amy Poehler: We were pleased to see a dose dependent increase in zinc finger expression that correlated with a dose dependent decrease of Tau expression.
Amy Poehler: Like in the prion experiments. This is a bulk analysis of whole brain punches. Its consist of 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 at the single cell level of neurons.
Amy Pooler: 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 PRIAM 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.
Amy Poehler: 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 geniculate nucleus, which is likely correlated to the higher proportion of neurologists in this region as illustrated by the dark standing in the image above from the same brain region in the J F. P arms of the study.
Amy Poehler: Let's take a moment to look more closely at the ponds part of the brainstem and it keep brain region and they tell us that they called Progressive Supranuclear palsy.
Amy Poehler: 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 think finger expression and decrease tau expression in a dose dependent manner.
Amy Pooler: 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 think finger expression that correlated with a dose-dependent decrease in tau expression. Like in the prion experiments, this is a bulk analysis of whole brain punches that consist 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.
Amy Poehler: 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 a minister chemistry approach to visualize CFR expression in tower impression in neurons.
Amy Poehler: The state it 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.
Amy Poehler: On the top of the Pons instrument control animal and the bottom is from an animal treated with the top dose of stock BBB encoding the tau clinical data zinc finger repressor.
Amy Poehler: And 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 of the neurons expressing fingers in this region, which resulted.
Amy Pooler: 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 zinc 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.
Amy Poehler: And almost complete repression of Thailand themselves.
Amy Poehler: Here, we show more of this beautiful single cell data demonstrating the power of both stack BBB and our zinc finger repressor working together in this instance in the motor cortex.
Amy Poehler: On the top row, you can see the vehicle control of our Tau mrna with clearly expressed across the brain region in particular, with the neurons and purple and glia and Orange.
Amy Poehler: No think finger repressor it was detected in the Tau mrna levels remained consistent between the different images.
Amy Poehler: Conversely at the bottom, we see a potent repression of tau mrna across the image on the left.
Amy Poehler: Going into this a little more in the middle image and as indicated in green, we detected the zinc finger repressor repressor, particularly in neurons and importantly, wherewithal to zinc finger repressor expression, we saw an almost complete elimination of Tau mrna most visible in the bottom right panel.
Amy Poehler: This is truly encouraging data that gives us great hope for the promise of a single administration of stack BBB and our Artale zinc finger repressor.
Amy Pooler: 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 StacBDB encoding the tau clinical lead zinc finger repressor. In 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 calculated that approximately 80% of the neurons expressed 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 StackPBB and our tau zinc finger repressor working together. In this instance, in the motor cortex.
Amy Poehler: For our Tau program, we have identified the clinical lead zinc finger and I N D. Enabling activities are well advanced making this program well suited to move into the clinic, either ourselves or with a potential partner.
Amy Poehler: The college studies could be initiated as early as the second quarter of this year with a potential NDA submission as early as the fourth quarter of 2025.
Amy Poehler: Finally, I'll outline our lead neurology indication not 1.7, and how we're using this program as a way to balance the portfolio through a diversified delivery approach.
Amy Poehler: Our NAV one seven program does not leverage that BBB, but instead uses a known AAV delivery capsid that it's already in the clinic. Our aim here is to develop a medicine capable of reaching the dorsal root ganglia is now $1 seven as a voltage gated sodium channel express their mutations in this channel play a critical role in pain perception.
Amy Poehler: By Potently, reducing that one seven in the DRG. We believe we can prevent the transmission of nociceptive turn signals in order to treat chronic neuropathic pain and a host of other indications.
Amy Pooler: 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 in on this a little more, in the middle image, and as indicated in green, we detected the zinc finger repressor, particularly in neurons.
Amy Poehler: There is an urgent need for new therapies in this space and a potentially very large patient population to address so we're very motivated to be moving forward, whether or not one seven program and plan to initially focus on patients with small fiber neuropathy.
Amy Poehler: As you see here preclinical data from our clinical lead zinc finger repressor targeting a C. N nine a the gene that encodes not 1.7 demonstrated a meaningful repression in vitro with exquisite levels of specificity as we only saw repression of novel 0.7 without impacting any other sodium channels. It's.
Amy Pooler: 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 StackPBB and our Taos Zinc Finger Repressor. For our TAO program, we have identified the clinical lead, Syncfinger, 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.
Amy Poehler: 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 him well suited to the zinc finger technology.
Amy Poehler: Taking this into animal models on the left you see a study targeting neurons in the DRG tour groups themselves outside the spinal column in the blood brain barrier.
