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Enabling Greater Patient Access to CAR-T Cell Therapies with Off-the-Shelf Delivery Solutions

Enabling Greater Patient Access to CAR-T Cell Therapies with Off-the-Shelf Delivery Solutions

Jan 03, 2023PAO-12-022-CL-04

Cell therapies offer significant therapeutic potential across oncology, including for both hematological malignancies and solid tumors. However, challenges remain in optimizing access and realizing the promise of these therapies in solid tumor indications. One company dedicated to resolving these challenges is Umoja Biopharma, which is uniting a diverse team of R&D experts and a number of platform technologies behind the goal of unlocking the full potential of CAR-T cell therapies. In this Q&A, Umoja’s Vice President and Head of Immunology Ryan Larson, Ph.D., answers questions by Pharma’s Almanac Editor in Chief David Alvaro, Ph.D., about Umoja’s sense of mission, technologies, and vision for the future of cell therapy.

David Alvaro (DA): Can you explain the mission and vision behind Umoja Biopharma, including the story behind the company’s name?

Ryan Larson (RL): Umoja is Swahili for unity, a theme that applies across Umoja’s mission and values. In our case, it means bringing together both a highly talented and passionate staff and multiple differentiated technology platforms intended to overcome major challenges associated with the treatment of solid tumor cancers. In the current cell and gene therapy space, CAR-T cell therapies continue to demonstrate transformational benefit for patients with hematological malignancies. However, patient access to these medicines continues to face significant challenges. In addition, there are subsets of patients that do not respond –– or relapse –– following treatment with the current class of cell therapies. Furthermore, expanding this transformational impact beyond hematologic malignancies to solid tumors has proven challenging, largely due to heterogeneity and escape mechanisms employed by solid tumors.

At Umoja, we are building off-the-shelf delivery solutions to enable patient access and an improved patient experience. In addition, we are integrating multiple technologies into drug products intended to overcome the key challenges associated with resistance or lack of response to currently available therapies.

These technologies include internally developed platforms and technologies first developed at Seattle Children’s Research Institute and Purdue University. The founders and leaders of Umoja have a great deal of experience in the cell and gene therapy space, both in academia and industry. Umoja’s founders include our Chief Executive Officer Andy Scharenberg and Chief Technical Officer Ryan Crisman, in addition to Phil Low and Mike Jensen, who are professors at Purdue and Seattle Children’s Research Institute and Seattle Children’s Hospital, respectively. In addition, David Fontana, former Global Lead of Breyanzi, is our Chief Operating Officer.

DA: You mentioned the considerable success that CAR-T cell therapies have had in the treatment of hematological cancers. Do you expect to see measurable progress with solid tumors in the near future?

RL: There have been significant advances in the context of a variety of different immunotherapy approaches for the treatment of solid tumors, including immune checkpoint blockade, bispecific-type approaches that engage the immune system to attack cancers, and so on. However, I think that limitations remain in terms of the ability to overcome the heterogeneity of solid tumors, including both the heterogeneity across different types of solid tumor cancers and patient heterogeneity within each type.

While the current class of immunotherapies has moved the needle in terms of overcoming this heterogeneity, there is still a lot of room for improvement. For instance, layering checkpoint inhibitors on top of other checkpoint inhibitors might continue to move the needle, but it might also raise toxicity issues and may select for alternative resistance mechanisms.

There have been hints of promise for the application of CAR-T cell therapy in solid tumors. The majority of current CAR-T cell therapy approaches in clinical trials are limited in the number of tumor targets engaged, and targeting one aspect of a tumor is not going to be sufficient to overcome tumor heterogeneity and the escape mechanisms that exist in many solid tumor microenvironments. There has also been evidence of activity in the context of tumor-infiltrating lymphocyte (TIL) therapy, which engages a broad repertoire of endogenous antitumor immune specificities. Unfortunately, manufacturing TIL therapies can be extremely challenging.

Overall, there is considerable evidence that we are moving in the right direction for unlocking the potential of cell therapy for the treatment of solid tumors. However, there is a need for advancements across all the different modalities. In some cases, targeting multiple aspects of solid tumors may require combinations of those modalities or different approaches to combining those modalities into unique delivery platforms, such as engineered lentiviral vectors or cells.

DA: What differentiates Umoja’s approach to developing solutions to the challenges remaining in the field of oncology?

