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and its subsidiaries.
−Removed: We are a preclinical biotechnology company developing next-generation cell and gene therapies engineered with our gene circuit platform technologies to fight challenging diseases.
−Removed: Our mission is to create a new generation of smarter medicines that outmaneuver complex diseases using novel and unprecedented approaches.
−Removed: To accomplish this mission, we have built a synthetic biology platform that we believe may enable us to program next-generation cell and gene therapies with what we refer to as “gene circuits.” These gene circuits, which we created from novel and proprietary combinations of genetic parts, are designed to reprogram cells with biological logic to sense inputs, compute decisions and respond to their respective cellular environments.
−Removed: We aim to design and optimize gene circuits and to improve the “intelligence” of cell and gene therapies in order to enhance their therapeutic effectiveness against a broad range of diseases that conventional medicines are unable to address.
−Removed: Our gene circuit platform technologies are designed to be applied in a modality-agnostic manner, with applicability to natural killer (NK) cells, T cells, tumor infiltrating lymphocytes (TILs), stem cells including induced Pluripotent Stem Cells (iPSCs) Hematopoietic Stem Cells (HSCs), in vivo gene therapy, such as adeno associated virus (AAV), and messenger ribonucleic acid (mRNA).
−Removed: Our internal pipeline is focused on using these gene circuits we engineer onto off-the-shelf healthy adult donor derived NK cells to create chimeric antigen receptor (CAR) NK cells to potentially address the high unmet need in multiple oncology indications.
−Removed: All of our current product candidates are in preclinical development.
−Removed: We expect to file an investigational new drug application, or IND, for our lead product candidate SENTI-202 in the second half of 2023.
−Removed: Key Challenges to Existing Disease Treatments and Our Gene Circuit Solutions
−Removed: Key Challenges to Existing Disease Treatments
−Removed: Diseases often involve complex biological interactions, which limit the effectiveness of existing therapeutics that have single mechanisms of action and are unable to adapt to dynamic disease states.
−Removed: We characterize these key challenges in the following four categories:
−Removed: Disease Evasion:
−Removed: Disease pathologies are multifaceted.
−Removed: For example, diseases can evade the immune system or acquire resistance to single-target treatments by activating other biological pathways.
−Removed: The tumor microenvironment (TME) of many solid tumors suppresses cancer-fighting immune cells via multiple pathways.
−Removed: A gene or cell therapy with the ability to activate multiple anti-tumor pathways within a single product could help limit disease evasion and may improve the durability of responses to treatment.
−Removed: Target Heterogeneity:
−Removed: Many diseases are heterogeneous and express antigens that are also present on healthy cells.
−Removed: The overlap of antigen expression on diseased and healthy cells limits the ability of existing therapies to target diseased cells at therapeutically relevant doses due to undesirable effects against healthy cells.
−Removed: For example, most cancers do not have a single antigen target that is uniformly expressed on all cancer cells with limited to no expression on non-cancerous cells.
−Removed: Thus, the ability to precisely distinguish between diseased cells and healthy cells has been a central challenge to date with current therapeutic approaches that do not encode logic, such as monoclonal antibodies, antibody-drug conjugates and single-target CAR therapies.
−Removed: Modalities that can respond to multiple biomarkers, rather than just a single one, have the potential to open up the opportunity for more precise and efficacious medicines.
−Removed: Narrow Therapeutic Window:
−Removed: Once administered to a patient, conventional medicines, including cell and gene therapies, cannot be tuned up or down, which makes it difficult to find the optimal dose, especially for diseases that have a narrow therapeutic window.
−Removed: The ability to create therapeutics that can be titrated or regulated in vivo in the patient may lead to enhanced efficacy and safety.
−Removed: Dynamic Disease Conditions:
−Removed: Disease conditions are dynamic and vary in space and time.
−Removed: For example, diseases may manifest only in certain tissues, or have a waxing and waning progression over time.
−Removed: Conventional therapies (i) are static, (ii) have a predefined activity around a single mechanism of action that cannot be modified post-administration and (iii) do not adapt to these dynamic conditions, thus limiting their efficacy, specificity and safety.
−Removed: For example, current cell and gene therapies are not dynamic or highly specific, thus limiting the indications that they can address.
−Removed: Developing dynamic therapeutics that are able to sense, and respond to, these spatially or temporally varying conditions would address this challenge.
−Removed: Our Gene Circuit Solutions
−Removed: In our pursuit to create a new generation of smarter medicines, we have built a toolbox of proprietary gene circuit platform technologies that we believe may enhance the risk benefit paradigm of cell and gene therapy products.
−Removed: Four core categories of gene circuits comprise our gene circuit platform:
−Removed: Multi-Arming, Logic Gating, Regulator Dials and Smart Sensors.
−Removed: Each of our gene circuit platform technologies is designed to confer greater clinical and therapeutic activity, precision and control to cell and gene therapies.
−Removed: We believe that our core gene circuit platform technologies may enable us to engineer smarter medicines.
−Removed: These technologies can be categorized as follows:
−Removed: Multi-Arming:
−Removed: Multi-Arming gene circuits are designed to incorporate multiple payloads into a single cell or gene therapy product.
−Removed: These gene circuits are intended to activate various biological pathways in complementary ways to prevent diseases from evading single-target treatments, and thereby potentially improve treatment efficacy.
−Removed: Existing combination therapies that target complex diseases require the application of multiple individual drugs, which is difficult due to research, clinical development, regulatory and pharmacology barriers.
−Removed: Logic Gating:
−Removed: Logic Gating gene circuits are designed to enable cell and gene therapies to control their therapeutic activity in response to the presence or absence of multiple disease biomarkers.
−Removed: Below are examples of Logic Gates applied to cancer, although Logic Gating may also be applied to various other disease indications.
−Removed: NOT GATE gene circuits are designed to widen the therapeutic window by enabling effective killing of cancer cells while preserving healthy cells.
−Removed: The NOT GATE functions by recognizing Protective Antigens (PAs), or antigens that are selectively expressed on healthy cells and not on cancer cells, thus limiting on-target, off-tumor killing.
−Removed: By protecting healthy cells, the NOT GATE has the potential to enable more effective on-target, on-tumor killing of tumor cells that express Tumor- Associated Antigens (TAAs).
−Removed: Generally, existing cancer drugs target only a single antigen, which means they can only be effectively and safely used in situations where that antigen is uniquely expressed on tumors and not in healthy cells, or where the on- target, off-tumor effects are tolerable.
−Removed: OR GATE gene circuits are designed to address tumor heterogeneity and limit antigen escape.
−Removed: The OR GATE functions by killing tumor cells that express any one of multiple antigens.
−Removed: Generally, current medicines are unable to address more than one target at a time and are thus susceptible to tumor evasion.
−Removed: Regulator Dial:
−Removed: Regulator Dial gene circuits are designed to enable the precise tuning of therapeutic activity from a cell or gene therapy product.
−Removed: For example, this can be implemented by regulating therapeutic payload expression in response to varying concentrations of FDA-approved drugs.
−Removed: Regulator Dials are expected to enable the exogenous regulation of next-generation cell and gene therapies even after they have been delivered in vivo.
−Removed: Existing cell and gene therapies cannot be modulated once they have been delivered into patients.
−Removed: Smart Sensor:
−Removed: A Smart Sensor is a gene circuit, or combination of gene circuits, designed to precisely detect distinct cell types or disease environments, and thus distinguish between the “disease state” and “healthy state.” For example, Smart Sensors can be engineered to detect whether certain conditions, or disease biomarkers, are present before responding with a specific therapeutic response.
−Removed: Conventional medicines are generally unable to dynamically change their behavior in response to cell or disease specific conditions.
−Removed: The rationale behind each gene circuit technology is explained in detail below:
−Removed: Multi-Arming gene circuits are designed to incorporate multiple payloads into a single cell or gene therapy product.
−Removed: These gene circuits are intended to activate various biological pathways in complementary ways to prevent diseases from evading single-target treatments, and thereby improve treatment efficacy.
−Removed: Existing combination therapies that target complex diseases require the application of multiple individual drugs, which is difficult due to research, clinical development, regulatory and pharmacology barriers.
−Removed: The Need for Targeting Multiple Biological Pathways
−Removed: Many diseases are difficult to treat because they result from the dysfunction of numerous biological pathways, or they evolve strategies to evade single-target therapies.
−Removed: Combination therapies involving multiple distinct drugs are being used to tackle this problem, but manufacturing, developing and delivering multiple individual drugs into the body is challenging.
−Removed: Our Gene Circuit Solution:
−Removed: We believe our Multi-Arming gene circuits can be used to create a single cell or gene therapy product candidate that includes multiple payloads capable of combating multiple disease pathways more effectively.
−Removed: Multi-Arming gene circuits can be controlled by any of our other gene circuit technologies, including Regulator Dials, Logic Gates and Smart Sensors, to achieve conditional therapeutic activity.
−Removed: Our Calibrated Release (cr) Technology
−Removed: Cytokines and other immune stimulatory proteins may be useful in overcoming the immunosuppressive TME in solid tumors by activating endogenous anti-tumor immune cells and to provide support for adoptive cell therapies.
−Removed: However, traditional approaches to use cytokines in combination with adoptive cell therapies have relied on systemic injection of cytokines or engineering the cell therapies themselves to secrete the cytokines or to display them on the cell surface.
−Removed: Systemic injection of cytokines has been challenging due to poor tumor penetration and the risk of systemic immune toxicity.
−Removed: Engineering cell therapies to secrete cytokines has the potential to activate endogenous immune cells, but these secreted cytokines may not provide optimal stimulation of the cell therapies themselves.
−Removed: Engineering cell therapies to display cytokines on the cell surface can stimulate the cell therapies themselves, but may not provide optimal activation of endogenous immune cells.
−Removed: To overcome these limitations, we have created a novel engineered protein technology called calibrated release (cr).
−Removed: Our cr engineered cytokines are engineered with a designed protease cleavage site.
−Removed: These cr cytokines are expressed by our engineered cells and are released from the cell in a calibrated fashion via a protease ubiquitously expressed by the cell, wherein the release rate is calibrated by engineering modifications to the protease cleavage site.
−Removed: We believe this platform is translatable to various proteins, including IL-15 and IL-12.
−Removed: We are using this approach to optimize IL-15 in our CAR–NK product candidates to simultaneously stimulate surrounding immune cells and promote CAR-NK cell expansion, persistence, and tumor killing.
−Removed: As shown in the figure below, crIL-15 is functional when cleaved and released into the supernatant, resulting in activation of pSTAT5 signaling in T cells from resting peripheral blood mononuclear cells or PBMCs.
−Removed: In the left panel below, comparable pSTAT5 induction was observed in T cells exposed to supernatant from engineered CAR-NK cells that expressed either crIL-15 or recombinant human IL-15 (rhIL-15), demonstrating benefits of crIL-15 in activating other immune cells.
−Removed: Furthermore, in the right panel, crIL-15 was shown to improve serials cancer cell killing with a 3-round serial killing assay.
−Removed: Our engineered SENTI CAR-NK cells armed with our crIL-15 or with rhIL-15, or unengineered NK cells were co-cultured with tumor cells, which were added at hour 0, hour 96, and hour 168, to repeatedly challenge the effector cells with new cancer target cells.
−Removed: While all three NK cells showed tumor cell killing at the first challenge, crIL-15 engineered CAR-NK cells retained cancer cell killing even at the third challenge in contrast to the remaining two conditions.
−Removed: We believe this data shows the potential of our calibrated release technology platform to functionally enhance the killing activity of CAR-NK cells in challenging conditions.
−Removed: Additionally, incorporating our proprietary crIL-15 onto our CAR-NK cells resulted in prolonged persistence, and increased viability and cell count in vitro compared to unengineered NK cells (viable cells detected for 3 weeks in vitro with crIL-15 CAR-NK vs < 1 week for unengineered NK cells).
−Removed: We are also leveraging our calibrated release technology for other cytokines, such as IL-12, where crIL-12 expression is modulated using a small molecule Regulator Dial gene circuit to control crIL-12 expression levels, with the goal of stimulating the immune system and overcome the challenges of immunosuppressive TME while potentially avoiding safety issues.
−Removed: Logic Gating gene circuits are designed to enable cell and gene therapies to control their therapeutic activity in response to the presence or absence of multiple disease biomarkers.
−Removed: This capability has the potential to enable more accurate and efficient targeting of heterogeneous diseased cells while sparing healthy ones.
−Removed: Our initial product candidates for oncology will utilize our NOT GATE and OR GATE gene circuit technology.
−Removed: Furthermore, we believe this technology can be utilized across a broad range of oncology indications.
−Removed: To this end, we have established a proprietary Tumor-Associated Antigen, or TAA, and Protective Antigen, or PA, Paired Discovery Platform as detailed later in the Tumor-Associated Antigen and Protective Antigen Paired Discovery Platform section to enable the expansion of our Logic Gating approach against novel Tumor-Associated Antigen and Protective Antigen pairs across multiple cancer indications.
−Removed: The Need for Precision Targeting
−Removed: The expression of a single CAR in T cells or NK cells can redirect them to kill cancer cells that express a specific surface antigen.
−Removed: This technology has led to breakthrough therapies for B cell malignancies and multiple myeloma, where targeting of tissue-lineage antigens – CD19 or B Cell Maturation Antigen, or BCMA – rather than Tumor-Associated Antigens, is tolerated.
−Removed: Beyond these initial applications, the lack of uniquely specific tumor antigens presents a great challenge because on-target, off-tumor toxicity to vital tissues significantly limits the cancer indications addressable by single-target CAR-NK or CAR-T therapies.
−Removed: Similar limitations are faced by monoclonal antibodies and antibody-drug conjugates that rely on a single target to distinguish cancer cells from healthy ones.
−Removed: Our Logic Gating Solution:
−Removed: The application of CAR-immune cells may be broadened to many cancer types if recognition of a Protective Antigen that is selectively expressed on healthy cells, but not on cancer cells, could selectively block killing against the healthy cells.
−Removed: We believe this feature enables a widened therapeutic window and aggressive treatment of cancers with the potential for enhanced efficacy and reduced risk of undesirable side effects, as well as the expansion of cell therapies into cancer indications where there are no ideal Tumor-Associated Antigens.
−Removed: We are currently leveraging our NOT GATE gene circuit technology in our SENTI-202 and SENTI-401 CAR-NK programs in liquid and solid tumors.
−Removed: Furthermore, we believe the NOT GATE has the potential to significantly increase the applicability of CAR-NK cells against a wide range of liquid and solid tumors that currently do not have ideal Tumor-Associated Antigen targets and are thus currently unaddressed.
−Removed: As shown in the figure below, we have engineered NK cells with a synthetic NOT GATE gene circuit, where an activating CAR, or aCAR, can drive the killing of cancer cells presenting an activating, Tumor-Associated Antigen, shown in green, while an inhibitory CAR, or iCAR, can suppress cytotoxicity against normal healthy cells that express both the activating Tumor-Associated Antigen and a Protective Antigen, shown in purple.
−Removed: Future Applications and Alternate Gene Circuits
−Removed: We believe the potentially enhanced precision enabled by our NOT GATE gene circuit technology may improve the therapeutic window, and thus the potential efficacy and safety, of our product candidates against the cancer types targeted by our pipeline.
−Removed: Furthermore, the NOT GATE has the potential to significantly increase the applicability of CAR-NK cells against a wide range of liquid and solid tumors that currently do not have ideal Tumor-Associated Antigen targets and are thus currently unaddressed.
−Removed: The Need for Targeting Multiple Antigens
−Removed: Many cancers are heterogeneous, making it difficult to treat them by only targeting a single antigen.
−Removed: For example, the development of targeted acute myeloid leukemia, or AML treatments is difficult due to more than 200 types of chromosome translocations and mutations having been identified in patients.
−Removed: Thus, therapies targeting a single AML-associated antigen are often insufficient to kill all of the tumor subsets, including both AML leukemic stem cells, or LSCs, and blasts.
−Removed: Consequently, most AML patients treated with these therapies die from disease relapse and progression due to incomplete therapeutic activity.
−Removed: Additionally, due to the highly mutagenic nature of cancer cells, targeting single antigens allows for cancers to more easily escape or acquire resistance to treatment.
−Removed: example, while recent triumphs of CD19-directed autologous CAR-T therapies have brought renewed hope to patients with relapsed/refractory B cell malignancies, up to 50% of patients with pre-B cell acute lymphoblastic leukemia, or ALL, suffer disease relapse within twelve months after treatment.
−Removed: Many of those patients who relapse toward the latter end of the twelve-month period have cancers that have been associated with loss of the CD19 epitope.
−Removed: These clinical observations demonstrate the potential benefit of developing therapeutics that are capable of simultaneously targeting multiple Tumor-Associated Antigens across heterogeneous cancers using OR GATE gene circuit technology.
−Removed: Our Logic Gating Solution:
−Removed: Our OR GATE gene circuits are designed to simultaneously target multiple Tumor-Associated Antigens.
−Removed: We are currently leveraging our OR GATE gene circuit technology in our SENTI-202 CAR-NK program for liquid tumors.
−Removed: Regulator Dial
−Removed: Our Regulator Dial gene circuits are designed to enable the precise tuning of therapeutic activity from a cell or gene therapy product.
−Removed: For example, this can be implemented by regulating therapeutic payload expression in response to varying concentrations of FDA-approved drugs.
−Removed: Regulator Dials are designed to enable the exogenous regulation of next-generation cell and gene therapies in vivo even after they have been delivered.
−Removed: We have generated numerous Regulator Dial gene circuits that have the potential to be controlled by a variety of FDA-approved small molecule oral drugs, and that are designed to implement various control behaviors, such as ON switches, OFF switches and rheostats.