Amy Poehler: Using interesting co injection of the thing finger repressor in mice, we observed significant expression, which you see in red.
Amy Poehler: This resulted in an almost complete elimination of the S. N 90 expression shown by the absence of light, which indicated a potent knockdown of the novel <unk> 17 at the mrna level.
Amy Poehler: If you look at the Middle pain, you can understand what this looks like in a mouse model. We use the gold standard mouse model of neuropathic pain called the spared nerve entry model and performed a single injection of the thing finger repressor interest equally after the nurse or cartoon this pain.
Amy Pooler: 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 StackBBB, 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 has a voltage-gated sodium channel expressed there, and mutations in this channel play a critical role in pain perception.
Amy Poehler: Ministration 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, and the bottom middle pain, which are very similar to the results of the those animals that had never received surgery as indicated in blue which is very impressive.
Amy Poehler: Finally, you see the nonhuman primate study on the far right, where we wanted to show that we can target the DRG and achieved potent repression of S. C. On nine eight in our study we administered three different doses of zinc fingers entrance equally and we saw dose dependent and potent repression of mouth 1.7 importantly, there's a lot of research emphasis and parakeet publication.
Amy Pooler: 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 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 zinc finger technology.
Amy Poehler: It's 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 Navajo plant seven program and we look forward to completing its final toxicology studies, we expect to submit an NDA for this program in the fourth quarter of this year.
Amy Poehler: I'll hand back to Sandeep to wrap this up before we open for Q&A.
Thank you Amy really appreciate everyone joining us today as we look forward to answering your questions.
Sandeep: And what we've outlined we strongly believe in the power of our science to address devastating neurological conditions.
Sandeep: We're advancing epigenetic regulation cargo a novel AAV capsid for our high value gateway neurological diseases, like chronic neuropathic pain and prion disease.
Sandeep: Today, we have shown with the capsid that demonstrated the ability to penetrate the blood brain barrier and exhibited industry, leading CNS tropism in nonhuman primates.
Amy Pooler: Taking this into animal models, on the left, you see a study targeting neurons in the DRG through groups of cells outside the spinal column in the blood-brain barrier. Using intrathecal injection of the zinc finger repressor in mice, we observe 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 image, 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 development of stock P. B b potentially unlocks multiple neurology programs. So it could be advanced ourselves or with partners as a potential source of non dilutive funding.
Sandeep: And we have the prion disease program, which we believe could quickly Paula P. P.
Sandeep: And proteins in humans.
Sandeep: In order to 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 ft and multiple collaboration discussions in progress.
Sandeep: We have transformed sangamo into focus neurology business with the potential to transform the lives of patients with debilitating neurological conditions.
Amy Pooler: 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 pane, 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 could target the DRG and achieve potent repression of SCN9A. In the study, we administered three different doses of zinc fingers intrathecally, and we saw dose-dependent and potent repression of NAV1.7.
Sandeep: We have also made the necessary, but very difficult decisions to focus our company and streamline our opex with intention of reducing our burn but without impairing potential found you.
Sandeep: We believe these changes enabled us to set forth an attractive opportunity to raise additional funds via additional potential collaborations.
Alongside this we have the Pfizer collaboration he me.
Sandeep: It brings revenue bearing opportunity with $220 million in potential milestones.
Sandeep: As you can see we believe our company is well positioned to change the lives of patients. So neurology genomic medicine company.
Amy Pooler: Importantly, there's a lot of research emphasis and 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 NAV1.7 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 this back to Sandy to wrap this up before we open for Q&A. Thank you, Amy.
Speaker Change: Operator, please open the lines for questions.
Speaker Change: And thank you as a reminder to ask a question. Please press star one on your telephone and wait for your name to be announced to withdraw. Your question. Please press star one again, please standby, while we compile the Q&A roster and one moment for your first question.
Speaker Change: And our first question comes from Patrick <unk> from H C. Wainwright. Your line is now open.
Speaker Change: Hello, everyone Hi team. This is luis sensors on for Patrick Congrats.
Luis: Congratulations on this as you said beautiful and fantastic data are we are.
Alexander D. Macrae: We really appreciate everyone joining us today as we look forward to answering your questions. And as 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 high value gateway neurological diseases like chronic neuropathic pain and prion disease.
Speaker Change: Interestingly, knowing a little bit more what data do you still have left or completion of the.
Luis: Package for the Cta in the prion disease.
Luis: So on the Tao group.