RL: It comes back to the name Umoja: this idea of unity. We think of unity in terms of bringing together differentiated technology platforms into therapeutic products. We think of unity in terms of Umoja as a high-performing team. We think of unity with respect to our existing and future partnerships. And we think of unity in terms of Umoja’s vision to revolutionize patient access to therapy and the patient experience.

Umoja is unique in that we’ve identified some of the key challenges in the solid tumor space and are integrating novel technologies with the goal of solving many of those challenges simultaneously in a single delivery platform. That’s where the vision translates into our four platform technologies.

There are different levels to Umoja’s technologies. One level relates to how therapeutic effects are delivered, for which we have two approaches:

  • VivoVec™ is a surface-engineered lentiviral vector platform designed to be administered directly to the patient, enabling generation of CAR-T cells in vivo.

 

  • Our induced cytotoxic innate lymphocyte (iCIL) platform is a synthetically differentiated allogeneic cell therapy product that is manufactured ex vivo from induced pluripotent stem cells (iPSCs) that have been genetically engineered to express tumor-targeting CARs.


Both platforms are modular and compatible with a multitude of different targeting modalities for treating many different types of cancer.

In addition, Umoja is developing solutions to overcome challenges related to solid tumor heterogeneity and therapeutic cell engraftment, expansion, and persistence with our TumorTag™ and RACR™ technology, respectively. Both of these technologies are compatible with the above-described delivery platforms.

  • TumorTags are bispecific small molecular adapters that are specific for unique tumor targets and compatible with a single adapter-specific CAR termed TagCAR, such that an engineered cell expressing the TagCAR can be combined with multiple TumorTags to simultaneously target multiple elements of the solid tumor microenvironment. This approach is intended to address the challenges associated with solid tumor heterogeneity and antigen-escape mechanisms.

 

  • The rapamycin-activated cytokine receptor (RACR) technology system is designed to enable small-molecule controlled and consistent delivery of engraftment, pro-survival, and expansion signals to an engineered cell, whether engineered to express the RACR system in vivo using the VivoVec platform or ex vivo within our induced cytotoxic innate lymphocyte (iCIL) platform. In addition, rapamycin can inhibit immunogenicity response against the VivoVec particles or transgenes expressed by engineered cells. Indeed, rapamycin has been used to inhibit or suppress transplanted organ rejection for decades. In the context of our allogeneic cell therapy product, it can inhibit the anti-allograft response against our therapeutic cells.


This technology is important because immune cells in general require these pro-survival signals to engraft, expand, and persist in the patient following treatment –– all of which are necessary to maintain an appropriate exposure window of therapeutic cells to mediate the desired antitumor effect. Tumors are large and, in some cases, rapidly growing, and a sufficiently large therapeutic cell exposure area under the curve is required to eradicate the tumor cells. Common approaches to achieve a desired exposure profile involve lymphodepleting chemotherapy followed by dosing of therapeutic cells. In the autologous CAR-T cell setting, therapeutic cells expand dramatically in response to the trophic factors made available by the lymphodepleting chemotherapy and cognate antigen; this expansion correlates with both positive clinical response and toxicity. In the allogeneic cell therapy space, high therapeutic cell doses are employed due to limitations in engraftment and expansion capacity, and the high and in some cases multiple dose regimens can have a real impact on drug product supply in the context of an off-the-shelf therapy. We are able to promote engraftment, expansion, and persistence engraftment through our RACR system.

The RACR system may allow us to eliminate the toxic lymphodepleting regimens currently employed in the adoptive cell therapy space. Lymphodepletion is effective at allowing the engineered cells to engraft and expand through making available key cytokines that provide pro-survival and expansion signals, but it carries both short-term and long-term toxicity risks and thus can contribute to variability in the safety and efficacy of the overall treatment. It also eliminates a population of endogenous immune cells that are likely providing antitumor benefit synergistic or complementary to the engineered cell population, as well as providing long-term antitumor benefit. Some patients cannot undergo lymphodepleting chemotherapy because they’re too sick, which limits access to these therapies.

DA: Are there other companies developing therapies that avoid the issues associated with lymphodepletion, and how do those approaches compare with yours?