−Removed: The Need for Dynamic Regulation
−Removed: Existing cell and gene therapies cannot be regulated once they are delivered into the patient.
−Removed: This lack of in vivo control makes it difficult to control dosing within the ideal therapeutic window.
−Removed: This problem makes it challenging to expand cell and gene therapies to many disease indications and to engineer these products to have increased potency and safety.
−Removed: As a result, gene therapies have focused on indications where constitutive expression is acceptable, rather than diseases where expression of the therapeutic payload must be regulated within a specific range or be toggled on and off over a period of time.
−Removed: As another example, CAR-T cell therapies for oncology have exhibited clinical toxicity due to lack of control post-infusion.
−Removed: The efficacy of adoptive cell therapies in solid tumors is hampered by the poor persistence and dysfunction of these cell therapies in the immunosuppressive TME.
−Removed: Inflammatory cytokines, such as IL-12, have been shown in preclinical studies to enhance CAR-mediated effector functions and stimulate the innate immune response to further support tumor killing.
−Removed: However, clinical trials involving systemic use of IL-12 have demonstrated severe unexpected toxicity, limiting its clinical application.
−Removed: Overexpressing IL-12 from adoptive T cell therapies using a poorly regulated promoter has also resulted in significant clinical toxicities.
−Removed: Beyond toxicity issues, persistent stimulation by inflammatory cytokines has been associated with cell exhaustion and may limit anti-tumor activity.
−Removed: Thus, we believe a mechanism to dynamically regulate cytokine production by armored CAR-immune cells could enable enhanced anti-tumor activity without triggering unacceptable levels of toxicity in patients.
−Removed: Our Gene Circuit Solution:
−Removed: Regulator Dial
−Removed: One example of our Regulator Dial gene circuit technology is a system designed to regulate gene expression through FDA-approved orally dosed nonstructural protein 3, or NS3, inhibitors.
−Removed: This type of Regulator Dial consists of a synthetic drug-regulated transcription factor and a synthetic promoter responsive to this regulated transcription factor.
−Removed: In the absence of the drug, the transcription factor is inactive, and no therapeutic protein is produced from the engineered cells.
−Removed: In the presence of the drug, the small molecule triggers expression of the therapeutic protein in a
−Removed: dose-dependent manner through which the Regulator Dial “computes” the level of induction based on the concentration of the drug.
−Removed: We have also examined the potential of our Regulator Dial gene circuits in vivo .
−Removed: Immune-deficient NSG mice received NK cells engineered with our Regulator Dial gene circuit, followed by dosing of the small molecule that controls release of IL-12.
−Removed: We measured circulating levels of IL-12 and found a correlation between increasing levels in response to the small molecule which could be elicited with repeat dosing.
−Removed: This data demonstrates the potential that crIL-12 expression from engineered NK cells can be regulated in a repeated ON/OFF/ON fashion through the GRZ small molecule.
−Removed: A Smart Sensor is a gene circuit, or combination of gene circuits, designed to precisely detect cell type or disease environments, and thus distinguish between the “disease state” and “healthy state.” For example, Smart Sensors can be engineered to detect whether certain conditions, or disease biomarkers, are present before responding with a specific therapeutic response.
−Removed: Conventional medicines are generally unable to dynamically change their behavior in response to cell or disease specific conditions.
−Removed: Diseases change over time and location in the body.
−Removed: Existing therapies are often unable to dynamically change their behavior in response to disease conditions or concentrate their activity only to specific places.
−Removed: Smart Sensors can be designed to sense diverse biomarkers that are specific to disease or cell states, including cell-surface antigens, soluble disease markers, metabolites, transcription factors, microRNAs and others.
−Removed: For example, we have created artificial receptors that are displayed on the surface of engineered cells and activate gene expression within these cells when they encounter specific cytokines or small molecule chemicals.
−Removed: We have also designed gene regulatory elements such as promoters and RNA elements that respond to specific intracellular signals, such as transcription factors and microRNAs.
−Removed: The Need for Novel Sensors in Smart Medicine
−Removed: Cell and gene therapies have long held out the promise of curing a myriad of diseases, including cancer and genetic disorders.
−Removed: These therapies are generally comprised of three components:
−Removed: (i) the vector, which is used to deliver the transgene into cells;
−Removed: (ii) the promoter, which is a regulatory DNA sequence that drives expression of the transgene;
−Removed: and (iii) a transgene, which is the therapeutic payload.
−Removed: While early successes in the field have led to recently approved gene therapies, it remains challenging to precisely target gene expression only in diseased cells.
−Removed: This is a significant limitation because many genetic disorders require controlled or targeted activity in certain cell types in order to correct diseases while preventing undesirable side effects.
−Removed: Similarly, in cancer gene therapy, it is important to achieve selective killing in cancer cells while sparing healthy tissues.
−Removed: Engineering viral vectors that are biased toward specific cell types is limited by the availability of a unique feature on the outside of the target cell that a viral vector can harness.
−Removed: Additionally, many of the promoters used in current gene therapies are not disease, cell or tissue specific and thus lack the ability to dynamically regulate therapeutic protein production in response to the disease state or location.
−Removed: Our Smart Sensors Solution:
−Removed: Cell Type or Cell State Specific Conditional Synthetic Promoters
−Removed: Our solution to address these limitations is to construct Smart Sensors that are selectively activated by cell type or cell state.
−Removed: For example, these Smart Sensors are synthetic promoters that sense internal control mechanisms that cells already possess, such as transcription factors.
−Removed: Transcription factors modulate regulatory elements encoded in the DNA sequence of promoters to direct gene transcription to occur in a specific cell type, or even a specific cell state.
−Removed: Selected Smart Sensor Proof-of-Concept Data
−Removed: Candidate sequences were chosen via bioinformatics analyses based on differentially active/expressed genomic sequences.
−Removed: We performed multiple rounds of functional screenings to build synthetic promoters with high and specific activity in the target cell line chosen.
−Removed: As shown below, we started with clonal screening of native promoters and enhancers (lower left of the graph).
−Removed: Based on the data from the first round, the sequences with the highest activity were chosen, and ablation studies were performed (middle portion of the graph).
−Removed: Finally, the most significant DNA fragments were grouped and matched in various combinations (with additional sequences derived from high throughput screening), to build synthetic promoters with the highest and most specific activity (upper right of the graph).
−Removed: We Believe Our Gene Circuits May Have Broad Applicability in Multiple Treatment Modalities and Disease Areas
−Removed: We believe that our gene circuit platform may have broad applicability across treatment modalities and disease areas.
−Removed: Treatment Modalities :
−Removed: Our gene circuit biological “software” can be used to program numerous cell and gene therapy products, or “hardware.” Specifically, these modalities include NK cells, T cells, TILs, stem cells including HSCs, in vivo gene therapy and mRNA.
−Removed: We have conducted research in multiple cell types and vector types, and the initial focus of our internal pipeline is implementing gene circuits within off-the-shelf CAR-NK cells.
−Removed: Disease Areas :
−Removed: Our gene circuits can be customized to address many aspects of disease biology.
−Removed: We have demonstrated and published on applications of gene circuits across many different in vivo disease models.
−Removed: Thus, we believe that our gene circuit platform technologies can be used against a broad range of diseases that span therapeutic areas such as oncology, immunology, genetic diseases, neurology, cardiology, metabolic diseases, ophthalmology and regenerative medicine.
−Removed: The following figure presents our perspective on how our gene circuit technologies can be utilized across modalities and corresponding therapeutic areas:
−Removed: We are advancing a broad pipeline of gene circuit-enabled product candidates focused on three distinct categories:
−Removed: (i) our internal pipeline consisting of off-the-shelf CAR-NK cell therapy programs for oncology indications, (ii) our partnered programs related to gene therapies for tissue-directed targets (Spark Therapeutics, Inc.) and (iii) our partnered programs related to cell therapies for regenerative medicines (BlueRock Therapeutics, Inc.).
−Removed: Our most advanced programs are from our internal pipeline of off-the-shelf CAR-NK programs under which we are pursuing the discovery and development of product candidates designed to improve the therapeutic outcome in certain oncology indications as outlined below:
−Removed: Our CAR-NK Cell Source
−Removed: Our preferred cell source for our off-the-shelf CAR-NK cell pipeline is peripheral blood NK cells because it allows us to immediately leverage an established supply chain, a mature GMP process, and extensive clinical experience to develop our next generation CAR-NK cell therapies as illustrated below.
−Removed: We have chosen to engineer NK cells with our gene circuits based on our belief that NK cells confer the following advantages in relation to other potential immune cell types in oncology:
−Removed: • Innate Killing:
−Removed: NK cells naturally carry multiple activating and inhibitory receptors that enable them to innately kill tumor cells while sparing healthy tissues.
−Removed: Furthermore, NK cells have been engineered with CARs to enhance their targeted killing activity.
−Removed: We leverage these features to create Logic Gated CAR-NKs, such as OR GATE CAR-NKs that enhance the killing of heterogeneous tumors and NOT GATE CAR-NKs that spare healthy cells from undesired toxicity and thereby potentially improve on- target, on-tumor killing.
−Removed: • Immune Activation:
−Removed: NK cells have been shown to support robust activation of anti-tumor immune pathways through pro-inflammatory cytokine and chemokine secretion.
−Removed: We leverage this feature with our Multi-Arming gene circuits to further improve their ability to trigger endogenous, complementary anti-tumor activity by engaging the rest of the tumor immunity cycle.
−Removed: • Validated Clinical Activity and Tolerability:
−Removed: Approximately 70 global peripheral blood derived off-the-shelf, as in healthy donor-derived, unengineered CAR-NK cells have been shown in the clinical setting to have the potential to promote anti-tumor activity along with relatively low risks of graft versus host disease, or GvHD, severe cytokine release syndrome, or CRS, and neurotoxicity.
−Removed: • Off-the-Shelf Manufacturing for Broad Patient Access:
−Removed: We have established proprietary protocols to derive NK cells from healthy donors, manufacture them at scale with a projected low cost, and cryopreserve them with high retained viability post-thaw.
−Removed: As a result, we believe that CAR-NK cells have the potential to be broadly accessible to patients as they may be delivered rapidly to patients in an off-the-shelf manner and in an outpatient setting.
+Added: We are a clinical-stage biotechnology company developing next-generation cell and gene therapies engineered with our gene circuit platform technologies for patients living with incurable diseases.
+Added: Our mission is to create a new generation of smarter medicines that outsmart complex diseases using novel and unprecedented approaches.
+Added: To accomplish this mission, we have built a synthetic biology platform that we believe may enable us to program next-generation cell and gene therapies with gene circuits.
+Added: These gene circuits, which we created from novel and proprietary combinations of DNA sequences, are designed to reprogram cells with biological logic to sense inputs, compute decisions and respond to their respective cellular environments.
+Added: Using gene circuits, our product candidates are designed to precisely kill cancer cells, spare healthy cells, increase specificity to target cells and control the expression of drugs even after administration.
+Added: We are applying our gene circuit technologies to develop a pipeline of medicines that use off-the-shelf chimeric antigen receptor natural killer (“CAR-NK”) cells with the goal of addressing major challenges and providing potentially lifesaving treatments for people living with cancer.
+Added: Our lead product candidates utilize off-the-shelf healthy adult donor derived NK cells to create CAR-NK cells outfitted with Gene Circuit technologies in several oncology indications with high unmet need.
+Added: We expect to initiate clinical trials of two of our product candidates in 2024.
+Added: Our lead product candidate SENTI-202, a potentially first-in-class Logic Gated off-the-shelf CAR-NK cell therapy for the treatment of acute myeloid leukemia (“AML”), received clearance of its Investigational New Drug application (“IND”) by the U.S.
+Added: Food and Drug Administration (“FDA”) in December 2023, and we anticipate dosing the first patient with SENTI-202 in the second quarter of 2024.
+Added: Our second clinical development program SENTI-301A, a multi-armed off-the-shelf healthy donor derived CAR-NK cell therapy, is expected to begin in the second quarter of 2024.
+Added: We are primarily focused on off-the-shelf CAR-NK cell therapy programs for oncology indications.
+Added: Our lead product candidate, SENTI-202, is on track to begin dosing patients in a Phase 1 clinical trial for the treatment of hematological malignancies including AML in the second quarter of 2024.
+Added: We also have three partnered programs:
+Added: (i) our SENTI-301A pipeline program for the treatment of HCC is partnered in China with Celest Therapeutics, (ii) our partnered programs related to gene therapies for tissue-directed targets with Spark Therapeutics, Inc.
+Added: (“Spark Therapeutics”) and (iii) our partnered programs related to cell therapies for regenerative medicines with BlueRock
+Added: Therapeutics, Inc.
+Added: (“BlueRock Therapeutics”).
+Added: Our most advanced programs, SENTI-202 and SENTI-301A, originate from our internal pipeline of off-the-shelf CAR-NK programs.
+Added: Our goal is to maintain and build upon our leadership position in the cell and gene therapy landscape utilizing our proprietary gene circuit technology and synthetic biology expertise.
+Added: We are pursuing this goal by leveraging our unique approach to programming gene circuits, which we believe may be broadly applicable toward engineering optimal efficacy, precision and control into cell or gene-based medicines, rapidly advancing our pipeline of off-the-shelf CAR-NK cell therapies for oncology indications and establishing strategic collaborations/partnerships to support our non-oncology programs and manufacturing.
+Added: We plan to develop and, if approved, commercialize allogeneic cell therapy products for the treatment of cancer.
+Added: We believe achieving this goal will play a critical role in addressing major challenges in oncology and providing potentially lifesaving treatments for people living with cancer.
+Added: Key elements of our strategy include:
+Added: • Advance internal pipeline of off-the-shelf CAR-NK cell therapies for oncology indications through the clinical development of our lead product candidate, SENTI-202;
+Added: ▪ Advance the clinical development of the SENTI-301A program work through a strategic partnership with Celest Therapeutics;
+Added: • Leverage partnering to support non-oncology indications, including our ongoing partnerships with Spark Therapeutics to develop gene therapies for tissue-directed targets, and with BlueRock Therapeutics to develop cell therapies for regenerative medicines;
+Added: • Establish additional value-creating collaborations to access the full potential of our technology in additional modalities including T cells, tumor infiltrating lymphocytes (TILs), stem cells including induced Pluripotent Stem Cells (iPSCs) and Hematopoietic Stem Cells (HSCs), in vivo gene therapy such as adeno associated virus (AAV), and messenger ribonucleic acid (mRNA).
SENTI-202 for the Potential Treatment of Hematologic Malignancies including Acute Myeloid Leukemia
−Removed: We are developing our SENTI-202 product candidate as a Logic Gated (OR + NOT) off-the-shelf CAR-NK cell therapy designed to target and eliminate cancer cells while sparing the healthy bone marrow.
−Removed: We are engineering SENTI-202 to express a bivalent CAR as an OR GATE directed against the Tumor-Associated Antigens, FLT3 and/or CD33, where one or both are expressed in 95% of AML patients.
−Removed: FLT3 is highly expressed on LSCs, while CD33 is highly expressed on AML blasts.
−Removed: AML is a heterogeneous disease composed of both AML LSCs and blasts.
−Removed: Thus, we believe that targeting FLT3 OR CD33 will enhance the overall killing activity against diseased cells in AML.
−Removed: However, FLT3 is also expressed on HSCs in the bone marrow.
−Removed: In order to spare FLT3-expressing healthy HSCs,
−Removed: we have further engineered SENTI-202 with a NOT GATE gene circuit consisting of an iCAR targeted against EMCN.
−Removed: EMCN is a Protective Antigen with high expression on HSCs and no or low expression on AML LSCs and blasts identified using our robust paired tumor-healthy target identification paradigm as outlined in the Tumor-Associated Antigen and Protective Antigen Paired Discovery Platform section.
−Removed: We believe this NOT GATE gene circuit could allow SENTI-202 to eliminate LSCs that cause relapse while preserving the patient’s healthy HSCs.
−Removed: Further, SENTI-202 is engineered to express our proprietary crIL-15 to simultaneously stimulate surrounding immune cells and promote NK cell expansion, persistence and tumor killing.
−Removed: This proprietary product profile has the potential to drive towards deeper and longer remissions for AML by enabling killing of diverse AML cells while sparing HSCs that regenerate the blood and the immune systems.
−Removed: Acute Myeloid Leukemia:
+Added: Our lead product candidate SENTI-202 is a potentially first-in-class Logic Gated off-the-shelf CAR-NK cell therapy designed to selectively target and eliminate CD33 and/or FLT3 expressing hematologic malignancies,
+Added: including AML, while sparing healthy bone marrow cells.
+Added: We are on track to begin clinical trials in the United States and Australia in 2024 with the first patient anticipated to be dosed in the second quarter of 2024.
+Added: SENTI-202 has been designed to incorporate three chimeric proteins using a Logic Gated gene circuit and delivered through a single retrovirus.
+Added: The first chimeric protein that we have engineered SENTI-202 to express is a bivalent CAR as an OR GATE directed against the tumor-associated antigens (“TAAs”), CD33 and/or FLT3, where one or both are expressed in 95% of AML patients.
+Added: CD33 is typically found on bulk AML blasts and FLT3 is typically found on leukemic stem cells (“LSCs”).
+Added: LSCs are a rare sub-population of AML cells that possess stem cell like properties of self-renewal and drug resistance, contributing to relapse and poor prognosis after treatment.
+Added: We believe that targeting FLT3 in addition to CD33 could result in deeper and more prolonged remissions.