Luis: Graham did you release them, which epitope of how you are targeting maybe I'll have a follow up question. Thank you.
Alexander D. Macrae: 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 StackBBB potentially unlocks multiple neurology programs that could be advanced by 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 stack 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.
Luis: Thank you Patrick these are really good questions.
Speaker Change: It's beautiful daytime and for the team that he's been working on this for several years as a fulfillment of their.
Speaker Change: Scientific careers truly so I'm going to split into two so the section on how do we get private into the clinic, we will go to Natalie had to development.
Natalie: Hi, everyone.
Natalie: So far the CPA prion now that we have the stack B D. V. We are going to do a G. L. P. Tox study, which will be required for the IND in order to do this we have to manufacture the product put in the Tox study and we're going to do this year.
Natalie: For filing in R&D in the end of 'twenty 25, well so need to do a clinical manufacturing lot with the clinical candidate.
Natalie: <unk> had great discussions already in the UK with the with people.
Speaker Change: The enthusiasm to take this forward absolutely.
Speaker Change: There is a really good system here where the.
Speaker Change: The Ah patient that have prion disease are going to a common center and have a we have linked to our really deep expertise prion disease in the U K and they have also a direct communication with.
Operator: We believe these changes enable us to set forth an attractive opportunity to raise additional funds via additional potential collaboration. Alongside this, we have the Pfizer collaboration in Hime that brings revenue-bearing opportunities 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 neuroscience genomic medicine company. Operator, please open the lines for questions, 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.
Speaker Change: The regulatory authority in England. So we think that we're well positioned to really move quickly in the U K. Thank you Natalie and then for for types of tone, Amy How do you think about that Sir 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 is.
Amy Poehler: So much complexity for Tao the different spice variance at the RNA level and then many many different different configurations of pile at the protein level, because we are targeting upstream up all of that we believe that we are able to address really all all different top with these and all of these different possible forms of toxic Tau.
Operator: Please stand by while we compile the Q&A roster and one moment for our first question. And our first question comes from Patrick Trucchio from H.C. Wainwright. Your line is now open. Hello, everyone. Hi, team. This is Luis Santos on for Patrick.
Amy Poehler: Which would be a real competitive and patient advantage absolutely.
Speaker Change: Just a very quick follow up on the dose response.
Patrick Ralph Trucchio: Congratulations on this. As you said, beautiful and fantastic data. We are interested in knowing a little bit more about what data 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 epitope of Tau you are targeting? Maybe I'll have a follow-up question. Thank you. Thank you, Patrick. These are really good questions.
Speaker Change: Okay.
What level of of reduction of Tau do you expect will be enough to choose to be promising and translational into into humans. So what levels of retail reduction will we see well we need to see not just from the beauty.
Speaker Change: Florida and scope images, but apps after the pathologic level after a physiological level and mice and hps. So that we can be more confidence in humans.
Alexander D. Macrae: It is beautiful data, and for the team that has been working on this for several years, it's the culmination of their scientific careers, truly. So I'm going to split into two, so the section on how we get prion into the clinic will go to Nathalie, the Head of Development. Hi, everyone.
Speaker Change: Yeah.
Yeah, that's a great question.
Speaker Change: It depends on the the the different brain regions really at the level of her impression that we're targeting but we believe especially when you look at the outstanding efficacy in the prion studies.
Nathalie Dubois: So for the CTA pre-on, now that we have the STAGG 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.
Speaker Change: We're in the range that we would be expecting to see some clinical results.
Speaker Change: 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 were saying was that the P. B, but also at a single cell level that we see that's really a complete repression of Tau.
Nathalie Dubois: For filing an IND at the end of 2025, we'll also need to do a clinical manufacturing lot with the clinical candidate. You've had great discussions already in the UK with people about their enthusiasm to take this forward. 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 the most experienced prion disease experts in the UK, and they also have direct communication with the regulatory authority in England.
You make when you speak to potential partners, what's the level of repression.
Speaker Change: Interests people.
Speaker Change: That's a great question and I think it depends on the indication for some telepathy is I think something between 10% to 30% depending on the brain region would be important.
Speaker Change: Thank you.
Speaker Change: And thank you.
Speaker Change: And one moment our next question.
Speaker Change: And our next question comes from Maury Raycroft from Jefferies. Your line is now open.
Maurice Thomas Raycroft: Hi, Thanks for taking my questions and congrats on the update today with that the new capsid.