RL: There are different approaches being pursued, and in establishing a relevant strategy, it is important to understand the pleiotropic effects of lymphodepleting chemotherapy as they pertain to engraftment, survival, and expansion of the types of therapeutic cells that are being employed. In the allogeneic cell therapy space, a number of companies are employing hypo-immune editing, in which numerous features that make engineered allogeneic cells visible to the patient’s immune system are eliminated using gene editing. Another involves engineering cells to constitutively express key pro-survival factors, such as IL-15. Unlike our RACR system, which is developed and engineered to synthetically replicate common gamma-chain cytokine signaling, including both IL-2 and IL-15, these other systems comprise cells engineered to overexpress IL-15 constitutively. Further advanced approaches include engineering of orthogonal cytokine and cytokine receptor systems distinct from the endogenous pathways, however this approach alone does not address all the features of lymphodepleting chemotherapy.

The RACR system is designed to enable suppression of immune responses against a drug, whether it be a VivoVec particle or therapeutic cell expressing non-native transgene, through rapamycin-mediated effects on non-engineered cells, while simultaneously providing pro-survival and proliferative signals through replicating IL-2/15 signaling. If rapamycin is withdrawn, the signal rapidly dissipates, which is expected to provide a level of control that does not exist in the current class of cell therapies that rely on the presence of endogenous trophic factors to expand, which are highly variable from patient to patient.

DA: What other primary technologies is Umoja developing?

RL: We are developing modular technology platforms compatible with a variety of tumor-targeting and synthetic biology approaches and leveraging those platforms to develop a drug product that, when combined with our TumorTag portfolio, addresses key challenges associated with solid tumor mechanisms of resistance and escape. For this application, Umoja has developed TagCAR, another technology presented as a poster at the Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting in early November 2022 by Kristen Mittelsteadt. This system comprises a CAR that is specific for an adapter present on our TumorTags, which are bispecific adapter molecules. One side of the bispecific targets a tumor-specific antigen, while the other is the adaptor molecule for which our universal TagCAR is specific. Conventional CAR technology typically involves a CAR that is specific for a tumor antigen expressed on the cell surface. The easiest example is CD19 on a CD19+ tumor cell, which is also expressed on endogenous B cells.

What we showed in the SITC poster was proof of concept for the combination of our UB-VV200 drug product, a VivoVec particle, combined with the folate receptor (FR)-specific TumorTag UB-TT170, to eradicate FR-expressing solid tumors in a xenograft mouse model. UB-VV200 is a VivoVec particle that is designed to engineer T cells in vivo to express the RACR and TagCAR. The UB-TT170 TumorTag targets FRs, which are expressed in a variety of different tumor types, including gynecological malignancies and pediatric osteosarcoma. Ex vivo–manufactured TagCAR T cells in combination with our TumorTag UB-TT170 are being administered to treat patients in an active clinical trial in pediatric osteosarcoma right now. The intent there is to show proof of concept in the clinic for the TagCAR–TT170 combination while we progress through preclinical development of our UB-VV200 product candidate, which generates TagCAR T cells in vivo following direct administration of UB-VV200 to the patient.

DA: How big is your current library of TumorTags, and how do you see that growing?

RL: The universality of the system allows for flexibility in the type and number of TumorTags that can be employed, –– you can imagine that the space could be as big as you want it to be depending on what is required to overcome the solid tumor challenges highlighted above.

Umoja currently has four TumorTags in our pipeline. The TumorTag furthest in development is the folate receptor–targeting TumorTag UB-TT170, which is already in the clinic in the ENLIGHTen trial (NCT05312411). We also have tags under development targeting prostate-specific membrane antigen (PSMA), carbonic anhydrase nine (CAIX), and fibroblast-activating protein (FAP), all of which are expressed on various aspects of the tumor microenvironment, including tumor cells, tumor stroma, and immunosuppressive myeloid cells.

The TagCAR–TumorTag system is anticipated to provide many advantages related to control of TagCAR-mediated antitumor response. We contemplate that dosing regimens would be designed to minimize T cell dysfunction that is often encountered in the context of chronic antigen exposure and conventional CARs that bind directly to the tumor-expressed target antigen. Furthermore, to manage a potential toxicity event, TumorTag could be withdrawn and/or sodium fluorescein, an FDA-approved drug, could be administered to stop the TagCAR T cell–TumorTag interaction. A common side effect of CAR-T therapy is cytokine-release syndrome (CRS) resulting from rapidly expanding CAR-T cells activated by their cognate antigen and producing cytokines as well as interacting with pro-inflammatory myeloid cells. Conventional CAR-T cell therapies directly target tumor antigens, resulting in a fixed engagement between the tumor cell and the CAR, an interaction that is impossible to reverse in a controlled manner. With Umoja’s approach using the universal TagCAR combined with a TumorTag, if CRS occurs, it is believed that withdrawal of the TumorTag and infusing the patient with sodium fluorescein would displace the CAR-T cell from the tumor cell.