+Added: In order to protect the healthy cells that express FLT3, the second chimeric protein we have engineered SENTI-202 to include is an inhibitory CAR (“iCAR”), which we refer to as a NOT Gate, to protect the healthy cells from potential on-target/off-tumor toxicity.
+Added: The iCAR is designed to recognize the healthy cell surface protein endomucin (EMCN).
+Added: EMCN was chosen as the protective antigen using a multi-step unbiased bioinformatics pipeline designed to identify a cell surface antigen specifically expressed on healthy HSCs but absent on AML tumor cells including both blasts and LSCs.
+Added: EMCN is expressed on healthy cells, specifically HSCs (and early progenitors) which we believe will confer protection from an activating CAR (“aCAR”)-mediated cytotoxicity on EMCN-expressing cells, even if those cells express CD33 and/or FLT3, thus expected to impart selectivity to SENTI-202 anti-cancer cytotoxicity.
+Added: The final protein in the SENTI-202 Gene Circuit is a calibrated release interleukin-15 (“crIL15”), an engineered protein technology that is designed with a protease cleavage site to be able to express and release cytokines from the cell in a calibrated fashion via a protease ubiquitously expressed by the cell.
+Added: We believe that crIL15 stimulates surrounding immune cells and promotes CAR-NK cell expansion, persistence, and tumor killing activity.
+Added: The SENTI-202 gene circuit design was systematically optimized through evaluation of over 500 constructs by initially optimizing each component separately and then together.
+Added: The following figure illustrates the design of SENTI-202 Logic Gating gene circuits to kill AML LSCs and blasts, while sparing healthy HSCs via (CD33 OR FLT3) NOT EMCN logic.
+Added: Acute Myeloid Leukemia (AML):
an Unmet Medical Need
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Patients with CD33 and/or FLT3 expressing malignancies, which includes myeloid malignancies such as AML, have a grim prognosis and a high unmet need.
−Removed: At diagnosis, the 5-year survival for patients with AML is 30.5% in the US (SEER 2022).
−Removed: As noted, AML is typically a disease of the elderly with a median age of diagnosis being approximately 65 years.
−Removed: The treatment at diagnosis for the majority of patients who cannot tolerate the toxicities of intensive chemotherapy, ie, older, unfit patients, includes either hypomethylating agents or low-dose cytosine arabinoside (Ara C, also known as cytarabine), as monotherapy or in combination with venetoclax, or best supportive care (NCCN AML 2022).
−Removed: In younger, fitter patients, the goal of treatment is to induce a complete remission (CR) with intensive chemotherapy and consolidate with allogeneic hematopoietic cell transplantation (HCT).
+Added: AML is typically a disease of the elderly with a median age of diagnosis being approximately 65 years.
+Added: The treatment at diagnosis for the majority of patients who cannot tolerate the toxicities of intensive chemotherapy includes either hypomethylating agents or low-dose cytosine arabinoside (“Ara-C”, also known as cytarabine), as monotherapy or in combination with venetoclax, or best supportive care.
+Added: In patients who can tolerate more intensive treatments, the goal of treatment is to induce a complete remission (“CR”) with intensive chemotherapy and consolidate with allogeneic hematopoietic cell transplantation (“HCT”).
Treatment is combined with the respective targeted agents in patients who have CD33‑positive disease or a FLT3‑mutated disease (Mylotarg USPI;
Xospata USPI).
−Removed: Other therapies for AML include targeted
−Removed: agents for the minority of patients with either isocitrate dehydrogenase (IDH)-1 or-2 mutated disease (Tibsovo USPI;
−Removed: Idhifa 2017).
−Removed: Despite these therapies being recently approved for patients with AML, the prognosis continues to be poor with the majority of patients refractory to or relapsing from front-line therapy and a median overall survival (OS) of 5 months at relapse (Brandwein 2020).
−Removed: Development of targeted AML treatments is difficult due to the fact that the disease is highly heterogeneous, with more than 200 types of chromosome translocations and mutations having been identified in AML patients.
−Removed: Therapies targeting a single Tumor-Associated Antigen are therefore often insufficient to kill all of the cancer cell subsets in AML, leading to eventual disease relapse.
+Added: Other therapies for AML include targeted agents for the minority of patients with either isocitrate dehydrogenase (IDH)-1 or IDH-2 mutated disease.
+Added: Despite these therapies being recently approved for patients with AML, the prognosis continues to be poor with the majority of patients refractory to or relapsing from front-line therapy and a median overall survival (OS) of 5 months at relapse.
+Added: Development of targeted AML treatments is difficult because the disease is highly heterogeneous.
+Added: More than 200 types of chromosome translocations and mutations have been identified in AML patients.
+Added: Therapies targeting a single TAA are therefore often insufficient to kill all the cancer cell subsets in AML, leading to eventual disease relapse.
To drive patients into deeper remissions and prevent relapses, therapies designed to target multiple AML antigens are needed.
Additionally, recent studies suggest relapse is associated with the less targeted AML subpopulation of LSCs.
−Removed: Thus, the development of therapies targeting AML LSCs is sorely needed, but this has been challenging because LSC targets are often expressed on healthy cells, such as HSCs, leading to on-target, off-tumor treatment-induced toxicities.
+Added: Thus, the development of therapies targeting AML LSCs is sorely needed, but this has been
+Added: challenging because LSC targets are often expressed on healthy cells, such as HSCs, leading to on-target, off-tumor treatment-induced toxicities.
CAR Cell Therapy for AML
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These described challenges also extend to other potential AML therapeutic modalities, such as antibodies and bispecific T cell engagers.
−Removed: SENTI-202 Approach to AML
−Removed: Our SENTI-202 off-the-shelf CAR-NK cells are engineered with gene circuits that are designed to enable identification of cancerous versus healthy cells using NOT GATE + OR GATE logic decisions, and potentially improved persistence and more durable antitumor functions.
−Removed: SENTI-202 combines two different Logic Gates, and crIL-15 expression, as follows:
−Removed: An iCAR NOT GATE gene circuit to prevent CAR-mediated killing of cells expressing either FLT3 or CD33 and a Protective Antigen, EMCN.
−Removed: The EMCN iCAR is intended to suppress CAR-NK cell cytotoxicity against healthy HSCs, reducing the risk of potential life-threatening bone marrow toxicity and potentially increasing the therapeutic window and on-target, on-tumor activity.
−Removed: An aCAR OR GATE gene circuit to activate CAR-mediated killing of AML cells expressing either or both of the Tumor-Associated Antigens FLT3 and CD33, thus increasing the targeting of both AML LSCs and blasts.
−Removed: A crIL-15 gene circuit to simultaneously stimulate surrounding immune cells and promote NK cell expansion, persistence and tumor killing.
−Removed: The following figure illustrates the design of SENTI-202 Logic Gating gene circuits to kill AML LSCs and blasts, while sparing healthy HSCs via (FLT3 OR CD33) NOT EMCN logic.
−Removed: Based on the medical community’s substantial clinical experience from autologous and allogeneic-bone marrow transplantations.
−Removed: Using our proprietary Tumor-Associated Antigen and Protective Antigen Paired Discovery Platform, we identified FLT3 and CD33 as desirable TAAs for an OR GATE gene circuit to have the potential for comprehensive CAR-mediated killing of AML, including AML LSCs and blasts.
−Removed: As well as the corresponding PA, EMCN, for application in AML.
SENTI-202 Preclinical Data
−Removed: As shown below, in comparison to unengineered NK cells, SENTI-202 CAR-NK cells exhibited increased and more consistent cell killing across a variety of primary patient AML or MDS blasts, or AML leukemia stem cells in vitro.
−Removed: Similarly, in a luciferase tagged MV4-11 AML xenogenic tumor model in immunocompromised mice, we observed decreased bioluminescence indicating decrease in AML tumor burden, and increased survival when the mice were treated with a single dose of SENTI-202 compared to unengineered NK cells or vehicle control.
−Removed: Using the same proprietary transcriptomics and proteomics-based bioinformatics methodology discussed earlier, we identified EMCN as a target antigen that is highly expressed on healthy HSCs but not on AML LSCs or blasts.
−Removed: This validates EMCN’s potential as a Protective Antigen to protect HSCs from potential on-target, off-tumor CAR-NK mediated toxicity.
−Removed: The rationale for utilizing EMCN as the Protective Antigen is further bolstered by a previous finding in the literature that identified EMCN as a marker of the key cell type for repopulating the blood and immune systems.
−Removed: Upon selection of EMCN as our primary Protective Antigen target, we next incorporated binders for the FLT3 activating CAR (aCAR) and the EMCN Protective Antigen into our internal NOT GATE (iCAR) discovery and development platform in order to best identify the optimal iCAR architecture for the SENTI-202 program.
−Removed: Using different FLT3 NOT EMCN CAR-NK cells (primary NK cells engineered to co-express the same FLT3 aCAR with one of dozens of different proprietary EMCN iCARs), we performed an in vitro cytotoxicity protection assay screen using target cells that expressed only the FLT3 Tumor-Associated Antigen and not the EMCN PA or target cells that expressed both the FLT3 Tumor-Associated Antigen and the EMCN PA.
−Removed: This latter target cell population should be protected from aCAR-mediated killing if the particular iCAR is functional.
−Removed: Using this approach, we identified multiple functional EMCN iCAR architectures that enabled robust target cell killing in the absence of the PA (model cancer cells) and provided significant antigen-dependent target cell protection in the presence of the EMCN PA (model healthy cells).
−Removed: AML cell line or healthy primary hematopoietic stem cells (HSC) were co-cultured with either a CAR-NK cell that only expressed the activating CAR (i.e.
−Removed: CD33 and/or FLT3 CAR) or SENTI-202 (i.e., with the activating CAR and the EMCN-recognising inhibitory CAR).
−Removed: We saw identical killing activity of the leukemia cells with both CAR-NKs.
−Removed: We saw significant selective protection of healthy HSC when exposed to SENTI-202 demonstrating in vitro protection of healthy cells from our proprietary EMCN targeting NOT gate.
−Removed: We observed greater than 90% protection of model “healthy” cells in vivo.
−Removed: We injected 1:1:1 ratio of effector cells with model leukemia cells that expressed CD33 and FLT3 target antigens, and model “healthy” cells that expressed CD33, FLT3 and the protective EMCN antigen.
−Removed: The three effector cells used in this experiment were either unengineered NK cells, CAR-NK cells with just the CD33 and/or FLT3 activating CAR, and SENTI-202.
−Removed: We observed that only in the SENTI-202 group, there was selective killing of the leukemia cells and sparing of the model “healthy” cells after greater than 3 weeks in vivo.
+Added: In preclinical studies, as shown below, in comparison to non-engineered NK cells, SENTI-202 CAR-NK cells exhibited increased and more consistent cell killing across a variety of primary patient AML or MDS blasts, or AML leukemia stem cells in vitro .
+Added: Similarly, in a luciferase tagged MV4-11 AML xenogenic tumor model in immunocompromised mice, decreased bioluminescence indicating decrease in AML tumor burden, and increased survival were observed when the mice were treated with a single dose of SENTI-202 compared to non-engineered NK cells or vehicle control.
+Added: AML cell line or healthy primary HSCs were co-cultured with either a CAR-NK cell that only expressed the aCAR (i.e.
+Added: CD33 and/or FLT3 CAR) or SENTI-202 (i.e., with the aCAR and the EMCN-recognizing iCAR).
+Added: Preclinical data also demonstrated identical killing activity of the leukemia cells with both CAR-NKs and significant selective protection of healthy HSC when exposed to SENTI-202 demonstrating in vitro protection of healthy cells from our proprietary EMCN targeting NOT gate.
+Added: In preclinical studies, 1:1:1 ratio of effector cells were injected with model leukemia cells that expressed CD33 and FLT3 target antigens, and model “healthy” cells that expressed CD33, FLT3 and the protective EMCN antigen.
+Added: The three effector cells used in this experiment were either non-engineered NK cells, CAR-NK cells with just the CD33 and/or FLT3 aCAR, and SENTI-202.
+Added: Results demonstrated that in the SENTI-202 group, leukemia cells were selectively killed while the model “healthy” cells were spared after greater than 3 weeks in vivo .
In the other two groups, there was non-selective killing of both the leukemia and the “healthy” cells.
Development Plan and Key Next Steps for SENTI-202
−Removed: We have demonstrated, in preclinical studies, the functionality of the full gene circuit components of SENTI-202, and we selected our lead development candidate in 2022.
−Removed: We plan to submit an IND application in the second half of 2023 to support the clinical evaluation of SENTI-202.
−Removed: Our planned Phase 1 study aims to evaluate SENTI-202 in patients with R/R CD33 and /or FLT3 positive hematologic malignancies including AML.
−Removed: We plan to administer multiple doses of study drug following standard fludarabine/cyclophosphamide based lymphodepletion as “Cycles” of study treatment.
+Added: In December 2023, our IND application for evaluation of SENTI-202 in patients with hematologic malignancies was cleared by the FDA, and we expect to start dosing patients in a Phase 1 clinical trial in the second quarter of 2024.
+Added: Our Phase 1 clinical trial aims to evaluate SENTI-202 in patients with relapsed/refractory CD33 and/or FLT3 positive hematologic malignancies including AML.
+Added: Key features of the study design that are intended to increase the potential for deep, durable remissions for AML patients include:
+Added: • Disease-specific lymphodepletion (“LD”) :
+Added: We plan to administer three doses of SENTI-202 following a disease-specific LD regimen known as fludarabine (flu) and cytarabine (ara-C), or flu/ara-C.
+Added: The use of flu/ara-C is an NCCN Category 2a chemotherapy regimen for patients with relapse-refractory AML.
+Added: In large Phase 3 randomized trials, where flu/ara-C with or without idarubicin, another chemotherapeutic agent approved for AML, has been administered as control arm chemotherapy, the regimen was well tolerated with mild non-hematologic toxicities, most commonly mucositis, and true CR rates of ~10% (cumulative CR rates including CR with incomplete bone marrow recovery of ~ 20%) have been reported.
+Added: Flu/ara-C LD conditioning followed by multiple doses of NK cell therapies have been well-tolerated, with CR rates in the range of 50-60%.
+Added: Further, preclinical data reveals that pre-treatment with ara-C increases CD33 and FLT3 expression of a CD33/FLT3-negative AML cell line (e.g., KG-1a), leading to enhanced SENTI-202-mediated cytotoxicity in vitro, which could contribute to potential clinical synergistic anti-AML activity along with the additive debulking of AML blasts prior to administering SENTI-202 to potentially achieve deep responses.
+Added: 72h Ara-C Treatment Significantly Upregulated CD33 and FLT3 Expression in KG-1a Cells
+Added: **p < 0.01, *** p < 0.001
+Added: Ara-C Pre-Treated KG-1a Cells Sensitized to SENTI-202-Mediated Cytotoxicity
+Added: *** p < 0.001, **** p < 0.0001
+Added: • Multi-dose and multi-cycle administration :
+Added: The starting dose of SENTI-202, as approved by the FDA in our IND, will be 1 billion CAR-NK cells.
+Added: The Phase 1 study will evaluate three doses of 1 billion CAR-NK cells, each dose administered a week apart, after LD, followed by bone marrow assessment at the end of the 4 th week (and these 4 weeks make up one cycle).
At the end of a cycle, we will evaluate both efficacy and safety.
Patients may be eligible to receive additional such cycles based on both tumor response and tolerability of treatment.
−Removed: The study will evaluate 2-3 dose levels of cells and evaluate efficacy and pharmacodynamic markers in addition to standard Phase 1 objectives of safety, pharmacokinetics and dose finding.
−Removed: National Cancer Institute (NCI) Contract to Support Development of SENTI-202
−Removed: In September 2021, we were awarded funding from the National Cancer Institute of the National Institutes of Health in the form of a Small Business Innovation Research (SBIR) contract to support further development of SENTI-202 for AML towards clinical development.
−Removed: The Direct to Phase II SBIR contract will provide us with approximately $1.99 million in federal funding for the SENTI-202 program over two years.
−Removed: SENTI-401 for the Potential Treatment of CRC and Other Solid Tumors
−Removed: Through our SENTI-401 program, we are pursuing the development of a Logic Gated off-the-shelf CAR-NK cell therapy product candidate designed to more precisely target and eliminate colorectal cancer, or CRC cells while sparing healthy cells elsewhere in the body.
−Removed: We are engineering NK cells to express a CAR directed against CEA, which is highly overexpressed in 85% to 90% of colorectal cancer samples but is also expressed in epithelial cells in healthy tissues.
−Removed: CEA is also expressed in other solid tumors, including lung, breast and gastric cancers.
−Removed: The expression profile of CEA in both tumor and healthy cells has resulted in on-target, off-tumor toxicities by other CEA-targeted therapies in clinical development, thus limiting their clinical success.
−Removed: To address this challenge, we are engineering NK cells with a NOT GATE implemented via an iCAR targeted against an epithelial cell Protective Antigen called VSIG2.
−Removed: Thus, the SENTI-401 program’s Logic Gating is intended to more effectively treat CRC patients by targeting a well-known Tumor-Associated Antigen, CEA, and widen the therapeutic window by preventing killing when CEA appears on healthy cells that also express the VSIG2 Protective Antigen.
−Removed: We are also engineering SENTI-401 to express a combination of potent immune effectors, including our proprietary crIL-15 protein to simultaneously stimulate surrounding immune cells and promote NK cell expansion, persistence and
−Removed: tumor killing, and an additional undisclosed potent immune effector to potentially enhance therapeutic function in solid tumors.
−Removed: Colorectal Cancer:
−Removed: an Unmet Medical Need
−Removed: CRC accounts for approximately 10% of all annually diagnosed cancers and cancer-related deaths worldwide and is the second and third most commonly diagnosed cancer in women and men, respectively.