Nathalie Dubois: So we think that we're well positioned to really move quickly in the UK. Thank you, Natalie. And then for types of tau, Amy, how do you think about that? Sure, I'm happy to take that one. I think one of the advantages of the Zingfinger platform is that we're targeting tau at the DNA level. We know that there's so much complexity in tau, with different splice variants at the RNA level and then many, many different configurations of tau at the protein level.
Maurice Thomas Raycroft: I'm wondering with the new caps any have you looked at a relative immunogenicity of it and how that would compare to a benign or other published capsid and based on this do you see any potential to have a re dosing option.
Maurice Thomas Raycroft: Amy can you cover that for us please.
Amy Poehler: And lastly, maybe you want to see some.
Amy Pooler: 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, which would be a real competitive and patient advantage. Absolutely. 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 to humans? So, what levels of tau reduction will we see? 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? Yeah, that's a great question.
Amy Poehler: That's a great question. Thank you.
Amy Poehler: He is a novel engineered capsid, they're being engineered in order to improve the crossing of the blood brain barrier and brain penetrant we've.
Amy Poehler: We believe that they have a similar profile compared to other natural cap sits with a similar range of of neutralizing antibody prevalence.
Amy Poehler: Of course, another frontier of of a capsid engineering could be to evade that but that was not what we set out to do in the study and we're really excited with the penetration that we saw in the brain of these animals.
Amy Poehler: Yeah, we don't expect to to be very different from either a visa of course patient in the trial will be screened for preexisting antibody to our novel AAV capsid.
Amy Pooler: It depends on the different brain regions, and 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 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, where we see this really complete repression of tau. Amy, when you speak to potential partners, what's the level of repression that interests people?
Speaker Change: Got it okay makes sense.
Speaker Change: Yeah for your figure where you compared your capsid to other published captives can you say, which captures these were or what the screening or inclusion criteria wise.
Speaker Change: And where any excluded for example, Voyager cap study.
Speaker Change: Thanks, Thanks Marty.
There are lots of cap such that people are talking about which I think reflects the interest in the field and trying to find that magic capsid, we know know from talking to many pharma.
Speaker Change: Pharma companies that they have capsid search groups in place because it feels like a next generation neurological disease set.
Alexander D. Macrae: 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. Thank you, and thank you. And one moment for our next question. And our next question comes from Maurice Raycroft from Jeffreys. Your line is now open.
Speaker Change: Set of medicines. So we just look to cross the literature and.
Speaker Change: Identified the mutations that'd be meeting those campuses and then recreated them.
Maurice Thomas Raycroft: Hi, thanks for taking my questions and congrats on the update with the new CAHPS. I'm wondering about the new capsid, have you looked at its relative immunogenicity 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?
Speaker Change: And our laboratory, which is something that everyone can do so we're pleased to Irish turned out to the top of the pile them, but what's more important is the characteristics of aercap sit on it so that it's widespread but it seasonally manufacturable did it hit sold the sports of transistors to zinc fingers and it reduces both tow in private.
Amy Pooler: Amy, can you cover that for us, please? and Nathalie, maybe you want to say something? That's a great question.
Nathalie Dubois: Thank you. These novel engineered capsids are being engineered in order to improve the crossing of the blood brain barrier and brain penetrance. However, we believe that they have a similar profile compared to other natural capsids with a similar range of neutralizing antibody prevalence.
Speaker Change: Got it that's helpful and last question and then I'll hop back in the queue.
Speaker Change: Just wondering if you can say anything additional on partnering conversations around these capsid data yet and.
Maurice Thomas Raycroft: 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 penetrant that we saw in the brains of these animals. Yeah, I think we don't expect it to be very different from other AAVs. Of course, patients in the trial will be screened for pre-existing antibody to our novel AAV caps. Got it. Okay, it makes sense. And for your figure where you compared your CAHPSID to other published CAHPSIDs, can you say which CAHPSIDs these were, what the screening or inclusion criteria was, and were any excluded?
Speaker Change: You can provide any more perspective around the <unk>.
Speaker Change: Terms that you would aim to get for partnering.
Any of your wholly owned CNS programs.
Speaker Change: Thanks, right so.
Speaker Change: We've known the and ultimate screening around Russo since.
Speaker Change: The end of last year, and so we've been we've been gradually talking socializing. This with our friends in pharma companies. When we showed the elite to state and some of it. The single cell data has told me out in the last week or so.
Speaker Change:
Speaker Change: 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 captured with our cargo. There is no way that sangamo couldn't funds all of the potential indications with this and that we can only two.