DA: Do you have any specific data regarding the performance of the VivoVec platform that you want to share?

RL: We shared data at SITC demonstrating in models of solid and liquid tumors that VivoVec engineers highly potent and persistent CAR-T cells in vivo that mediate rapid and durable antitumor responses in tumor xenograft models. In models of hematologic malignancy with an anti-CD19 CAR, the in vivo–generated CAR-T cells eradicate a primary tumor and persist and confer resistance to a tumor re-challenge. That speaks to the durability and the persistence of the properties of our T cells and the benefit of engineering cells inside the patient’s own body –– in contrast to conventional ex vivo manufacturing of primary T cells, in which extensive manipulation results in dysfunction.

In addition, we shared data from our RACR-engineered iPSC-derived iCIL platform at SITC. In this platform, we are able to leverage the RACR system both in the cell therapy manufacturing process and in the patient. Engaging the RACR system provides a controlled and consistent synthetic signal that promotes the differentiation and expansion of large numbers of therapeutic cells. While an iPSC-derived therapy offers the promise of an unlimited starting material, challenges remain with regard to the differentiation from iPSC to the intended therapeutic immune cell type. The current iPSC-derived cell manufacturing paradigm is fraught with technical bottlenecks that impact yield and scalability. Control of the differentiation and expansion of cells leveraging synthetic biology is a novel approach that overcomes the aforementioned challenges. Our presentation at SITC showed that our RACR-engineered iPSCs undergo a directed differentiation –– termed Synthetic Receptor Enabled Differentiation (ShRED™) –– that results in substantial yields of progenitors and induced cytotoxic innate lymphocytes. The ShRED approach is scalable in 3-D suspension bioreactor format and eliminates requirements for many complex raw materials, including feeder cells and cytokines employed in conventional cell therapy manufacturing. The yields achieved in the ShRED approach will reduce CMC constraints and enhance the potential benefit afforded by the RACR-engineered iCIL in the context of being able to dose at sufficiently high levels to achieve the exposure AUC (area under the curve) needed to achieve meaningful clinical responses. Furthermore, rapamycin treatment–mediated suppression of the endogenous immune system and engagement of the RACR system should further enhance the antitumor engraftment, expansion, and persistence relative to the current allogeneic cell therapy paradigm. Through the unprecedented yields achieved, we are able to deliver extremely high doses of iCILs in preclinical models with no apparent toxicity and rapamycin + RACR–enhanced antitumor control in a solid tumor xenograft model relative to controls treated with a conventional IL-2+IL-15 cytokine cocktail typically administered in combination with NK (natural killer) cells.

DA: How do you see your different technologies interacting, and what different combinations are you exploring?

RL: The VivoVec platform is a surface engineered lentiviral vector particle with a genetic payload that encodes a CAR and the RACR transgene. The VivoVec surface engineering includes a multidomain fusion protein that is composed of proprietary ligands that promote selective and high avidity binding to T cells. As a result of this novel surface engineering, the VivoVec lentiviral particle is able to selectively target, activate, and transduce T cells in vivo. The transduction results in integration of the RACR and the CAR into that T cell’s genome such that the T cell is reprogrammed to express the RACR and CAR. The CAR payload can be either a fixed-specificity CAR (e.g., CD19, BCMA, ROR-1) or our TagCAR. We have substantial data in tumor xenograft mouse models demonstrating the benefit of the novel surface engineering in the generation of CAR T cells in vivo that are able to mediate potent antitumor activity, in models of both solid and liquid tumors.

Combining VivoVec technology with the TumorTags involves administration of the VivoVec particles to a patient to generate a population of TagCAR T cells. The TumorTag is then administered to decorate tumors, enabling tumor targeting by the TagCAR T cells, which are specific for the adapter present on all of the TumorTags. The CAR-T cells are thus able to find their cognate antigens and mediate antitumor efficacy against the tumor cells bound by those TumorTags.