−Removed: The incidence of CRC worldwide is predicted to increase to 2.5 million new cases in 2035.
−Removed: Of new colorectal cancer diagnoses, 20% of patients present with metastatic disease and another 25% who present with localized disease will later develop metastases.
−Removed: Among patients with metastatic colorectal cancer, approximately 70% to 75% of patients survive after one year of their initial diagnosis;
−Removed: however, the five-year survival rate is less than 20% despite multiple lines of treatment, including combinations of chemotherapy and targeted therapies.
−Removed: SENTI-401 Approach to CRC
−Removed: CEA is a tumor-associated protein overexpressed in many epithelial cancers, most notably in colorectal cancer.
−Removed: However, it is also expressed in a variety of normal epithelial cells throughout the gastrointestinal tract.
−Removed: Bioinformatics analyses of RNA sequencing data collected from over 9,500 tumor and 8,500 healthy tissue samples showed that CEACAM5, one of the main isoforms of CEA, is overexpressed across many cancer types, especially colorectal cancer.
−Removed: CEACAM5 expression is also found in healthy organs, including tissues in the gastrointestinal tract and lungs.
−Removed: Cancer immunotherapies using vaccines and antibodies targeting CEA are actively being investigated in the clinical setting.
−Removed: However, recent clinical studies have shown dose-limiting on-target, off-tumor toxicities in these healthy tissues that also express CEA.
−Removed: We are pursuing the development of a potential SENTI-401 product candidate to overcome the challenges associated with targeting the CEA Tumor-Associated Antigen that is present on both tumor and healthy cells.
−Removed: mitigate the potential risk of on-target, off-tumor toxicity, we are designing our SENTI-401 product candidate with a NOT GATE gene circuit to differentiate between cancerous and healthy cells.
−Removed: Specifically, SENTI-401 incorporates the following gene circuits:
−Removed: An iCAR with a NOT GATE gene circuit that restricts CAR-mediated cell killing to CRC cells that express CEA but not healthy cells that express an epithelial cell Protective Antigen, VSIG2.
−Removed: This NOT GATE is designed to potentially reduce on-target, off-tumor toxicity, thus potentially enabling more effective treatment of CEA-expressing cancers.
−Removed: An aCAR that targets CEA, a well-characterized antigen that is overexpressed in many cancers, including CRC.
−Removed: A crIL-15 gene circuit to simultaneously stimulate surrounding immune cells and promote NK cell expansion, persistence and tumor killing.
−Removed: An IL-21 potent immune effector to potentially enhance therapeutic function in solid tumors.
−Removed: SENTI-401 Supporting Data
−Removed: Our CEA aCAR-NK cells significantly reduced tumor burden in a luciferase tagged human CRC xenograft (LoVo) tumor model in vivo especially with the addition of both crIL-15 and IL21 as shown below in terms of both enhanced survival and decreased tumor burden (as shown by decreased bioluminescence in the mouse photographs).
−Removed: Hence, we have incorporated both cytokines into our planned SENTI-401 circuit.
−Removed: Further, incorporation of IL21 along with crIL15 and the activating CAR resulted in enhanced serial killing with exposure to 3 rounds of tumor cells even in the presence of an inhibitory cytokine TGF-B.
−Removed: We believe this could potentially enhance the ability of SENTI-401 to be active in solid tumors by overcoming a relatively immuno-suppressive tumor milieu.
−Removed: Utilization of the VISG2 protein as our NOT GATE gene circuit Protective Antigen
−Removed: We have developed a robust Tumor-Associated Antigen and Protective Antigen Paired Discovery Platform for the development of NOT GATE CAR-NK therapies.
−Removed: Using this approach, we have identified genes that are differentially expressed in healthy versus tumor tissues and selected antigen candidates based on-target expression in tissues, subcellular localization, antigen topology or presence of extracellular domains and antibody availability.
−Removed: To protect healthy epithelial cells that also express CEA, we identified VSIG2 as a Protective Antigen candidate.
−Removed: VSIG2 exhibits a favorable pattern of expression in the membrane of epithelial cells of the gastrointestinal tract and lungs, which are CEA-positive tissues that are most at risk of on-target, off-tumor toxicity.
−Removed: We further validated the expression of VSIG2 using immunohistochemistry, or IHC, in healthy tissues and confirmed the lack of expression in primary CRC tumor tissue samples.
−Removed: Specifically, IHC analyses of colorectal tumor tissues and healthy colon epithelium demonstrated that CEA is expressed in both healthy samples, as shown in the upper left of the figure below, and tumor samples, as shown in the lower left of the figure below.
−Removed: In addition, the Protective Antigen VSIG2
−Removed: is only expressed in healthy colon epithelium, as shown in the upper right of the figure below, and not in tumor samples, as shown in the lower right of the figure below.
−Removed: Leveraging these findings, we have constructed VSIG2 iCARs that showed selective NOT GATE functions in vitro.
−Removed: As shown in the figure below, we engineered NK cells to express both our CEA-aCAR and VSIG2-iCAR to evaluate the protective function of the VSIG2 iCAR.
−Removed: When model “healthy” cells, which were engineered to express VSIG2 in addition to CEA, were exposed to CAR-NK cells that had both the aCAR and the iCAR, nearly 100% protection was observed in vitro.
−Removed: Furthermore, killing of cancer cells that only expressed CEA+ was unimpaired in the presence of the iCAR.
−Removed: Development Plan and Key Next Steps for SENTI-401
−Removed: SENTI-401 is our first planned IND for solid tumors and in 2023, we plan to present preclinical data from our SENTI-401 program at key scientific conferences.
+Added: The study will evaluate both 1 billion and 1.5 billion CAR-NK cell doses and evaluate efficacy and pharmacodynamic markers in addition to standard Phase 1 objectives of safety, pharmacokinetics and dose finding.
+Added: • Adaptive design and seamless transition to pivotal :
+Added: The Phase 1 study design also includes the ability to evaluate an ultra-low dose IL2 cohort, which could further augment SENTI-202 activity and persistence.
+Added: The study is designed to seamlessly expand and rapidly transition to a pivotal study assuming the data supports the expansion.
SENTI-301A for the Potential Treatment of HCC and Other Solid Tumors
−Removed: Through our SENTI-301A program we have pursued the development of a Multi-Armed off-the-shelf CAR-NK cell therapy product candidate for the treatment of advanced hepatocellular carcinoma, or HCC.
−Removed: This program requires the engineering of NK cells to target GPC3, which is highly expressed in 70% to 90% of HCCs and has low or no expression on normal adult tissues.
+Added: Our product program SENTI-301A is a multi-armed off-the-shelf healthy donor derived CAR-NK cell therapy designed for the treatment of advanced GPC3 positive tumors.
+Added: In partnership with Celest Therapeutics, a product candidate for the SENTI-301A program is in clinical development in China in patients with hepatocellular carcinoma (“HCC”).
+Added: We anticipate that Celest Therapeutics will begin dosing patients with product candidate SENTI-301A in the second quarter of 2024.
+Added: This program requires engineering NK cells with a CAR to target GPC3, which is highly expressed in 70% to 90% of HCCs and has low or no expression on normal adult tissues.
SENTI-301A is armed with our proprietary crIL-15 gene circuit, intended to simultaneously stimulate surrounding immune cells and promote NK cell expansion, persistence, and tumor killing.
+Added: The cell source for SENTI-301A is peripheral blood NK cells.
+Added: The following figure illustrates the design of SENTI-301A.
Hepatocellular Carcinoma:
1 unchanged sentence
HCC accounts for approximately 90% of primary liver cancers and represents a large unmet medical need due to the lack of effective treatment options.
−Removed: Globally, it is the sixth most commonly diagnosed cancer, and the fourth leading cause of cancer deaths.
+Added: Globally, it is the sixth most diagnosed cancer, and the fourth leading cause of cancer deaths.
In the United States, the rate of death from liver cancer increased by 43% from 7.2 to 10.3 deaths per 100,000 people between 2000 and 2016.
Frequently, HCC develops in patients with liver disease such as chronic hepatitis B or C virus, alcoholic liver disease or non-alcoholic steatohepatitis.
+Added: In China, where we have partnered with Celest Therapeutics, there were approximately 400,000 new cases of HCC in 2020, accounting for approximately 65% of worldwide liver cancer diagnoses.
Available therapies are only modestly efficacious and the mortality rate in advanced HCC remains high despite recent improvements in treatment options.
5 unchanged sentences
crIL-15 to simultaneously stimulate surrounding immune cells and promote NK cell expansion, and persistence, and tumor killing.
−Removed: GPC3 is a Tumor-Associated Antigen expressed in approximately 70% to 90% of human HCCs and in 29-54% of other solid tumors, but not expressed in healthy liver tissue or other human organs after birth.
+Added: GPC3 is a TAA expressed in approximately 70% to 90% of human HCCs and in 29-54% of other solid tumors (including lung, ovarian, and thyroid), but not expressed in healthy liver tissue or other human organs after birth.
GPC3 has previously been clinically evaluated as a therapeutic target for immunotherapy in HCC.
1 unchanged sentence
Functionally, GPC3 is associated with the control of cell division and growth regulation.
−Removed: We built GPC3 CAR constructs to redirect NK-mediated cytotoxicity against advanced HCC using a GPC3 binder that associates to the membrane proximal region of the GPC3 protein.
+Added: We engineered GPC3 CAR constructs to redirect NK-mediated cytotoxicity against advanced HCC using a GPC3 binder that associates to the membrane proximal region of the GPC3 protein.
IL-15 has been shown to improve NK cell persistence in vivo and maintain cytotoxicity.
2 unchanged sentences
Development Plan and Key Next Steps for SENTI-301A
−Removed: We have demonstrated in preclinical studies the full gene circuit components of SENTI-301A In January 2023, we paused development of SENTI-301A for financial, not scientific considerations, and we are planning to pursue potential partnering opportunities or future clinical development, especially in territories within Asia where HCC is more prevalent than in the United States.
−Removed: Accordingly, we are actively pursuing strategic geographic partnerships for the clinical development of SENTI-301A.
−Removed: Our Gene Circuit Application Outside of Oncology
−Removed: In addition to our off-the-shelf CAR-NK programs, we have discovery stage programs focused on gene therapies for tissue-directed targets and cell therapies for regenerative medicines.
−Removed: In particular, we have entered into collaborations with Spark Therapeutics, Inc (subsidiary of Roche Holding AG) for the design of Smart Sensors for disease- and tissue-specific gene therapy, and with Bluerock Therapeutics LP (subsidiary of Bayer AG) for the use of Smart Sensors and Regulator Dials for regenerative medicines.
−Removed: The following pipeline chart depicts our discovery stage programs under the two collaborations.
+Added: In November 2023, we announced our strategic collaboration with Celest Therapeutics for the clinical development of product candidate SENTI-301A to treat solid tumors in China.
+Added: Through this collaboration, Celest Therapeutics will lead clinical development, operations, and manufacturing for the advancement of product candidate SENTI-301A with technical support from Senti.
+Added: Celest Therapeutics plans to enroll patients initially through a pilot trial in mainland China and expects to enroll the first patient in the second quarter of 2024.
+Added: Celest Therapeutics and Senti have the option to expand clinical development of SENTI-301A to Hong Kong, Macau and Taiwan.
+Added: We retain all commercialization rights outside of mainland China, Hong Kong, Macau, and Taiwan for SENTI-301A.
+Added: The pilot study aims to evaluate the product candidate SENTI-301A in patients with GPC3 positive advanced HCC in China.
+Added: Key features of the study design include:
+Added: • Lymphodepletion (LD) before product administration :
+Added: Celest Therapeutics plans to administer 3 doses of product candidate SENTI-301A following fludarabine/cyclophosphamide lymphodepletion which has been widely used to support the expansion of NK cells in prior clinical trials.
+Added: • Multi-dose and multi-cycle administration :
+Added: The starting dose of product candidate SENTI-301A will be 1 billion CAR NK cells.
+Added: The pilot study will evaluate three doses of 1 billion CAR-NK cells each.
+Added: Each individual dose will be administered one week after LD.
+Added: After treatment, at the end of the fourth week, tumor response assessment will be performed utilizing imaging and biomarkers.
+Added: At the end of a cycle, Celest Therapeutics will evaluate both efficacy and safety.
+Added: Patients may be eligible to receive additional cycles based on both tumor response and tolerability of treatment.
+Added: The study will evaluate 2 dose levels of cells and evaluate efficacy and pharmacodynamic markers in addition to standard Phase 1 objectives of safety, pharmacokinetics and dose finding.
+Added: Our CAR-NK Cell Source
+Added: Our preferred cell source for SENTI-202 and SENTI-301A, our off-the-shelf CAR-NK cell product programs, is peripheral blood NK cells because it allows us to immediately leverage an established supply chain, a mature GMP process, and extensive clinical experience to develop our next generation CAR-NK cell therapies as described below.
+Added: Natural killer (“NK”) cells are an integral part of the innate immune system and comprise 5 to 20% of circulating lymphocytes.
+Added: They play a key immune surveillance role by recognizing and killing malignantly or virally transformed cells by directed release of lytic granules or by inducing death receptor-mediated apoptosis.
+Added: Unlike T cells, NK cells possess intrinsic or endogenous anti-cancer activity without engineering or specific antigen priming.
+Added: NK cells sample potential target cells on a cell-by-cell basis to recognize transformed cells based on the balance of activating and inhibitory signals received by the NK cell from the individual target cell.
+Added: Other key differences of NK cells compared to T cells, which we believe make NK cells attractive candidates as cellular backbones for novel anti-cancer therapies, include:
+Added: • Lack of explosive proliferation and outpouring of cytokines when exposed to target cells, have shown to result in an improved safety profile and to allow repeat dosing due to a general lack of chimeric antigen receptor
+Added: (“CAR”) T cell-like adverse events such as cytokine release syndrome (“CRS”) or immune effector cell-associated neurotoxicity syndrome (“ICANS”),
+Added: • Lack of a T cell receptor (“TCR”) in NK cells have shown to result in inability to initiate graft-versus-host disease (GvHD), enabling NK cells to be used in allogeneic therapies without need for additional genetic manipulation, and
+Added: • Allogeneic NK cells have shown to have a finite lifespan of approximately 2-3 weeks in patients when administered after LD due to clearance from host immune cell recovery, leading to decreased potential for long term side effects such as second primary malignancies.
+Added: Over 900 patients have safely received NK cell-based therapies since 2005.
+Added: This includes over 800 patients across more than 30 single institution academic studies who received non-engineered allogeneic NK cell therapy, the majority from healthy adult donors, and nearly 100 patients who have received CAR NK cells via single and multi-center early phase trials.
+Added: NK cell products are generally well tolerated and show clinical efficacy as a stand-alone treatment, with 20-60% CR rate on average across a wide variety of oncological conditions, including in patients with AML.
+Added: This clinical activity was enhanced under several different conditions:
+Added: 1) when the NK cells had been engineered with CARs.
+Added: 2) cultured with cytokines.
+Added: 3) after ‘activation’ by co-culturing with K562 cell lines (themselves modified to express cytokines), 4) when NK cell doses increased, and 5) for AML patients when fludarabine/ara-C (flu/ara-C) LD was used as lymphodepleting conditioning.
+Added: Key limitations of the clinical experience with NK cells in AML patients include limited persistence of the infused cells, short durability of the observed responses, and immune evasion of LSCs.
+Added: Other challenges include manufacturing, with culturing and cryopreserving NK cells precluding higher or multiple doses.
+Added: We also believe that our proprietary donor selection process could confer us unique advantages.
+Added: The process begins with healthy donors screened by our vendor(s) via their protocol(s) for various viruses and ability to undergo leukapheresis.
+Added: Senti then performs a manufacturing suitability assessment of a research use only leukopak from the healthy donors selected by the vendor(s).
+Added: The results are then utilized to specify which healthy donors we would like to request for clinical grade leukopaks to be used in our GMP manufacturing process.
+Added: Gene Circuits Could Enhance Precision, Control, and Activity of Cell & Gene Therapies
+Added: Our Gene Circuit Solutions
+Added: In our pursuit to create a new generation of smarter medicines, we have built a toolbox of proprietary gene circuit platform technologies that we believe may enhance the risk benefit paradigm of cell and gene therapy products.
+Added: Four core categories of gene circuits comprise our gene circuit platform:
+Added: Multi-Arming, Logic Gating, Regulator Dials and Smart Sensors.
+Added: Each of our gene circuit platform technologies is designed to confer greater clinical and therapeutic activity, precision and control to cell and gene therapies.
+Added: We believe that our core gene circuit platform technologies are the foundation of smarter medicines that are designed to precisely kill diseased cells, spare healthy cells, increase specificity to target cells and control the expression of drugs even after administration.
+Added: These technologies can be categorized as follows:
+Added: Multi-Arming:
+Added: Multi-Arming gene circuits are designed to incorporate multiple payloads into a single cell or gene therapy product.
+Added: These gene circuits are intended to activate various biological pathways in complementary ways to prevent diseases from evading single-target treatments, and thereby potentially improve treatment efficacy.
+Added: Existing combination therapies that target complex diseases require the application of multiple individual drugs, which is difficult due to research, clinical development, regulatory and pharmacology barriers.
+Added: Logic Gating:
+Added: Logic Gating gene circuits are designed to enable cell and gene therapies to control their therapeutic activity in response to the presence or absence of multiple disease biomarkers.
+Added: Below are examples of Logic Gates applied to cancer, although Logic Gating may also be applied to various other disease indications.
+Added: NOT GATE gene circuits are designed to widen the therapeutic window by enabling effective killing of cancer cells while preserving healthy cells.