Alexander D. Macrae: For example, the Voyager CAHPSID? 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 meds. 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.
Speaker Change: It through partnership with kind of pharma ecosystem of course, the money is valuable but it would be wrong for me to start talking about numbers here.
Speaker Change: And we look forward to finding ways to move this into as many indications as possible.
Speaker Change: Got it makes sense. Thank you for taking my questions.
Speaker Change: And thank you.
Speaker Change: And one moment Bob next question.
Alexander D. Macrae: 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. 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 capsule data yet, and 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. Thanks, Maurice.
Speaker Change: And our next question comes from the Colds Romito from Truest. Your line is now open.
Speaker Change: Hi, This is Alex on for the call and congrats on the data on all the progress.
Alex: A couple from from US can you remind us for your stack ABB.
Alex: Alzheimer's given our credit focus on the amyloid plaque.
Alex: And could stack BBB have any impact on existing plaque or do you think that this could be potentially after protein antibodies and then I have a follow up.
Alex: Okay.
Speaker Change: So I think we and we heard your question said if it wasn't quite clear Amy can you repeat the what you think we're answering and then take it from there sure I 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.
Alexander D. Macrae: We've known the penultimate screening round results since the end of last year, and so we've been gradually talking and socializing this with our friends in the pharma companies. But when we showed the latest data, 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 Sangamo can advance all of the potential indications with this, and we can only do it through partnership with that kind of pharma ecosystem. Of course, money is valuable, but it would be wrong for me to start talking about numbers here.
Speaker Change: Yes.
Amy Poehler: Okay, great Great I think that theres been accumulating evidence over the past years, which once again is the data that I showed today auto from the Biogen trial at the Asos targeting Tau really have shown how important tau is in driving the pathology of the disease there.
Amy Poehler: There are patients or let's say people, who hadn't yet that have a lot of amyloid in their brands, but actually don't have alzheimers disease and it's only when you have this development of Tao. The telepathy is that's correlated with cognitive decline that's associated with the disease. So we believe I'm like others actually the towers are a critical step in that pathway.
Maurice Thomas Raycroft: And we look forward to finding ways to move this into as many indications as possible.
Nicole Germino: Thank you for taking my question, and thank you. And one moment for our next question. And our next question comes from Nicole Germino from Truist. Your line is now open. Hi, this is Alex. I'm from Truist.
Amy Poehler: And then it's reduction will be really important for for slowing or stopping the progression of the disease and particularly when compared to lose here. So she can give you hopefully we expect to be able to give it once and it will help a longtime effect.
Nathalie Dubois: Congratulations on the data and all the progress. A couple from us: can you remind us about your stack? And finally, we're going to see how this fits into Alzheimer's, given the current focus on the amyloid plaque. And could stack BBB have any impact on existing plaque, or do you think that... after-approved antibodies, and then I have a follow-up. So I think we heard your questions. It wasn't quite clear.
Speaker Change: 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, which is which are so strong in August that's right.
Speaker Change: Can you repeat your second question. Please.
Speaker Change: Where do you think that you can achieve.
<unk> landscape, where this would play out.
Alexander D. Macrae: Amy, can you repeat the quote you think we're answering and then take it from there? 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. Yeah. Okay, 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 ASOS targeting tau, really show 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.
Speaker Change: The improved antibodies and you see that.
Speaker Change: As for antibodies afterwards, how do you think the community is doing it.
Speaker Change: So.
Speaker Change: Perhaps I can take that.
Speaker Change: 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 to collect a lot of data with other forms of Tau antibodies or air source and understand the benefit.
Speaker Change: And gradually.
Speaker Change: The benefit that we show.
Amy Pooler: 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 then its reduction will be really important for slowing or stopping the progression of the disease. And particularly when compared to those ASOs, hopefully, we expect you'll be able to give it once and it will have a long-term effect. That's right. Not only would it be a single administration, but it would also be able to target all of the different brain regions that we think are involved in the disease. Which ASOs don't always do.
Speaker Change: It will be understood, particularly that it's a one one time treatment, which compare that to repeated intra C code.
Speaker Change: Injections I think is very appealing it is 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.
Amy Pooler: That's right. Can you repeat your second question, please? Where do you think this would play out in the treatment landscape? Where would Proof to Antibody, for Antibodies, then? How do you think? So perhaps I can take that.
Speaker Change: If time is as important as we're open leafing, having a single injection intravenously. The crosses the blood brain barrier and completely reduces the production of Taiwanese cells offers an enormous opportunity for <unk> is a devastating disease.