For the ex vivo–engineered RACR–iCILs, iPSCs are engineered to express the RACR system and a CAR. The RACR system is engaged during the manufacturing process and provides consistent Jak/Stat signaling, which promotes differentiation and expansion of progenitors and the iCIL drug product, substantially reducing the complexity, in contrast to conventional cell therapy manufacturing, which requires many complex cytokines and feeder cells. This approach results in the generation of a large number of the appropriate progenitor cell types as well, including hematopoietic cells and iCILs. The yields that we observe are truly differentiated from what we can see across the competitive landscape. Overall, the manufacturing process is greatly simplified and is anticipated to overcome many of the challenges that exist in the allogeneic cell therapy manufacturing setting, with the intent being that clinical application (dose level and number of doses) is not limited due to CMC constraints.

DA: How do you envision a technology like VivoVec impacting the patient experience?

RL: In our R&D efforts, we are thinking about all aspects of patient access, safety, and efficacy. We are translating our two delivery platforms (VivoVec and iCIL) into truly off-the-shelf therapies with cutting-edge manufacturing processes developed and produced in our own manufacturing facility. Our delivery platforms are composed of synthetic biology and targeting properties that enable unrivaled control in terms of safety and efficacy, with the RACR system potentially replacing the need for lymphodepleting chemotherapy and providing consistent pro-survival and persistence signals to engineered cells in vivo and the TumorTag portfolio enabling controlled targeting of TagCAR T cells to multiple tumor targets simultaneously, with the ability to turn that signal on and off or to modulate through TumorTag dosing regimens. For the current class of CAR-T therapies, the processes that patients go through to receive one of those therapies are quite extensive. For autologous therapies, patients undergo leukapheresis, and the resultant material is shipped off for engineering and expansion at a centralized manufacturing facility. Furthermore, process and product consistency are challenging to achieve with an autologous cell therapy where significant variability is introduced through the patient cells. Meanwhile, that patient is potentially on a bridging therapy to ensure that they can survive until their cell product is ready to be administered, which can be weeks to months. Patients also have to undergo lymphodepleting chemotherapy before receiving their cell product. While there is growing movement into outpatient treatment paradigms, executing these treatments in this type of setting is challenging, given the toxicity profile associated with those types of CAR-T products.

Allogeneic cell therapies are a little bit different in that they are considered off-the-shelf products. However, they generally still require lymphodepleting chemotherapies, and persistence and durability have been lacking in the allogeneic cell therapy space.

DA: Are Umoja’s technologies completely dedicated to building the company’s internal pipeline, or are you looking to partner with other companies or license them out?

RL: Both, absolutely. We are developing a pipeline of therapeutic products on the foundation of our integrated core technologies. Both delivery platforms (VivoVec and RACR-iCIL) are modular, and they are compatible with any number of tumor-targeting moieties. If a development partner has an existing CAR cassette that they want to deliver to a cell in vivo, they can drop it into our VivoVec particle or our engineered RACR–iCIL platform. We are actively partnering on the technology front with an ongoing collaboration with TreeFrog Therapeutics, a next-generation iPSC manufacturing technology. We have a therapeutic R&D collaboration with IASO Biotherapeutics to evaluate our RACR–iCIL platform together with their best-in-class CAR technology in AML (acute myeloid leukemia). For our internal pipeline, Umoja is currently focused on solid tumor oncology with our TumorTags, but we’re very open to expanding the application of our platform technology to develop therapeutics with partners. I can also see applications beyond oncology for our platform technologies.

DA: Could Umoja’s technologies be used with different types of CAR cells beyond T cells?

RL: Theoretically, yes. Our ex vivo allogeneic cell therapy process is leveraging the RACR system to generate first hematopoietic progenitors. Those hematopoietic progenitors are theoretically capable of repopulating the white blood cell milieu, including a large variety of cell types. Our focus right now is on a cytotoxic innate lymphocyte, which is somewhat akin to an NK cell, although we see quite distinct features from a conventional NK cell. In particular, the fitness and proliferative potential of our iCILs is quite unique when compared with conventional iPSC-derived NK cells or even conventional blood-derived NK cells. But we absolutely do have hematopoietic progenitors that could be differentiated into a variety of different effector cell types.