+Added: The NOT GATE functions by recognizing Protective Antigens (PAs), or antigens that are selectively expressed on healthy cells and not on cancer cells, thus limiting on-target, off-tumor killing.
+Added: By protecting healthy cells, the NOT GATE has the potential to enable more effective on-target, on-tumor killing of tumor cells that express TAAs.
+Added: Generally, existing cancer drugs target only a single antigen, which means they can only be effectively and safely used in situations where that antigen is uniquely expressed on tumors and not in healthy cells, or where the on- target, off-tumor effects are tolerable.
+Added: OR GATE gene circuits are designed to address tumor heterogeneity and limit antigen escape.
+Added: The OR GATE functions by killing tumor cells that express any one of multiple antigens.
+Added: Generally, current medicines are unable to address more than one target at a time and are thus susceptible to tumor evasion.
+Added: Regulator Dial:
+Added: Regulator Dial gene circuits are designed to enable the precise tuning of therapeutic activity from a cell or gene therapy product.
+Added: For example, this can be implemented by regulating therapeutic payload expression in response to varying concentrations of FDA-approved drugs.
+Added: Regulator Dials are expected to enable the exogenous regulation of next-generation cell and gene therapies even after they have been delivered in vivo.
+Added: Existing cell and gene therapies cannot be modulated once they have been delivered into patients.
+Added: Smart Sensor:
+Added: A Smart Sensor is a gene circuit, or combination of gene circuits, designed to precisely detect distinct cell types or disease environments, and thus distinguish between the “disease state” and “healthy state.” For example, Smart Sensors can be engineered to detect whether certain conditions, or disease biomarkers, are present before responding with a specific therapeutic response.
+Added: Conventional medicines are generally unable to dynamically change their behavior in response to cell or disease specific conditions.
+Added: We Believe Our Gene Circuits May Have Broad Applicability in Multiple Treatment Modalities and Disease Areas
+Added: We believe that our gene circuit platform may have broad applicability across treatment modalities and disease areas, and is also potentially applicable toward engineering optimal efficacy, precision and control into cell or gene-based medicines.
+Added: Treatment Modalities :
+Added: Our gene circuit platform technologies are designed to be applied in a modality-agnostic manner, with applicability to NK cells, T cells, TILs, stem cells including iPSCs and HSCs, in vivo gene therapy such as AAV, and mRNA.
+Added: We have conducted research in multiple cell types and vector types, and the initial focus of our internal pipeline utilizes off-the-shelf CAR-NK cells outfitted with Gene Circuit technologies in oncology indications.
+Added: Disease Areas :
+Added: Our gene circuits can be customized to address many aspects of disease biology.
+Added: We have demonstrated and published applications of gene circuits across many different in vivo disease models.
+Added: Thus, we believe that our gene circuit platform technologies can be used against a broad range of diseases that span therapeutic areas such as oncology, immunology, genetic diseases, neurology, cardiology, metabolic diseases, ophthalmology and regenerative medicine.
+Added: The following figure presents our perspective on how our gene circuit technologies can be utilized across modalities and corresponding therapeutic areas:
Portfolio Expansion Opportunities
−Removed: Our Discovery Stage Programs
−Removed: We believe our gene circuits can be readily adapted to new disease contexts to enable a variety of additional CAR-NK product candidates that address important cancers.
−Removed: For example, there are additional opportunities for the application of the NOT GATE gene circuit toward other solid and/or liquid tumor indications beyond SENTI-401.
−Removed: Toward that end, we have developed a Tumor-Associated Antigen and Protective Antigen Paired Discovery Platform to identify future opportunities.
−Removed: Our platform has the potential to enable the development of multiple product candidates that harness the full breadth of our gene circuit platform beyond Logic Gating and Multi-Arming of off-the-shelf CAR-NK cells within oncology.
+Added: We have developed a proprietary, versatile, and robust internal research engine to enable development and adaptation of our gene circuits to address broad set of new disease and therapeutic modality challenges:
+Added: We believe that our REVEAL TM platform enables us to effectively explore innumerable application opportunities for gene circuits and efficiently optimize best-in-class solutions.
+Added: Opportunities include, but are not limited to:
+Added: (i) the application of the NOT GATE gene circuit toward new solid and/or liquid tumor CAR-NK or CAR-T cell therapies, (ii) the application of the Multi-Arming gene circuit to enhance and power new solid and/or liquid tumor CAR or TCR based cell therapies (iii) the development of promoters that are multi-fold stronger than current commonly used promoter benchmarks for various cell types, and (iv) cell-type and cell-state specific promoters for gene and cell therapies.
+Added: We believe our platform can enable the development of multiple product candidates that harness the full breadth of our gene circuit platform beyond Logic Gating and Multi-Arming of CAR or TCR based cell therapies within oncology.
Our additional discovery efforts are focused on a diverse set of cell and gene therapy applications outside of oncology.
−Removed: In particular, we have entered into collaborations with Spark Therapeutics, Inc.
−Removed: (subsidiary of Roche Holding AG) for the design of Smart Sensors for disease- and tissue-specific gene therapy, and with Bluerock Therapeutics, Inc.
−Removed: (subsidiary of Bayer AG) for the use of Smart Sensors and Regulator Dials for regenerative medicines.
+Added: We have entered into collaborations with Spark Therapeutics (subsidiary of Roche Holding AG) for the design of Smart Sensors for disease- and tissue-specific gene therapy, and with Bluerock Therapeutics (subsidiary of Bayer AG) for the use of Smart Sensors and Regulator Dials for regenerative medicines.
Tumor-Associated Antigen and Protective Antigen Paired Discovery Platform
−Removed: We have developed a proprietary Tumor-Associated Antigen and Protective Antigen Paired Discovery Platform to select and validate NOT GATE antigen candidates, as shown in the figure below.
−Removed: We have built a generalizable bioinformatics pipeline that uses RNA transcriptomics data to discover and prioritize tumor and healthy tissue Protective Antigens.
−Removed: We identify Tumor-Associated Antigens that are highly expressed in cancer cells with as little healthy tissue expression as possible, for example Tumor-Associated Antigen A in the figure below.
−Removed: We then identify healthy tissue selective Protective Antigens, for example Protective Antigen E in the figure below, that can protect those healthy tissues that express the Tumor-Associated Antigens, for example Tissues 2 and 5 in the figure below.
−Removed: This process looks at differences in Protective Antigen gene expression in healthy versus tumor tissue.
−Removed: Leads are selected based on the co-expression of Tumor-Associated Antigens and Protective Antigens in healthy tissues, the localization of the Protective Antigens to the cell surface, Protective Antigen topology (presence of extracellular domain) and Protective Antigen-specific antibody availability.
−Removed: Prioritized Tumor-Associated Antigen and Protective Antigen pairs are further validated in primary cancer and primary healthy tissue samples.
−Removed: We leveraged this platform to identify the Protective Antigen targets for the SENTI-202 and SENTI-401 programs, thus demonstrating our ability to target both liquid and solid tumors.
+Added: We have developed a proprietary TAA and PA paired discovery platform to select and validate NOT GATE antigen candidates, as shown in the figure below.
+Added: We have built a generalizable bioinformatics pipeline that uses RNA transcriptomics data to discover and prioritize tumor and healthy tissue PAs.
+Added: We identify TAAs that are highly expressed in cancer cells with minimal healthy tissue expression (antigen A in figure below).
+Added: We then identify healthy tissue selective PAs (antigen E in figure below) that can protect those healthy tissues that express the TAAs (tissues 2 and 5 below).
+Added: This process evaluates differences in PA gene expression in healthy versus tumor tissue.
+Added: Leads are selected based on the co-expression of TAAs and PAs in healthy tissues, the localization of the PAs to the cell surface, PA topology (presence of extracellular domain) and PA-specific antibody availability.
+Added: Prioritized TAA and PA pairs are further validated in primary cancer and primary healthy tissue samples.
+Added: We leveraged this platform to identify PA targets for the SENTI-202 and other internal programs, thus demonstrating our ability to target both liquid and solid tumors.
This approach allows us to potentially expand our NOT GATE approach to additional cancer indications in which existing single-target approaches, such as monoclonal antibodies, antibody-drug conjugates and single-target CAR cells, are inadequate due to a lack of specificity for cancer cells.
Manufacturing
−Removed: Manufacturing capabilities are central to our business strategy, because they can enable us to control the quality and supply of our off-the-shelf CAR-NK cell therapies for clinical studies and ultimately commercialization.
−Removed: A key advantage of off-the-shelf cell therapies, versus autologous products that use each patient’s own cells, is the ability to manufacture large batches of drug product from healthy donor cells that can be produced in advance of clinical use, and then stored in frozen vials.
−Removed: Upon commercialization, we expect to be able to make our cell therapies, if approved, broadly accessible in an off-the-shelf manner to cancer patients.
−Removed: Critical aspects of the cell manufacturing process include the ability to perform four key steps in the CAR-NK cell manufacturing process:
−Removed: Source, Isolate and Bank Purified NK Cells as Starting Cells.
−Removed: Starting Cells are obtained from enriching and isolating NK cells from qualified healthy donors.
−Removed: Purified NK cells are subsequently cryopreserved and characterized for consistent performance, including assays for cell phenotype, transduction efficiency, cell expansion capability and anti-tumor cytotoxicity.
−Removed: For our initial SENTI-202, SENTI-401, and SENTI-301A product candidates, we plan to derive Starting Cells from leukapheresis products collected from qualified healthy donors.
−Removed: From each leukapheresis collection, we intend to isolate and cryopreserve hundreds of millions of Starting Cells to support multiple product production batches.
−Removed: We believe that peripheral blood derived leukapheresis products are an attractive starting material source due to (i) a mature and validated commercial supply chain, (ii) the large number of purified NK cells per collection and (iii) our ability to characterize the NK cells prior to initiation of manufacturing.
−Removed: An analysis of over a dozen recent isolations performed from different healthy donors demonstrated that our process achieved greater than 95% NK cell purity, greater than 90% viability and up to 500 million NK cells per collection.
−Removed: We select for preferred donors with high expansion potential in our CAR-NK process, which allows us to generate ~70 trillion NK cells from a single donor collection, as shown in the figures below.
−Removed: Genetically Engineer Starting Cells with Gene Circuits.
−Removed: We genetically modify our NK cells through a viral vector transduction process focused on enhancing gene circuit expression while minimizing impacts on compromising cell viability or cell expansion.
−Removed: our CAR-NK products, the Starting Cells are first thawed and activated.
−Removed: On a specific day post activation, the activated cells undergo our vector transduction process to genetically incorporate our gene circuits.
−Removed: The figures below show that transduction of our activated Starting Cells did not reduce cell expansion rate and provided superior cancer cell killing compared to unengineered cells.
−Removed: Expand and Scale CAR-NK Cells.
−Removed: Our expansion process is designed to generate large numbers of final product doses per manufacturing batch.
−Removed: As shown in the figures below, our current process has consistently produced greater than 6,000-fold expansion of CAR-NK cells in a 21 day process with high harvest recovery and viability, achieving a planned clinical manufacturing scale of hundreds of patient doses per a single manufacturing batch.
−Removed: We are developing additional
−Removed: technologies and processes to further enhance NK cell expansion for commercial manufacturing, including alternative methods for cell activation and expansion using perfusion bioreactors.
−Removed: Formulate and Cryopreserve CAR-NK Cells.
−Removed: For freezing and distribution, we intend to formulate and cryopreserve our final product to retain viability, persistence and cytotoxic function post-thaw for off-the-shelf use.
−Removed: Each batch of CAR-NK cells will be filled into vials and cryopreserved for long term storage.
−Removed: The CAR-NK cell product candidates will be shipped in vials to clinical sites, where they will be thawed and infused on demand.
−Removed: We have demonstrated that cryopreserved CAR-NK cells can retain key functional properties required for cancer treatment, including stable transgene expression for over one month.
−Removed: As shown below, our cryopreserved CAR-NK cells retained viability and anti-tumor functions in both in vitro and in vivo models of AML:
−Removed: Technical Expertise and Facilities for Clinical and Commercial Manufacturing
−Removed: Our corporate headquarters is located in South San Francisco, CA, where we lease approximately 40,000 square feet of research and development and corporate office space.
−Removed: In this location, we have approximately 10,000 square feet dedicated to manufacturing development labs.
−Removed: We have established research and development teams with extensive experience in cell and gene therapy manufacturing operations, including vector process development, cell process development, analytical development, quality control and quality assurance.
−Removed: In June 2021, we signed a lease agreement for a property in Alameda, California with approximately 92,000 square feet for development as a state-of-the-art Current Good Manufacturing Practices, or cGMP, facility to support clinical and commercial-scale manufacturing of multiple off-the-shelf CAR-NK cell product candidates.
−Removed: This manufacturing facility is designed as a customized end-to-end manufacturing solution to give us the ability to isolate NK cells, engineer these cells with proprietary gene circuits, perform cell culture expansion in large batches, and cryopreserve and store the final cGMP products.
−Removed: In January 2023, we initiated the technology transfer of SENTI-202 to our cGMP manufacturing facility as part of our goal to provide clinical-scale manufacturing for off-the-shelf CAR-NK cell product candidates.
−Removed: We anticipate that this facility will be suitable to support initial clinical trials for our lead product candidates.
−Removed: We plan to leverage the latest cell therapy manufacturing technologies as we strive to optimize quality, maximize scalability and minimize cost.
−Removed: Our off-the-shelf production process and proprietary manufacturing capabilities are central to our business strategy of maintaining control over the quality and supply of our present and future product candidates for off-the-shelf CAR-NK cell therapies.
−Removed: In addition, we believe that our proprietary manufacturing process enables an anticipated cost in line with competitive off-the-shelf production process estimates.
−Removed: Continued advancements in cell culture scale and process efficiencies may further reduce this cost over time.
−Removed: In addition, we may also leverage our manufacturing facility to expand the application of our gene circuit technology to biomanufacturing in partnership with one or more third parties.
−Removed: See the section titled “Potential Collaboration Related to Gene Circuits and GMP Manufacturing.”
+Added: In August 2023, we announced the sale of our manufacturing assets and a sublease of our 92,000 square foot manufacturing facility to a private equity group, Celadon Partners, who created a new independent contract manufacturing organization for cell and gene therapy, and synthetic biology biofoundry called GeneFab, LLC (“GeneFab”).
+Added: In connection with the transaction, we are entitled to receive total consideration of $37.8 million before the end of 2025, of which $18.9 million was due at closing and was netted against prepayment owed by us for manufacturing and research activities to GeneFab.
+Added: The remaining consideration of $18.9 million will be received in installments during 2024 and 2025, subject to satisfaction of certain conditions.
+Added: We also received $8 million in manufacturing services credit and subleased our 92,000 square foot good manufacturing practice (“cGMP”) facility in Alameda, CA to GeneFab.
+Added: The transaction has allowed us to focus on advancing our oncology programs into the clinic.
+Added: GeneFab will conduct the clinical manufacturing of our CAR-NK pipeline in the United States, including SENTI-202, through a service contract.
+Added: Our Material Agreements
Exclusive/Co-Exclusive Patent License Agreement with the National Cancer Institute for FLT3 Technology
In July 2020, we entered into an Exclusive/Co-Exclusive Patent License Agreement, as amended, or the NCI FLT3 Agreement, with the U.S.
−Removed: Department of Health and Human Services, as represented by the National Cancer Institute, or the NCI, under which the NCI granted us a worldwide, royalty-bearing, sublicensable license under the NCI’s patent rights related to FLT3-targeting chimeric antigen receptor, or CAR, technology (i) exclusively for the development of a universal or split CAR-based immunotherapy using T-cells or NK cells transduced with lentiviral vectors or other retroviral vectors, depending on the cell type, for the prophylaxis or treatment of cancers expressing FMS-like tyrosine kinase 3, or FLT3, where the CAR construct binds to specific domains and (ii) co-exclusively, with a third party, for the development of a multi-specific FLT3 CAR-based immunotherapy or FLT3-specific regulated or switch or Logic Gated CAR-based immunotherapy using T-cells or NK cells transduced with lentiviral vectors or other retroviral vectors, depending on the cell type, for the prophylaxis or treatment of FLT3-expressing cancers, where the CAR construct contains specific domains, in each case of (i) and (ii), to make and have made, use and have used, sell and have sold, offer to sell and import products covered by the licensed patent rights and to practice and have practiced processes covered by the licensed patent rights.
+Added: Department of Health and Human Services, as represented by the National Cancer Institute, or the NCI, under which the NCI granted us a worldwide, royalty-bearing, sublicensable license under the NCI’s patent rights related to FLT3-targeting chimeric antigen receptor, or CAR, technology (i) exclusively for the development of a universal or split CAR-based immunotherapy using T-cells or NK cells transduced with lentiviral vectors or other retroviral vectors, depending on the cell type, for the prophylaxis or treatment of cancers expressing FMS-like tyrosine kinase 3, or FLT3, where the CAR construct binds to specific domains and (ii) co-exclusively, with a third party, for the development of a multi-specific FLT3 CAR-based immunotherapy or FLT3-specific regulated or switch or Logic Gated CAR-based immunotherapy using T-cells or NK cells transduced with lentiviral vectors or other retroviral vectors, depending on the cell type, for the prophylaxis or treatment of FLT3-expressing cancers, where the CAR construct contains specific domains, in each case of (i) and (ii), to make and have made, use and have used, sell and have sold, offer to sell and import products covered by the licensed patent rights and to
+Added: practice and have practiced processes covered by the licensed patent rights.