Alexander D. Macrae: And 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 will collect a lot of data with other forms of tau antibodies or ASOs and understand the benefits, 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. Nathalie.
Speaker Change: Natalie.
Speaker Change: In addition, if you compare the street went to antibody as Amy was saying, we're targeting the expression of Tau, we're not targeting a specific epitopes other tau protein.
Speaker Change: Which you know are there isn't any form of tau protein in patients and we don't know exactly which one is the most relevant for each patient. So we're going at the root with <unk> gene P epigenetic regulation approach.
Speaker Change: Thanks, and thanks for all the color.
Speaker Change: And thank you.
Speaker Change: And one moment our next question.
Speaker Change: And our next question comes from Luca E C from RBC. Your line is now open.
Speaker Change: Oh, great. Thanks for taking.
Speaker Change: Our questions separately.
Speaker Change: Uh huh.
Speaker Change: Well congrats on all the progress I have a few questions on that.
Speaker Change: That type of program.
Speaker Change: I'm just wondering if you can add any color on how your conversations with potential partners. This change I think you have reached alignment with the FDA on a registrational path forward.
Nathalie Dubois: Yeah, in addition, if you compare this treatment to antibody therapy, 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 are 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, gene epigenetic regulation of, and thanks for all the color. And thank you. And one moment for our next question. And our next question comes from Luca Issi from RBC. Your line is now open. Oh, great. Thanks for taking our questions. This is Lisa Amperluka. Well, congrats on all the progress. I have a few questions about the FEDFiber program.
Speaker Change: <unk>.
Speaker Change: On the pivotal study.
Speaker Change: Can you share some more additional color on what the primary endpoint will be is it fair to assume the FDA would want to see reduction in G. L. Three inclusion by kidney biopsies similar what we've seen with <unk> any color here would be helpful. Thanks, So much.
Speaker Change: Natalie you had been having a lot of these discussions recently.
Natalie: 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 our BLA submission and approval are at this point.
Luca Issi: Just wondering if you can add any color on how your conversations with potential partners have 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 Abrazyne? Any color here would be helpful.
Natalie: Commenting on the endpoint for this trial and are of course, we had a and I'll, let sandy comment further but this is very exciting for the potential partner. We are in conversation with I think really accelerate the path to BLA approval and it's also reduce the cost sandy.
Nathalie Dubois: Thanks so much. Nathalie, you've been having a lot of these discussions recently. Yes, so we're 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, you know, we're not commenting on the endpoint for this trial. And, of course, we've had to now let Sandy comment further, but 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?
Alexander D. Macrae: Yeah, I think an enormous credit is due to feature marks and his group at the agency they have broken a log jam.
Alexander D. Macrae: Made a public statement that they wanted more gene therapies for our genomic medicines for rare diseases to move forward and that to do that you have to look.
Alexander D. Macrae: Studies are manageable and endpoints are achievable.
Alexander D. Macrae: And that's why this study has been got the notice of lots of people who.
Alexander D. Macrae: Yeah, I think an enormous credit is due to Peter Marks and his group at the agency. They have broken the logjam. They've made a public statement that they want more gene therapies for 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 got the notice of lots of people who, frankly, were standing on the sidelines of Fabry disease, wondering how to get it registered. This is a very manageable study that will look not only at biopsy results but will also look at the, and this is a direct quote from the agency, 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 forward to getting this into the hands of the partners and to patients and registration as quickly as possible. Thanks so much, and thank you.
Alexander D. Macrae: Frankly, we're standing on the sidelines of Fabry disease wondering how to get it to registration. This is a very manageable study that not only we will look at biopsy results, but we'll also look at the and this is a direct quote from agents here at the totality of the data and the benefit there too.
Alexander D. Macrae: <unk> to patients and I think that is such a healthy way to look at.
Alexander D. Macrae: <unk> approval and we look for getting to this too.
Into the hands of a partner and to patients and registration as quickly as possible.
Speaker Change: Got it thanks, so much.
Speaker Change: And thank you.
Speaker Change: Okay.
Yanan Zhu: And one moment for our next question. And our next question comes from Yanan Zhu from Wells Fargo. Your line is now open. Hi, thanks for taking our question. This is Kwan Ang for Yanan. So just a follow up on the prior February questions. Can you share what the potential partners might be looking for?
Speaker Change: And one moment our next question.
Speaker Change: And our next question comes from Ian Ing Xu from Wells Fargo. Your line is now open.