DA: Are there any therapeutic pipeline programs at Umoja you would like to particularly highlight?

RL: The ENLIGHTen clinical trial evaluating the combination of ex vivo–manufactured TagCAR expressed in T cells together with our small molecule adapter TumorTag UB-TT170 is actively enrolling. Building on that, ongoing efforts are underway to develop our first VivoVec product, UB-VV200. In this case, the VivoVec particle has all the unique surface engineering components with a payload that encodes the RACR and universal TagCAR. It will allow engineering of cells in the patient to express that universal TagCAR, and when combined with our suite of TumorTags will allow effective tumor targets. We expect to file an IND as soon as 2023.

The ex vivo–manufactured, iPSC-derived cytotoxic innate lymphoid cells or lymphocytes program is currently in the preclinical phase, with IND filing anticipated as soon as 2024.

DA: Going forward, is Umoja looking to follow that existing pipeline through before expanding into other areas or to do both simultaneously?

RL: Our near-term focus is bringing forward a successful UB-VV200 and UB-TT170 combined IND as early as 2023. With that, our internal pipeline becomes TumorTags. We will develop this first TumorTag cocktail and then start to layer on additional tags.

With that being said, another goal is to expand the pipeline through external partnerships: developing our VivoVec and iCIL platforms with partners who have active therapeutic programs complementary to our own and tumor-targeting technology that can plug and play into either platform.

In addition to our pipeline and product development efforts, we also have an incredible Discovery organization that is continuing to progress our core technologies and continuously pushing the leading edge of science with patients in mind.

DA: Given the many different disciplines involved in Umoja’s technologies, can you tell me about your R&D team, the different kinds of expertise they bring to bear, and how that is all organized and integrated?

RL: The Umoja team is incredibly diverse in terms of breadth and depth. We have deep expertise in lentiviral vector biology, synthetic biology, stem cell biology, and immunology with respect to targeting and engaging different immune cell types with VivoVec products and how engineering those cells in vivo in a patient creates therapeutic effects. Altogether, we have a highly collaborative R&D team across these areas that enables rapid advancement of novel discoveries into our product pipeline.

Another unique feature of Umoja is that we are building our own manufacturing facility in Louisville, Colorado. For that, we have an incredible multidisciplinary team that is able to translate our deep expertise in lentiviral vector biology, iPSC, and immune cells to GMP manufactured products. Such a capability is unique for a small biotech and allows Umoja to be nimble, move fast to the clinic, and iterate as we learn.

DA: Looking forward, how do you see the CAR-T sector and cell therapy as a whole evolving? What impact do you think Umoja Biopharma and its technologies might have on that evolution?

RL: With the transformational impact of the current class of cell and gene therapies and the potential of our platforms to further positively impact patients in solid tumor indications, we are working diligently to advance our pipeline. I’m optimistic that in five years we will have successful early-phase clinical data and will be entering into later stages of clinical development with a line of sight to a future commercial product. We will also be building out our manufacturing capabilities to make sure that we can support that transition from first-in-human phase I clinical trials into pivotal trials, commercial production, and beyond.

I can also see — in the next number of years — expanding the applications of these therapies beyond T cells or NK cells. There are obviously other therapeutic cell types that can be leveraged in oncology, and I see potentially expanding beyond oncology. Such programs would likely proceed in collaboration with a partner that has expertise in areas outside of oncology.

In the near term, we need to focus on showing that these types of products are as transformational as we believe them to be. Achieving that goal will open up so many opportunities for Umoja and for patients.

 

Cautionary Note Regarding Forward-Looking Statements

This article contains forward-looking statements about Umoja Biopharma, Inc. (the “Company,” “we,” “us,” or “our”). The Company has based these forward-looking statements largely on its current expectations, estimates, forecasts and projections about future events and financial trends that it believes may affect its financial condition, results of operations, business strategy and financial needs. In light of the significant uncertainties in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. These statements are subject to risks and uncertainties that could cause the actual results to vary materially, including, among others, the risks inherent in drug development such as those associated with the initiation, cost, timing, progress and results of the Company’s current and future research and development programs, preclinical and clinical trials, as well as the economic, market and social disruptions due to the ongoing COVID-19 public health crisis. Except as required by law, the Company undertakes no obligation to update publicly any forward-looking statements for any reason. 

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