In addition to the co-exclusive rights held by a third party, the foregoing license is subject to (a) certain rights of the United States government, including an irrevocable, non-exclusive, non-transferable, royalty-free license for the government to practice all licensed patent rights throughout the world and (b) the NCI’s reserved rights to grant a non-exclusive license to practice the licensed patent rights for purposes of internal research (and not for purposes of commercial manufacture or distribution) at an academic or corporate facility.
−Removed: Pursuant to the NCI FLT3 Agreement, we must use commercially reasonable efforts to adhere to a commercial development plan, including by achieving certain specified development and regulatory milestones by certain dates, provided that we may request to extend the timelines of such milestones, which the NCI shall not unreasonably deny if the request is supported by a reasonable showing of our diligent performance under the commercial development
+Added: Pursuant to the NCI FLT3 Agreement, we must use commercially reasonable efforts to adhere to a commercial development plan, including by achieving certain specified development and regulatory milestones by certain dates, provided that we may request to extend the timelines of such milestones, which the NCI shall not unreasonably deny if the request is supported by a reasonable showing of our diligent performance under the commercial development plan.
Upon the first commercial sale of a licensed product or process, we must also use commercially reasonable efforts to make the licensed product or process reasonably accessible to the United States public.
12 unchanged sentences
Department of Health and Human Services, as represented by the NCI, under which the NCI granted us an exclusive, royalty-bearing, sublicensable, worldwide license under the NCI’s patent rights related to CD33 targeting CAR technology to make and have made, use and have used, sell and have sold, offer to sell and import products covered by the licensed patent rights and to practice and have practiced processes covered by the licensed patent rights, for the development of a CD33-specific logic-gated CAR-based immunotherapy using autologous human T cells transduced with lentiviral vectors or off-the-shelf human NK cells transduced with retroviral vectors for the prophylaxis or treatment of CD33-expressing cancers.
−Removed: The foregoing license is subject to (i) certain rights of the United States government, including an irrevocable, non-exclusive, nontransferable, royalty-free license for the government to practice all licensed patent rights throughout the world and (ii) the NCI’s reserved rights to grant a non-exclusive license to practice the licensed patent rights for purposes of internal research (and not for purposes of commercial manufacture or distribution) at an academic or corporate facility.
+Added: The foregoing license is subject to (i) certain rights of the United States government, including an irrevocable, non-exclusive, nontransferable, royalty-free license for the government to practice all licensed patent rights throughout the world and (ii) the NCI’s reserved rights to grant a
+Added: non-exclusive license to practice the licensed patent rights for purposes of internal research (and not for purposes of commercial manufacture or distribution) at an academic or corporate facility.
Pursuant to the NCI CD33 Agreement, we must use commercially reasonable efforts to adhere to a commercial development plan, including by achieving certain specified development and regulatory milestones by certain dates, provided that we may request to extend the timelines of such milestones, which the NCI shall not unreasonably deny if the request is supported by a reasonable showing of our diligent performance under the commercial development plan.
11 unchanged sentences
Research Collaboration and License Agreement with Spark Therapeutics, Inc.
−Removed: In April 2021, we entered into a Research Collaboration and License Agreement, or the Spark Agreement, with Spark Therapeutics, Inc., or Spark.
−Removed: Under the Spark Agreement, we engaged in a collaborative research program with Spark to design, build and test synthetic promoters that are intended to have each one of five sets of desired characteristics, or promoter profiles.
−Removed: Spark is obligated to reimburse us for our costs and expenses incurred in connection with the conduct of the research program.
−Removed: Upon completion of work under the research program for a particular promoter profile, Spark may select and designate, subject to a specified maximum, a certain number of synthetic promoters that are designed, built and tested or identified by us under the research program with respect to such promoter profiles as optioned promoters.
−Removed: On a promoter profile-by-promoter-profile basis, for each optioned promoters, Spark will have the right to obtain an exclusive, royalty-bearing, sublicensable, worldwide license under our intellectual property rights to develop, manufacture, commercialize and otherwise exploit, for the cure, treatment, palliation, prevention or diagnosis of specified indications, or a licensed field, in vivo gene therapy products incorporating such applicable optioned promoter with respect to such promoter profile and is directed towards specific cell types in the central nervous system, eye, or liver.
−Removed: Spark may exercise its option for any optioned promoter prior to the expiration of the applicable evaluation period.
−Removed: After exercise of an option, Spark will be responsible for all development, manufacture, commercialization and exploitation in the licensed field, at its own cost and expense, of all in vivo gene therapy products containing an applicable licensed promoter, and we will retain the right to develop, manufacture, commercialize and exploit other products that incorporate the licensed promoters as well as in vivo gene therapy products that incorporate the licensed promoters for uses outside the licensed field.
−Removed: If Spark does not exercise an option for a particular promoter profile prior to the expiration of the evaluation period for such promoter profile, we will retain all rights to the synthetic promoters developed under the Spark Agreement without any further obligations to Spark for such promoter profile.
−Removed: Pursuant to the Spark Agreement, we received an upfront payment from Spark of $3 million.
−Removed: If Spark exercises an option for a particular promoter profile, it will be required to pay us an option exercise fee in the low to mid-single digit millions.
−Removed: For each licensed promoter-containing in vivo gene therapy product, or licensed product, developed and commercialized by Spark or its affiliates or sublicensees, we are eligible to receive development, regulatory and commercialization milestone payments from Spark up to an aggregate dollar amount in the mid teens millions, and sales milestone payments from Spark up to an aggregate dollar amount in the low hundred millions.
−Removed: In total, we are potentially eligible to receive upfront, opt-in and milestone payments exceeding $645 million if Spark exercises its options for all five promoter profiles and Spark, its affiliates and its sublicensees successfully develop and commercialize five licensed products;
−Removed: we will be eligible to receive additional milestone payments if additional licensed products are developed and commercialized by Spark, its affiliates and its sublicensees.
−Removed: Further, Spark will be obligated to pay us royalties in the low-single digits percentage on net sales of each licensed product sold by Spark, its affiliates and its sublicensees, subject to specified reductions and offsets.
−Removed: Spark’s obligation to pay royalties to us will expire for each licensed product when certain licensed patents and regulatory exclusivities have expired in the country of sale and a minimum number of years has elapsed since the first commercial sale of such licensed product in such country.
−Removed: The Spark Agreement will expire at the end of the last evaluation period if Spark does not exercise any of its options.
−Removed: If Spark exercises at least one option, then the Spark Agreement will expire, on a licensed product-by- licensed product and country-by-country basis, upon the expiration of Spark’s royalty obligation for such licensed product in such country.
−Removed: Spark may terminate the Spark Agreement in its entirety, or on a promoter profile-by-promoter profile or licensed promoter-by-licensed promoter basis, following a specified notice period.
+Added: In April 2021, we entered into a Research Collaboration and License Agreement, or the Spark Agreement, with Spark Therapeutics.
+Added: Under the Spark Agreement, we engaged in a collaborative research program with Spark Therapeutics to design, build and test synthetic promoters that are intended to have each one of five sets of desired characteristics, or promoter profiles.
+Added: Spark Therapeutics is obligated to reimburse us for our costs and expenses incurred in connection with the conduct of the research program.
+Added: Upon completion of work under the research program for a particular promoter profile, Spark Therapeutics may select and designate, subject to a specified maximum, a certain number of synthetic promoters that are designed, built and tested or identified by us under the research program with respect to such promoter profiles as optioned promoters.
+Added: On a promoter profile-by-promoter-profile basis, for each optioned promoters, Spark Therapeutics will have the right to obtain an exclusive, royalty-bearing, sublicensable, worldwide license under our intellectual property rights to develop, manufacture, commercialize and otherwise exploit, for the cure, treatment, palliation, prevention or diagnosis of specified indications, or a licensed field, in vivo gene therapy products incorporating such applicable optioned promoter with respect to such promoter profile and is directed towards specific cell types in the central nervous system, eye, or
+Added: Spark Therapeutics may exercise its option for any optioned promoter prior to the expiration of the applicable evaluation period.
+Added: After exercise of an option, Spark Therapeutics will be responsible for all development, manufacture, commercialization and exploitation in the licensed field, at its own cost and expense, of all in vivo gene therapy products containing an applicable licensed promoter, and we will retain the right to develop, manufacture, commercialize and exploit other products that incorporate the licensed promoters as well as in vivo gene therapy products that incorporate the licensed promoters for uses outside the licensed field.
+Added: If Spark Therapeutics does not exercise an option for a particular promoter profile prior to the expiration of the evaluation period for such promoter profile, we will retain all rights to the synthetic promoters developed under the Spark Agreement without any further obligations to Spark Therapeutics for such promoter profile.
+Added: Pursuant to the Spark Agreement, we received an upfront payment from Spark Therapeutics of $3 million.
+Added: If Spark Therapeutics exercises an option for a particular promoter profile, it will be required to pay us an option exercise fee in the low to mid-single digit millions.
+Added: For each licensed promoter-containing in vivo gene therapy product, or licensed product, developed and commercialized by Spark Therapeutics or its affiliates or sublicensees, we are eligible to receive development, regulatory and commercialization milestone payments from Spark Therapeutics up to an aggregate dollar amount in the mid teens millions, and sales milestone payments from Spark Therapeutics up to an aggregate dollar amount in the low hundred millions.
+Added: In total, we are potentially eligible to receive upfront, opt-in and milestone payments exceeding $645 million if Spark Therapeutics exercises its options for all five promoter profiles and Spark Therapeutics, its affiliates and its sublicensees successfully develop and commercialize five licensed products;
+Added: we will be eligible to receive additional milestone payments if additional licensed products are developed and commercialized by Spark Therapeutics, its affiliates and its sublicensees.
+Added: Further, Spark Therapeutics will be obligated to pay us royalties in the low-single digits percentage on net sales of each licensed product sold by Spark Therapeutics, its affiliates and its sublicensees, subject to specified reductions and offsets.
+Added: Spark Therapeutics’s obligation to pay royalties to us will expire for each licensed product when certain licensed patents and regulatory exclusivities have expired in the country of sale and a minimum number of years has elapsed since the first commercial sale of such licensed product in such country.
+Added: The Spark Agreement will expire at the end of the last evaluation period if Spark Therapeutics does not exercise any of its options.
+Added: If Spark Therapeutics exercises at least one option, then the Spark Agreement will expire, on a licensed product-by- licensed product and country-by-country basis, upon the expiration of Spark Therapeutics’s royalty obligation for such licensed product in such country.
+Added: Spark Therapeutics may terminate the Spark Agreement in its entirety, or on a promoter profile-by-promoter profile or licensed promoter-by-licensed promoter basis, following a specified notice period.
Either party may terminate the Spark Agreement in its entirety or in part if the other party fails to cure its material breach of the Spark Agreement within a specified cure period, or immediately if the other party becomes bankrupt or insolvent.
−Removed: We may terminate the Spark Agreement if Spark or any of its affiliates commences any action challenging the validity or enforceability of the licensed patents, other than in certain specified circumstances, or if Spark’s sublicensee challenges our licensed patents, under certain specified circumstances.
+Added: We may terminate the Spark Agreement if Spark Therapeutics or any of its affiliates commences any action challenging the validity or enforceability of the licensed patents, other than in certain specified circumstances, or if Spark Therapeutics’s sublicensee challenges our licensed patents, under certain specified circumstances.
Collaboration and Option Agreement with BlueRock Therapeutics LP
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We have granted to BlueRock an option, on a collaboration program-by-collaboration program basis, to obtain an exclusive or non-exclusive license under our intellectual property rights to develop, manufacture and commercialize, for the prevention, treatment or palliation of specified indications, or a licensed field, cell therapy products that contain cells of specified types that incorporate an option gene circuit from such collaboration program or a closely related derivative gene circuit.
−Removed: For each collaboration program, BlueRock may conduct evaluation activities on the option gene circuits from such collaboration program to determine whether to exercise its option, and BlueRock may exercise its option to such option gene circuits together with certain closely related derivative gene circuits, or licensed gene circuits, prior to the expiration of a certain time period, or the option exercise period, which includes a minimum amount of time after the expiration of the three-year research term, delivery of a data package to
−Removed: BlueRock, and completion of a transfer of technology to enable BlueRock’s evaluation activities, whichever happens last.
+Added: For each collaboration program, BlueRock may conduct evaluation activities on the option gene circuits from such collaboration program to determine whether to exercise its option, and BlueRock may exercise its option to such option gene circuits together with certain closely related derivative gene circuits, or licensed gene circuits, prior to the expiration of a certain time period, or the option exercise period, which includes a minimum amount of time after the expiration of the three-year research term, delivery of a data package to BlueRock, and completion of a transfer of technology to enable BlueRock’s evaluation activities, whichever happens last.
If BlueRock exercises its option for a collaboration program, the parties shall negotiate the financial terms, which will be within certain pre-agreed parameters and may be determined by baseball arbitration if the parties do not reach agreement within the specified negotiation period, and enter into an otherwise agreed-upon written license agreement, or a commercial license.
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Such expiration shall occur no later than January 2026 unless the parties mutually agree to extend the research term.
−Removed: BlueRock may terminate the BlueRock Agreement in its entirety, or on a collaboration program-by-collaboration program basis, following a specified notice period.
+Added: terminate the BlueRock Agreement in its entirety, or on a collaboration program-by-collaboration program basis, following a specified notice period.
Either party may terminate the BlueRock Agreement if the other party fails to cure its material breach of the BlueRock Agreement within a specified cure period, or immediately if the other party becomes bankrupt or insolvent.
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National Cancer Institute (NCI) Contract to Support Development of SENTI-202 in Acute Myeloid Leukemia
−Removed: In September 2021, we were awarded funding from the National Cancer Institute in the form of a Small Business Innovation Research (SBIR) contract to support further development of SENTI-202 for acute myeloid leukemia (AML) towards clinical development.
−Removed: The Direct to Phase II SBIR contract will provide funding over two
−Removed: years from the NCI of the National Institutes of Health (NIH) and is titled:
−Removed: “Logic-Gated Chimeric Antigen Receptor- Natural Killer Cell Therapy for Acute Myeloid Leukemia.” With the award of this contract, the SENTI-202 program will be funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, under Contract No.
+Added: In September 2021, we were awarded funding from the National Cancer Institute in the form of a Small Business Innovation Research (“SBIR”) contract to support further development of SENTI-202 for AML towards clinical development.
+Added: The Direct to Phase II SBIR contract provided funding over two years from the NCI of the National Institutes of Health (“NIH”) and is titled:
+Added: “Logic-Gated Chimeric Antigen Receptor- Natural Killer Cell Therapy for Acute Myeloid Leukemia.” The period of funding and performance under this SBIR contract ended on July 31, 2023 and we received notice from the NIH that this SBIR contract has been administratively closed on February 26, 2024.
+Added: As a result of the award of this contract, the SENTI-202 program was funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, under Contract No.
75N91021C00026.
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Additionally, the NCI reserves the right to terminate or modify the NCI GPC3 Agreement if the NCI determines that such action is necessary to meet the requirements for public use specified by federal regulations issued after the date of the license and these requirements are not reasonably satisfied by us.
−Removed: Potential Collaboration Related to Gene Circuits and GMP Manufacturing
−Removed: We may seek to leverage our manufacturing capabilities and cGMP facility to enable us to expand the application of our gene circuit technology through a partnership in the biomanufacturing space.
−Removed: While we intend to use our proprietary gene circuit technology and manufacturing facility primarily for therapeutic product development and commercialization, our technology and facility can also be applied to noncompetitive biomanufacturing applications, which we believe is an approach well-suited for partnering.
−Removed: A potential biomanufacturing partnership could involve retaining operational control and manufacturing supply of our therapeutic candidates, while our partner could control part of the facility for its own use.
−Removed: We cannot provide any assurance that we will be able to enter into a biomanufacturing partnership on acceptable terms, or at all.
−Removed: We currently have no agreements or commitments for a manufacturing partnership, and we could determine to advance our manufacturing plans without a partner.
+Added: Framework Agreement with GeneFab, LLC
+Added: In August 2023, we completed a transaction with GeneFab, a contract manufacturing and synthetic biology biofoundry focused on next-generation cell and gene therapies.
+Added: Under a framework agreement entered into by us and GeneFab, we sold, assigned and transferred rights, title and interest in certain of our assets and contractual rights, including all of our equipment at our facilities in Alameda and certain of our intellectual property related to the schematics for and design of the Alameda facility.
+Added: We subleased our recently constructed 92,000 square foot current good manufacturing practice facility in Alameda, California to GeneFab which will support the clinical manufacturing of our CAR-NK programs, including SENTI-202.
+Added: The transaction provided us with additional capital in the form of a note receivable and rights to future manufacturing and research activities and reduced longer term operating expenses.
+Added: In connection with the transaction, we are entitled to receive total consideration of $37.8 million before the end of 2025, of which $18.9 million was payable at closing and was netted against prepayment owed by us for manufacturing and research activities to GeneFab under a development and manufacturing services agreement that was separately entered into by us and GeneFab as part of the transaction.
+Added: The remaining $18.9 million will be paid to us in installments in 2024 and 2025, subject to satisfaction of certain conditions.
+Added: The Company determined that the $18.9 million for future manufacturing and research activities, inclusive of the volume discount provided, was executed at market terms and does not result in any impact to the total consideration received from GeneFab for the disposal of the business.
+Added: We also agreed to grant a license to GeneFab under certain of our intellectual property rights to conduct manufacturing services and to research, develop, manufacture and commercialize products outside of oncology, pursuant to a license agreement that is still under negotiation as of March 2024.
+Added: GeneFab was provided an option to purchase up to 19,633,444 shares (i.e.
+Added: up to $20.0 million worth) of our common stock at an exercise price of $1.01867, or the GeneFab Option.