Speaker Change: Hi, Thanks for taking our question. This is one for you on that.
Speaker Change: So just a follow up on that.
Speaker Change: Fabric questions can you share what the.
Speaker Change: Potential partners might be looking for and can we expect to see additional kidney biopsy data from the STAAR study.
Alexander D. Macrae: And can we expect to see additional kidney biopsy data from the STAR study? And I have a follow-up question. So the partners are looking, we're very simply looking for compelling clinical data, real benefits that would make patients move from ERT, and we now have 13 patients that have been off ERT for over a year in some cases and no desire to go back onto ERT. I think that's really important, and some of them have been on ERT for a significant time, and some of them, and in those patients, their SF36 is significant, and they are moving into a changing category of FOSS MSSI, which is the investigator rating. So as they are now, even though they were treated with ERT, they're now even better with gene therapy. And finally, seven of them, in seven that came in with antibodies, five of them, the antibodies have completely disappeared, completely disappeared, and in two of them, they were significantly reduced. And those are the kind of antibodies that limit the effect, eventually limit the effectiveness of the treatment.
Speaker Change: A follow up.
Speaker Change: So the partners are looking for very simply looking for compelling clinical data real benefit that would make.
Speaker Change: Ah patients move from E. R T and we now have 13 patients that Rafi our T a over.
Speaker Change: Over a year in some cases are no desire to go back onto your Archie I think that's really important and some of them had been on New York too for a significant time and some end and in those patients. There SF 36 is significant and they are moving changing category of.
Speaker Change: Force M Ssi, which is the investigators reaching so as they are no even though the what they were.
Speaker Change: And treated with the E. R. T. There no even better with with the gene therapy, and finally certain of them in separate them that came in with antibodies Fife with them. The antibodies are completely disappeared completely disappeared and then two of them significantly reduced and those are the kind of antibodies that limit the effect.
Speaker Change: To limit the effectiveness of the treatment.
Nathalie Dubois: 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.
Speaker Change: What the partners see and think Wow. This is the medicine.
Speaker Change: We will be able to take forward.
But until we had the second part which was the regulatory pathway that was manageable.
Speaker Change: They were cautious.
Speaker Change: Know that we're the only.
Speaker Change: Clinical stage asset for Fabry disease.
Speaker Change: 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 III asset to come.
Amy Pooler: Thank you so much. And my second question is on your cap, on the StackBBB campaign. Can you share how you achieved the hundredfold? Thank you for detargeting the leader. Amy, Amy, can you explain that?
Speaker Change: Got it. Thank you so much and my second question is on the.
Speaker Change: So.
Speaker Change: And stacked BBB Cathy can you share how you achieved 100 coal.
Cathy: Are you targeting the vigor.
Cathy: <unk>.
Cathy: Amy Amy can you explain that yeah, 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 Capsid, and we went through a whole screening processes in nonhuman primates artists electric cabinets that were enriched in the brain.
Amy Pooler: Yeah, I'm happy to take that. Leslie, 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 de-targeted to the liver, we do believe that there's some relationship between that liver de-targeting 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 into the non-human primate brain.
Amy Poehler: Although we didn't design specifically the capsid to be targeted to the liver. We do believe that there is some relationship between that labor day 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 chance do you thing that the nonhuman primate brain and points out important Amy.
Amy Pooler: And why is that important, Amy? Well, it's important because the liver is such a sink for intravenously administered AAVs, actually, by any route. We know that the AAV can go to the liver, and that can potentially be 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 peripheral tissues for safety. I got it.
Amy Poehler: Well, it's important because the liver is such a sink for intravenously administered AAV is actually by any route we know that the Avi 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 transfer it to treat these diseases, which in this case, it's the central nervous system and.
Amy Poehler: Eliminates that exposure to the peripheral tissue for safety.
Anvita Gupta: Thank you so much for all. And thanks. And one moment for our next question. And our next question comes from Anvita Gupta from TD Cowan. Your line is now open.
Speaker Change: Got it. Thank you so much for all the colors.
Speaker Change: And thank you.
Speaker Change: And one moment our next question.
Speaker Change: And our next question comes from empirical data from T. D. Cowen. Your line is now open.
Nathalie Dubois: Hi guys, this is Anvita on for review today. Congratulations 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 NAV 1.7 in chronic neuropathic pain? And then if you could also provide some color on maybe who would be the ideal patient for this program, it would be super helpful. Thank you. Natalie, can you comment on the route to forward for NAV 1.7? Yes, thank you. Yes, we are planning to file an IND for NAV1.7 by the end of this year.
Speaker Change: Hi, guys.
With me 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 would be NAV, one seven in chronic neuropathic pain and then if you could.
Speaker Change: And also provide some color on maybe what would be the ideal patient for this program would be super helpful. Thank you.
Speaker Change: Natalie can you comment on the route to.
Natalie: Forward for enough 1.7, yes.
Natalie: Yes. Thank you.
Natalie: Yes, we are planning to file a 94 and a 1.7 by the end of this year and we are.
Alexander D. Macrae: And we are finishing our GLP-TUX 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. 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.
Natalie: We are finishing our G. L. P. 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 are the end points, but we are well underway and planning those studies.
Natalie: Agreed Natalie I read the protocol last week or the version that's being circulated.
Natalie: This struck me is second in one study is 17% of patients with intractable pain described their life as being worse than death. This is not a toothache or bunionectomy.
Natalie: Has it been described for not 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 we need to get this to patients as soon as possible. So we've got the protocol ready to go we've had discussions with them.
Nathalie Dubois: This is the kind of intractable pain that dominates your life and makes these patients consider suicide and think 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. Thank you. And one moment for our next question. And our next question comes from Gina Wang from Barclays. Your line is now open. Hi, good afternoon. This is Hershida on behalf of Gina.
Natalie: Agency about how to move forward once we get the <unk> 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 theres. This opportunity coming that will replace hopefully all of these.
Natalie: On Tia palette takes an opioids are used in the stressful condition.
Natalie: And thank you.
Natalie: Okay.
Natalie: And one moment our next question.
Natalie: And our next question comes from Gena Wang from Barclays. Your line is now open.
Gena Wang: Hi, Good afternoon. This is Hershey that Dana. Thank you so much for that detail card. This afternoon and thank you for taking our questions.
Huidong Wang: 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 Fabi. Given your recent update, I was curious, can you help categorize the importance of improvement in health scores, specifically for the SF-36 survey? Could you provide some color on how the general health and physical components scores are rated? Are they equally rated, or is there a higher rate for one of the components?
Gena Wang: Most of them have been answered, but I just had a quick follow up on that.
Gena Wang: Given your weekend.
Gena Wang: Was curious can you help categorize the importance of improvement in health scores.
Gena Wang: Specifically for the upgrade.
Gena Wang: Okay.
Gena Wang: Could you provide color on how the general health and physical components.
Gena Wang: Are they equally weighted or is there a higher rate to one of the components. Thank you so much.
Nathalie Dubois: Thank you so much. Nathalie, can you cover that? Yes. So in our phase one, two study, you know, it's primarily an initial safety study, but we're also collecting a lot of data from 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
Speaker Change: Not only can you cover the yes so.
Speaker Change: In our phase one two study.
Speaker Change: Primarily initially a safety study, but we're also collecting a lot of data.
Speaker Change: In the patient and really we are looking as you know February is a multifaceted disease and we're looking at many different parameters, including kidney function.
Speaker Change: Heart function pain score G I score and general health. So at this point, we're collecting all those point to end and every what is remarkable is that the.
Nathalie Dubois: 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 are 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 GI score, in FOSM SSI, in SF36, and in pain. So everything is tracking in the right direction.
Speaker Change: The body of these data all point in in the same direction of improvement in the patient of course, we're following those patients and the numbers of.
Speaker Change: Patients with more and more time in Switzerland is increasing every month and we're collecting this data, but the data well really show that we have.
Speaker Change: Maintenance of our Egfr slope, we have improvement in Ci score in first time Ssi in SF 36 in pain. So everything is tracking in the right direction. So at this point there is not one that is more let's say more important.
Nathalie Dubois: So at this point, there is not one that is, you know, necessarily more important than the other in the Phase 1-2 trial, and thank you. And I am showing no further questions. I would now like to turn the call back over to Louise Wilkie for closing remarks. 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 in the Investor Relations section of the Sangamo website after this call. We look forward to keeping you updated on our future developments. Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.
Speaker Change: Then the other in the phase two trial.
Speaker Change: And thank you.
Speaker Change: And I'm showing no further questions I would now like to turn the call back over to Louise 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 presentation 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. This concludes today's conference call. Thank you for participating you may now disconnect.
Louise Wilkie: Yeah.
Louise Wilkie: [music].
Louise Wilkie: Okay.
Louise Wilkie: Yeah.
Louise Wilkie: [music].