+Added: The GeneFab Option is exercisable upon the execution of the license agreement, no later than August 7, 2026.
+Added: The GeneFab Option may be exercised in installments of common stock equal to no more than 19.9% of our outstanding shares of common stock as of the closing date of the transaction.
+Added: As additional consideration for the transaction, we entered into a seller economic share agreement with GeneFab, pursuant to which we will be entitled to receive ten percent of the realized gains of GeneFab’s parent company arising and resulting from any cash or in-kind distributions from GeneFab in connection with a dividend or sale event, subject to the terms and conditions of the GeneFab Economic Share.
+Added: Collaboration and Option Agreement with Celest Therapeutics, (Shanghai) Co.
+Added: In November 2023, we entered into a Collaboration and Option Agreement, or the Celest Agreement, with Celest Therapeutics.
+Added: Under the Celest Agreement, we agreed to collaborate with Celest Therapeutics for Celest Therapeutics to carry out an investigator-initiated trial (“IIT”) of the SENTI-301A program in mainland China with certain technical support from us.
+Added: Celest Therapeutics will have an exclusive option to obtain an exclusive, royalty-bearing, license in mainland China, Hong Kong, Macau, and Taiwan under our intellectual property rights to research, develop, manufacture, commercialize and otherwise exploit an off-the-shelf CAR-NK cell therapy product candidate that consists of NK cells that have been engineered to express our CAR having an antigen binding portion that is directed to GPC3 and our crIL15, such product candidate the SN301A Product.
+Added: Celest Therapeutics may exercise its option prior to the expiration of a certain time period, or the option exercise period.
+Added: If Celest Therapeutics exercises its option during the option exercise period, the parties shall negotiate the terms of the license agreement, which will include and be consistent with pre-agreed financial terms, and Celest Therapeutics will be required to pay us an option exercise fee in the mid-single digit millions upon the execution of the license agreement.
+Added: If the parties enter into a license agreement having terms consistent with the pre-agreed financial terms, we will be eligible to receive certain option exercise fee and milestone payments, in an aggregate amount of $156.0 million, as well as certain tiered royalty payment.
+Added: During a certain time period, or the exclusivity period, we are prohibited from directly or indirectly, exploiting or enabling any third party to research, develop manufacture, commercialize or otherwise exploit in mainland China any off-the-shelf CAR-NK cell therapy having an antigen binding portion of the CAR directed to GPC.
+Added: Therapeutics does not exercise its option, then the exclusivity period will end on the expiration of the option period.
+Added: If Celest Therapeutics exercises its option, then the exclusivity period will end upon the expiration of the applicable negotiation period for the license agreement or the mutual execution of the license agreement, whichever is earlier.
+Added: If Celest Therapeutics exercises its option and the parties are unable to execute a mutually agreed license agreement during the negotiation period, then the option will automatically be deemed expired and we will have no further obligation to Celest Therapeutics under the Celest Agreement, except that for a certain time period following the expiration of the negotiation period, Celest Therapeutics will have certain rights if we receive a bona fide offer from a third party for such third party to obtain an exclusive license or similar exclusive rights under our technology to research, develop, manufacture, commercialize or otherwise exploit the SN301A Product in certain territories on certain terms and Celest Therapeutics will have certain rights if we enter into any arrangement with any third party pursuant to which we grant an exclusive license or similar exclusive right under technology to research ,develop, manufacture, commercialize or otherwise exploit the SN301A Product in certain territories on certain terms.
+Added: The Celest Agreement will expire upon the earliest of the expiration of the option exercise period, the expiration of the negotiation period of the license agreement, or on the date of execution of the license agreement.
+Added: We may terminate the Celest Agreement if Celest Therapeutics does not proceed to certain IIT preparation stages or if there is a delay to meeting the target date for the IIT initiation and the parties are unable to agree to an extension target date.
+Added: We may also terminate the Celest Agreement if Celest Therapeutics or any of its affiliates commences any action challenging the validity or enforceability of our patents, other than in certain specified circumstances.
+Added: Either party may terminate the Celest Agreement if the other party fails to cure its material breach of the Celest Agreement within a specified cure period, or immediately if the other party becomes bankrupt or insolvent.
We are aware of other companies that are developing technologies that may compete with elements of our gene circuit platform technologies, including A2 Biotherapeutics, Inc., Arsenal Biosciences, Inc., Beam Therapeutics Inc., CRISPR Therapeutics AG, Encoded Therapeutics, Inc., ImmPACT Bio USA, Inc., Intellia Therapeutics, Inc., MeiraGTx Holdings plc, Obsidian Therapeutics, Inc.
and Strand Therapeutics Inc.
−Removed: We are also aware of other companies that are focused on the application of engineered CAR-based immune cell therapies, including NK cells, to oncology, and such competitors include Allogene Therapeutics, Inc., Artiva Biotherapeutics, Inc., Atara Biotherapeutics, Inc., Bristol-Myers Squibb Company, Century Therapeutics, Inc., Caribou Biosciences, Inc., Catamaran Bio, Inc., Cytovia Therapeutics, Inc., Fate Therapeutics, Inc., Gilead Sciences, Inc., Lyell Immunopharma, Inc., Nkarta, Inc., Sana Biotechnology, Inc., Shoreline Biosciences, Inc., Takeda Pharmaceutical Company and Vor Biopharma Inc.
+Added: We are also aware of other companies that are focused on the application of engineered CAR-based immune cell therapies, including NK cells, to oncology, and such competitors include Allogene Therapeutics, Inc., Artiva Biotherapeutics, Inc., Atara Biotherapeutics, Inc., Bristol-Myers Squibb Company, Century Therapeutics, Inc., Caribou Biosciences, Inc., Cytovia Therapeutics, Inc., Fate Therapeutics, Inc., Gilead Sciences, Inc., Lyell Immunopharma, Inc., Nkarta, Inc., Sana Biotechnology, Inc., Shoreline Biosciences, Inc., Takeda Pharmaceutical Company and Vor Biopharma Inc.
Some of these companies may have substantially greater financial and other resources than we have, such as larger research and development staff and well- established marketing and salesforces.
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Intellectual Property
−Removed: Intellectual property is the foundation of our company and not only defines who we are, but is the lens through which we implement our business strategy and research and development.
+Added: Intellectual property is critical to our differentiated technology.
Our overall strategy is to own and control all intellectual property related to our gene circuits.
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Our general strategy includes protecting our proprietary technology and intellectual property rights domestically and in certain key foreign markets.
−Removed: We continually grow and supplement our intellectual property portfolio with new filings and applications not only to strengthen the protection of proprietary technology and intellectual property rights, but also to protect and support the development and commercialization of current and future product candidates.
+Added: We continually grow and supplement our intellectual property portfolio with new filings and
+Added: applications not only to strengthen the protection of proprietary technology and intellectual property rights, but also to protect and support the development and commercialization of current and future product candidates.
In addition, we seek to protect our technological innovations and branding efforts by filing new patent and trademark applications at the appropriate time and in strategically relevant jurisdictions.
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The patents and pending patent applications in our portfolio can be categorized as relating to our gene circuit platform technologies, including Logic Gating gene circuits, Multi-Arming gene circuits, Regulator Dial gene circuits and Smart Sensor gene circuits;
−Removed: our product candidates, including SENTI-202, SENTI-301A and SENTI-401, as well as other possible pipeline product candidates;
+Added: our product candidates, including SENTI-202 and SENTI-301A, as well as other possible pipeline product candidates;
and alternative technologies, and our patents and patent application include claims directed to compositions, methods (including preparation, use, or treatment), processes, dosing and formulations.
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Generally, patents issued from applications filed in the United States are effective for 20 years from the earliest non-provisional filing date of the patent application to which the patent claims priority.
−Removed: In the United States,
−Removed: a term of a patent may be lengthened by patent term adjustment (PTA), which compensates a patentee for administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent.
+Added: In the United States, a term of a patent may be lengthened by patent term adjustment (PTA), which compensates a patentee for administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent.
In addition, in certain instances, the patent term of a U.S.
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We also utilize trademark rights to protect our brand and have filed trademark applications for the marks “SENTI,” “SENTI BIOSCIENCES,” “SENTI BIO,” and Senti’s “S” logo in the United States and in certain marks in foreign countries.
−Removed: As of February 19, 2023, we own two United States trademark registrations, five pending and/or allowed United States trademark applications, five foreign trademark registrations, and one pending foreign trademark application.
+Added: As of February 16, 2024, we own two United States trademark registrations, four pending and/or allowed United States trademark applications, and five foreign trademark registrations.
We have also registered multiple internet domain names to further supplement the protection of our brand.
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• approval by an institutional review board, or IRB, or ethics committee at each clinical site before the trial is commenced;
−Removed: • performance of adequate and well-controlled human clinical trials according to the FDA’s regulations commonly referred to as good clinical practice, or GCP, regulations and any additional requirements for the
−Removed: protection of human research subjects and their health information to establish the safety, purity and potency of the proposed biologic product candidate for its intended purpose;
+Added: • performance of adequate and well-controlled human clinical trials according to the FDA’s regulations commonly referred to as good clinical practice, or GCP, regulations and any additional requirements for the protection of human research subjects and their health information to establish the safety, purity and potency of the proposed biologic product candidate for its intended purpose;
• preparation of and submission to the FDA of a Biologics License Application, or BLA, after completion of all pivotal clinical trials;
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The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises safety concerns or questions about the proposed clinical trial.
−Removed: In such a case, the IND may be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.
+Added: In such a case, the IND may be
+Added: placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.
Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.
−Removed: We anticipate filing an IND for Senti-202 in the second half of 2023.
In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules are subject to oversight of institutional biosafety committees, or IBCs, as set forth in the National Institutes of Health, or NIH, Guidelines for Research Involving Recombinant DNA Molecules, or the NIH Guidelines.
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Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical study.
−Removed: Clinical trials are conducted under protocols
−Removed: detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.
+Added: Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.
A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments.
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• Phase 3—The investigational product is administered to an expanded patient population to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites.
−Removed: These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval.
+Added: These clinical trials are intended to
+Added: establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval.
Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for approval of a BLA.
+Added: In March 2022, the FDA released final guidance titled “Expansion Cohorts:
+Added: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics,” which outlines how drug developers can utilize an adaptive trial design commonly referred to as a seamless trial design in early stages of oncology drug development (i.e., the first-in-human clinical trial) to compress the traditional three phases of trials into one continuous trial called an expansion cohort trial.
+Added: Information to support the design of individual expansion cohorts are included in IND applications and assessed by FDA.
+Added: Expansion cohort trials can potentially bring efficiency to drug development and reduce development costs and time.
In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product in the intended therapeutic indication, particularly for long-term safety follow-up.
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An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions.
−Removed: The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
+Added: The FDA is not
+Added: bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
Before approving a BLA, the FDA will typically inspect the facility or facilities where the product is manufactured.
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A CRL indicates that the review cycle of the application is complete, and the application will not be approved in its present form.
−Removed: A CRL will describe all of the deficiencies that the FDA has identified in the BLA, except that where the FDA determines that the data supporting the application are inadequate
−Removed: to support approval, the FDA may issue the CRL without first conducting required inspections, testing submitted product lots, and/or reviewing proposed labeling.
+Added: A CRL will describe all of the deficiencies that the FDA has identified in the BLA, except that where the FDA determines that the data supporting the application are inadequate to support approval, the FDA may issue the CRL without first conducting required inspections, testing submitted product lots, and/or reviewing proposed labeling.
In issuing the CRL, the FDA may recommend actions that the applicant might take to place the BLA in condition for approval, including requests for additional information or clarification.
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For example, new biological products are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.
−Removed: Fast track designation applies to the combination of the product and the specific indication for which it is being studied.
+Added: Fast track designation applies to the combination of the product and the specific indication for which it is
+Added: being studied.
The sponsor of a new biologic may request that the FDA designate the biologic as a fast track product at any time during the clinical development of the product.
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The FDA will attempt to direct additional resources to the evaluation of an application for a new biological product designated for priority review in an effort to facilitate the review.
−Removed: original BLAs, priority review designation means the FDA’s goal is to take action on the marketing application within six months of the 60-day filing date (as compared to ten months under standard review).
+Added: For original BLAs, priority review designation means the FDA’s goal is to take action on the marketing application within six months of the 60-day filing date (as compared to ten months under standard review).
Additionally, product candidates studied for their safety and effectiveness in treating serious or life-threatening diseases or conditions may receive accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.
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In addition, for products being considered for accelerated approval, the FDA generally requires, unless otherwise informed by FDA, that all advertising and promotional materials intended for dissemination or publication within 120 days of marketing approval be submitted to FDA for review during the pre-approval period.
−Removed: In 2017, the FDA established a new regenerative medicine advanced therapy, or RMAT, designation, which is intended to facilitate an efficient development program for, and expedite review of, any biologic that meets the following criteria:
+Added: The FDA established a new regenerative medicine advanced therapy, or RMAT, designation, which is intended to facilitate an efficient development program for, and expedite review of, any biologic that meets the following criteria:
(i) the biologic qualifies as a RMAT, which is defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, with limited exceptions;
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RMAT designation provides all the benefits of breakthrough therapy designation, including more frequent meetings with the FDA to discuss the development plan for the product candidate and eligibility for rolling review and priority review.
−Removed: Product candidates granted RMAT designation may also be eligible for accelerated approval on the basis of a surrogate or intermediate endpoint reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of clinical trial sites, including through expansion of trials to additional sites.
+Added: Product candidates granted RMAT designation may also be eligible for accelerated approval on the basis of a surrogate or intermediate endpoint reasonably likely to
+Added: predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of clinical trial sites, including through expansion of trials to additional sites.
RMAT-designated products that receive accelerated approval may, as appropriate, fulfill their post-approval requirements through submission of clinical evidence, clinical studies, patient registries, or other sources of real-world evidence (such as electronic health records);
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There also are continuing, annual program fees for any marketed products.
−Removed: Biologic manufacturers and other entities involved in the manufacture and distribution of approved biological products, and those supplying products, ingredients, and components of them, are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP requirements and other laws, which impose certain procedural and documentation requirements upon us and our third-party manufacturers.
+Added: Biologic manufacturers and other entities involved in the manufacture and distribution of approved biological products, and those supplying products, ingredients, and
+Added: components of them, are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP requirements and other laws, which impose certain procedural and documentation requirements upon us and our third-party manufacturers.
Manufacturers and other parties involved in the drug supply chain for prescription drug products must also comply with product tracking and tracing requirements and for notifying the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the United States.
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The federal government has levied large civil and criminal fines against companies for alleged improper promotion of off-label use and has enjoined companies from engaging in off-label promotion.
−Removed: The FDA and other regulatory agencies have also required that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.
+Added: The FDA and other regulatory agencies have also required that companies enter into consent
+Added: decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.
Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties.
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Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency, can be shown through analytical studies, animal studies, and a clinical study or studies.
−Removed: Interchangeability requires that a product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference product in any given patient and, for products that are administered multiple times to an individual, the
−Removed: biologic and the reference biologic may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.
+Added: Interchangeability requires that a product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference product in any given patient and, for products that are administered multiple times to an individual, the biologic and the reference biologic may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.
However, complexities associated with the larger, and often more complex, structures of biological products, as well as the processes by which such products are manufactured, pose significant hurdles to implementation of the abbreviated approval pathway that are still being worked out by the FDA.
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A biological product can also obtain pediatric market exclusivity in the United States.
−Removed: Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms.
−Removed: This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.
+Added: Pediatric exclusivity, if granted, adds six months to existing regulatory exclusivity periods for all formulations, dosage forms, and indications of the active moiety.
+Added: This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study, provided that at the time pediatric exclusivity is granted there is not less than nine months of term remaining.
The BPCIA is complex and continues to be interpreted and implemented by the FDA.
17 unchanged sentences
Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States.
−Removed: Increasingly, third-party payors are
−Removed: requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products.
+Added: Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products.
We cannot be sure that reimbursement will be available for any product candidate that we commercialize and, if reimbursement is available, the level of reimbursement.
11 unchanged sentences
A Member State may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.
−Removed: There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our product candidates.
+Added: There can be no
+Added: assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our product candidates.
Historically, products launched in the European Union do not follow price structures of the United States and generally prices tend to be significantly lower.
1 unchanged sentence
In the United States, there have been and continue to be a number of legislative initiatives to contain healthcare costs.
−Removed: For example, in March 2010, the Patient Protection and Affordable Care Act (the “ACA”) was enacted, which substantially changed the way healthcare is financed by both governmental and private insurers, and significantly impacted the U.S.
+Added: For example, in 2010, the Patient Protection and Affordable Care Act (the “ACA”) was enacted, which substantially changed the way healthcare is financed by both governmental and private insurers, and significantly impacted the U.S.
pharmaceutical industry.
5 unchanged sentences
• The Budget Control Act of 2011 and subsequent legislation, among other things, created measures for spending reductions by Congress that include aggregate reductions of Medicare payments to providers of 2% per fiscal year, which remain in effect through 2031.
−Removed: Due to the Statutory Pay-As-You-Go Act of 2010,
−Removed: estimated budget deficit increases resulting from the American Rescue Plan Act of 2021, and subsequent legislation, Medicare payments to providers will be further reduced starting in 2025 absent further legislation.
+Added: Due to the Statutory Pay-As-You-Go Act of 2010, estimated budget deficit increases resulting from the American Rescue Plan Act of 2021, and subsequent legislation, Medicare payments to providers will be further reduced starting in 2025 absent further legislation.
The American Taxpayer Relief Act of 2012 further reduced Medicare payments to several providers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
7 unchanged sentences
Specifically, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several U.S.
−Removed: Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, and review the relationship between pricing and manufacturer patient programs.
+Added: Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, and review the relationship between pricing and
+Added: manufacturer patient programs.
The Inflation Reduction Act of 2022, or IRA, includes several provisions that may impact our business to varying degrees, including provisions that reduce the out-of-pocket spending cap for Medicare Part D beneficiaries from $7,050 to $2,000 starting in 2025, thereby effectively eliminating the coverage gap;
4 unchanged sentences
and delay until January 1, 2032 the implementation of the HHS rebate rule that would have limited the fees that pharmacy benefit managers can charge.
−Removed: Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have one rare disease designation and for which the only approved indication is for that disease or condition.
−Removed: If a product receives multiple rare disease designations or has multiple approved indications, it may not qualify for the orphan drug exemption.
+Added: Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have one orphan designation and for which the only approved indication is for that disease or condition.
+Added: If a product receives multiple orphan designations or has multiple approved indications, it may not qualify for the orphan drug exemption.
+Added: The implementation of the IRA is currently subject to ongoing litigation challenging the constitutionality of the IRA’s Medicare drug price negotiation program.
The effects of the IRA on our business and the healthcare industry in general is not yet known.
4 unchanged sentences
For example, there have been several recent Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.
−Removed: At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient
−Removed: reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
+Added: At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
In addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other health care programs.
5 unchanged sentences
Healthcare providers, physicians and third-party payors, among others, will play a primary role in the prescription and recommendation of any product candidates for which we obtain marketing approval.
−Removed: Our arrangements with third-party payors, providers and customers, among others, may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations in the future that may constrain the business or financial arrangements and relationships through which we market, sell and distribute our product candidates for which we obtain marketing approval.
+Added: Our arrangements with third-party payors, providers and customers, among others, may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations in the future that may constrain the business or financial
+Added: arrangements and relationships through which we market, sell and distribute our product candidates for which we obtain marketing approval.
Restrictions under applicable federal and state healthcare laws and regulations in the United States and other countries, include the following:
21 unchanged sentences
Whether or not we obtain FDA approval for a product, we must obtain the requisite approvals from regulatory authorities in foreign countries prior to the commencement of clinical studies or marketing of the product in those countries.
−Removed: Certain countries outside of the United States have a similar process that requires the submission of a
−Removed: clinical study application much like the IND prior to the commencement of human clinical studies.
−Removed: In the European Union, for example, a CTA must be submitted to each country’s national health authority and an independent ethics committee, much like the FDA and the IRB, respectively.
−Removed: Once the CTA is approved in accordance with a country’s requirements, clinical study development may proceed.
+Added: Certain countries outside of the United States have a similar process that requires the submission of a clinical study application much like the IND prior to the commencement of human clinical studies.
The requirements and process governing the conduct of clinical studies, product licensing, pricing and reimbursement vary from country to country.
In all cases, the clinical studies are conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.
−Removed: To obtain regulatory approval of an investigational biological product under European Union regulatory systems, we must submit a marketing authorization application.
−Removed: The application used to file the BLA in the United States is similar to that required in the European Union, with the exception of, among other things, country-specific document requirements.
+Added: Similar to the United States, the various phases of preclinical and clinical research in the European Union are subject to significant regulatory controls.
+Added: In April 2014, the European Union adopted a Clinical Trials Regulation (EU) No 536/2014, which replaced the Clinical Trials Directive 2001/20/EC on January 31, 2022.
+Added: The Clinical Trials Regulation is directly applicable in all Member States (and so does not require national implementing legislation in each Member State), and aims at simplifying and streamlining the approval of clinical studies in the European Union.
+Added: For example, a single application is now made through the Clinical Trials Information System, for clinical trial authorization in up to 30 European Economic Area (“EEA”) (comprised of the EU Member States plus Norway, Iceland and Liechtenstein) countries at the same time and with a single set of documentation.
+Added: To obtain regulatory approval of a medicinal product under European Union regulatory systems, we must submit a marketing authorization application.
+Added: The application used to file the BLA in the United States is similar to that required in the European Union.
+Added: In the European Union, medicinal products can only be commercialized after obtaining a marketing authorization.
+Added: There are two types of marketing authorization:
+Added: • The centralized marketing authorization is issued by the European Commission through the centralized procedure, based on the opinion of the Committee for Medicinal Products for Human Use (“CHMP”) of the European Medicines Agency (“EMA”), and is valid throughout the entire territory of the EU.
+Added: The centralized
+Added: procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products, advanced therapy medicinal products (gene-therapy, somatic cell-therapy or tissue-engineered medicines) and medicinal products containing a new active substance indicated for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and other immune dysfunctions and viral diseases.
+Added: The centralized procedure is optional for products containing a new active substance not yet authorized in the European Union, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the European Union.
+Added: Under the centralized procedure, the maximum timeframe for the evaluation of a marketing authorization application by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP.
+Added: Clock stops may extend the timeframe of evaluation of a marketing authorization application considerably beyond 210 days.
+Added: Where the CHMP gives a positive opinion, the EMA provides the opinion together with supporting documentation to the European Commission, who makes the final decision to grant a marketing authorization, which is issued within 67 days of receipt of the EMA’s recommendation.
+Added: Accelerated assessment might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation.
+Added: The timeframe for the evaluation of a marketing authorization application under the accelerated assessment procedure is 150 days, excluding clock stops, but it is possible that the CHMP may revert to the standard time limit for the centralized procedure if it determines that the application is no longer appropriate to conduct an accelerated assessment.
+Added: • National marketing authorizations, which are issued by the competent authorities of the Member States of the European Union and only cover their respective territory, are available for products not falling within the mandatory scope of the centralized procedure.
+Added: Where a product has already been authorized for marketing in a Member State of the European Union, this national marketing authorization can be recognized in other Member States through the mutual recognition procedure.
+Added: If the product has not received a national marketing authorization in any Member State at the time of application, it can be approved simultaneously in various Member States through the decentralized procedure.
+Added: Under the above described procedures, before granting the marketing authorization, the EMA or the competent authorities of the Member States of the European Union make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.
The European Union also provides opportunities for market exclusivity.
−Removed: For example, in the European Union, upon receiving marketing authorization, new chemical entities generally receive eight years of data exclusivity and an additional two years of market exclusivity.
−Removed: If granted, data exclusivity prevents regulatory authorities in the European Union from referencing the innovator’s data to assess a generic application.
−Removed: During the additional two-year period of market exclusivity, a generic marketing authorization can be submitted, and the innovator’s data may be referenced, but no generic product can be marketed until the expiration of the market exclusivity.
+Added: For example, in the European Union, upon receiving marketing authorization, new chemical entities or innovative medicinal products generally receive eight years of data exclusivity and an additional two years of market exclusivity.
+Added: If granted, data exclusivity prevents generic or biosimilar applicants from referencing the innovator’s preclinical and clinical trial data contained in the dossier of the reference product when applying for a biosimilar or generic marketing authorization, for a period of eight years from the date on which the reference product was first authorized in the EU.
+Added: During the additional two-year period of market exclusivity, a biosimilar or generic marketing authorization can be submitted, and the innovator’s data may be referenced, but no biosimilar or generic product can be marketed in the EU until the expiration of the market exclusivity.
+Added: The overall ten-year period will be extended to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are determined to bring a significant clinical benefit in comparison with currently approved therapies.
However, there is no guarantee that a product will be considered by the European Union’s regulatory authorities to be a new chemical entity, and products may not qualify for data exclusivity.
−Removed: Products receiving orphan designation in the European Union can receive ten years of market exclusivity, during which time no similar medicinal product for the same indication may be placed on the market.
−Removed: An orphan product can also obtain an additional two years of market exclusivity in the European Union for pediatric studies.
−Removed: No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for orphan indications.
+Added: Even if a product gains the prescribed period of data exclusivity, another company may market another version of the product if such company obtained a marketing authorization based on an application with a complete and independent data package of pharmaceutical tests, preclinical tests and clinical trials.
The criteria for designating an “orphan medicinal product” in the European Union are similar in principle to those in the United States.
−Removed: Under Article 3 of Regulation (EC) 141/2000, a medicinal product may be designated as orphan if (1) it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition;
−Removed: (2) either (a) such condition affects no more than five in 10,000 persons in the European Union when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the European Union to justify investment;
+Added: Under Article 3 of Regulation (EC) 141/2000, the European Commission grants an orphan designation in respect of a product if its sponsor can establish that (1) the product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition;
+Added: (2) either (a) such condition affects no more than five in 10,000 persons in the European Union when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the European Union
+Added: to justify the necessary investment in its development;
and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the European Union, or if such a method exists, the product will be of significant benefit to those affected by the condition, as defined in Regulation (EC) 847/2000.
−Removed: Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers and are, upon grant of a marketing authorization, entitled to ten years of market exclusivity for the approved therapeutic indication.
−Removed: The application for orphan drug designation must be submitted before the application for marketing authorization.
−Removed: The applicant will receive a fee reduction for the marketing authorization application if the orphan drug designation has been granted, but not if the designation is still pending at the time the marketing authorization is submitted.
−Removed: Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.
+Added: Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers and are, upon grant of a marketing authorization, entitled to ten years of market exclusivity during which no marketing authorization may be granted in the EU for a “similar medicinal product” to the authorized orphan product for the same therapeutic indication (subject to limited exceptions outlined below).
+Added: A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.
+Added: An orphan product can also obtain an additional two years of market exclusivity in the European Union for pediatric studies submitted in compliance with an EMA-approved pediatric investigation plan.
+Added: The application for orphan designation must be submitted before the application for marketing authorization.
+Added: The applicant will receive a fee reduction for the marketing authorization application if the orphan designation has been granted, but not if the designation is still pending at the time the marketing authorization is submitted.
+Added: Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.
The 10-year market exclusivity may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.
−Removed: Additionally, marketing authorization may be granted to a similar product for the same indication at any time if:
−Removed: • The second applicant can establish that its product, although similar, is safer, more effective or otherwise clinically superior;
−Removed: • The applicant consents to a second orphan medicinal product application;
−Removed: • The applicant cannot supply enough orphan medicinal product.
−Removed: For other countries outside of the European Union, such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical studies, product licensing, pricing and reimbursement vary from
−Removed: country to country.
+Added: Additionally, marketing authorization may be granted to a similar medicinal product for the same indication as an authorized orphan product at any time if:
+Added: • The second applicant can establish that its product, although similar to the authorized orphan product, is safer, more effective or otherwise clinically superior;
+Added: • The marketing authorization holder for the authorized orphan product consents to a second orphan medicinal product application;
+Added: • The marketing authorization holder for the authorized orphan product cannot supply enough orphan medicinal product.
+Added: The aforementioned European Union rules are generally applicable in the EEA.
+Added: The European Commission introduced legislative proposals in April 2023 that, if implemented, will replace the current regulatory framework in the European Union for all medicines (including those for rare diseases and for children).
+Added: The European Commission has provided the legislative proposals to the European Parliament and the European Council for their review and approval.
+Added: In October 2023, the European Parliament published draft reports proposing amendments to the legislative proposals, which will be debated by the European Parliament.
+Added: Once the European Commission’s legislative proposals are approved (with or without amendment), they will be adopted into European Union law.
+Added: For other countries outside of the European Union, such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical studies, product licensing, pricing and reimbursement vary from country to country.
In all cases, again, the clinical studies are conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.
If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.
+Added: European Data Collection
+Added: The collection and processing of personal data (including health data) in the European Economic Area, or EEA and the United Kingdom, or UK is governed by the EU General Data Protection Regulation, or EU GDPR (with regards to the EEA) and the UK General Data Protection Regulation, or UK GDPR (with respect to the UK), as well as applicable data protection laws in effect in the Member States of the EEA and in the UK (including the UK Data Protection Act 2018).
+Added: The EU and UK data protection regimes are independent of each other but remain largely
+Added: However, the UK Government has introduced a Data Protection and Digital Information Bill, or Data Reform Bill into the UK legislative process to reform the UK data protection legal framework.
+Added: In this Form 10-K, “GDPR” refers to both the EU GDPR and the UK GDPR, unless specified otherwise.
+Added: The GDPR applies to any company established in the EEA/UK and to companies established outside the EEA/UK that process personal data in connection with the offering of goods or services to data subjects in the EEA/UK or the monitoring of the behavior of data subjects in the EEA/UK.
+Added: The GDPR imposes numerous stringent requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of data subjects, providing detailed information to data subjects about how personal data is used, conducting privacy impact assessments for “high risk” processing, implementing safeguards to protect the security and confidentiality of personal data, implementing limitations on the retention of personal data, providing mandatory data breach notification, implementing “privacy by design” requirements, and taking certain measures when engaging service providers acting as data processors.
+Added: The GDPR also imposes strict rules on the transfer of personal data to countries outside of the EEA/UK that do not ensure an adequate level of protection, including the United States in certain circumstances, unless derogation exists or a valid GDPR transfer mechanism (for example, the European Commission approved Standard Contractual Clauses, or SCCs, and the UK International Data Transfer Agreement/Addendum, or UK IDTA) have been put in place.
+Added: Where relying on the SCCs/UK IDTA for data transfers, transfer impact assessments are required to assess whether the recipient is subject to local laws which allow public authority access to personal data.
+Added: Although the UK is regarded as a third country under the European Union’s GDPR, the European Commission has now issued a decision recognizing the UK as providing adequate protection under the EU GDPR and the UK government has issued a similar decision, therefore, transfers of personal data between the EU to the UK remain unrestricted.
+Added: Failure to comply with the requirements of the GDPR and the related national data protection laws of the EEA Member States and the UK may result in fines up to €20 million (17.5 million for the UK GDPR) or 4% of a company’s global annual revenues for the preceding financial year, whichever is higher.
+Added: The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.
Employees and Human Capital Resources
−Removed: As of February 16, 2023, we had 122 employees, all of whom were full-time, consisting of clinical, research, operations, regulatory, finance and business development personnel.
+Added: As of March 13, 2024, we had 48 employees, all of whom were full-time, consisting of clinical, research, operations, regulatory, finance and business development personnel.
13 of our employees hold Ph.D.
1 unchanged sentence
We consider our relationship with our employees to be good.
−Removed: Of our executive officers, seventy-five percent (75%) are people of color and fifty percent (50%) are women.
−Removed: With respect to our employees overall, approximately sixty-nine percent (69%) are people of color and approximately fifty-two percent (52%) are women.
+Added: Of our executive officers, sixty-seven percent (67%) are people of color and sixty-seven percent (67%) are women.
+Added: With respect to our employees overall, approximately seventy-seven percent (77%) are people of color and approximately forty-six percent (46%) are women.
Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees.
1 unchanged sentence
We currently occupy approximately 40,000 square feet of office and research and development space in South San Francisco, CA under a lease that expires in April, 2027, with an option to extend for an additional eight years.
−Removed: We also currently occupy 92,000 square feet of manufacturing space under lease agreement that expires in September, 2032, with two five-year options to extend.
+Added: We also subleased our 92,000 square feet of manufacturing space under a sublease agreement to GeneFab that was executed in August 2023.
We believe that this space, collectively, is sufficient to meet our existing needs.
2 unchanged sentences
Smaller reporting companies may take advantage of certain reduced disclosure obligations, including, among other things, providing only two years of audited financial statements.
−Removed: We will remain a smaller reporting company if (1) the market value of our common stock held by non-affiliates is less than $250 million as of the last business day of the second fiscal quarter, or (2) our annual revenues in our most recent fiscal year completed before the last business day of our second fiscal quarter are less than $100 million and the market value of our common stock held by non-affiliates is less than $700 million as of the last business day of the second fiscal quarter.
+Added: We will remain a smaller reporting company if (1) the market value
+Added: of our common stock held by non-affiliates is less than $250 million as of the last business day of the second fiscal quarter, or (2) our annual revenues in our most recent fiscal year completed before the last business day of our second fiscal quarter are less than $100 million and the market value of our common stock held by non-affiliates is less than $700 million as of the last business day of the second fiscal quarter.
Corporate Information
1 unchanged sentence
Our principal executive office is located at 2 Corporate Drive, First Floor, South San Francisco, California 94080, and our telephone number is (650) 382-3281.
−Removed: Our website address is https://sentibio.com.
+Added: Our website address is www.sentibio.com.
References to our website address to not constitute incorporation by reference of the information contained on the website, and the information on the website is not part of this document.
3 unchanged sentences
The Merger was approved by DYNS’s stockholders at a meeting held on June 7, 2022.
−Removed: In connection with the consummation of the Merger on the Closing Date, DYNS changed its name from DYNS to Senti Biosciences,
+Added: In connection with the consummation of the Merger on the Closing Date, DYNS changed its name from DYNS to Senti Biosciences, Inc.
On June 9, 2022, our common stock, formerly of DYNS, began trading on the Nasdaq Global Market under the trading symbol “SNTI.”
2 unchanged sentences
The SEC maintains an Internet website that contains reports, proxy and information statements, and other information regarding us and other issuers that file electronically with the SEC.
−Removed: The SEC’s Internet website address is http://www.sec.gov.
−Removed: A copy of our Corporate Governance Guidelines, Code of Business Conduct and Ethics and the charters of the Audit Committee, Compensation Committee and Nominating and Corporate Governance Committee are posted on our website, www.sentibio.com, under “Investors”.
+Added: The SEC’s Internet website address is www.sec.gov.
+Added: A copy of our Corporate Governance Guidelines, Code of Business Conduct and Ethics and the charters of the Audit Committee, Compensation Committee and Nominating and Corporate Governance Committee of our Board of Directors are posted on our website, www.sentibio.com, under “Investors”.
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.