ImmunityBio, Inc. 10-K

ITEM 1. BUSINESS. Forward-Looking Statements This Annual Report contains forward-looking statements within the meaning of Section 27A of the Securities Act and Section 21E of the Exchange Act that are based on our management’s beliefs and assumptions and on information currently available to our management. Forward-looking statements include, but are not limited to: • our ability to successfully commercialize ANKTIVA; • our ability to obtain incremental approvals for ANKTIVA for new indications from the FDA or clearances or approvals from international regulatory agencies for the treatment of patients with NMIBC or other indications; • potential future uses and applications of ANKTIVA, including as a lymphopenia rescue agent, and use in cancer vaccines and across multiple tumor types; • our ability to develop next-generation therapies and vaccines that complement, harness, and amplify the immune system to defeat cancers and infectious diseases; • our ability to obtain additional financing to fund our operations and complete the commercialization of our approved product and the development and commercialization of our other product candidates; • our ability to meet our payment obligations under the RIPA and to service the interest on our related-party promissory note and repay such note, to the extent required; • our ability to comply with the terms, conditions, covenants, restrictions, and obligations set forth in the RIPA and related transaction documents; • our expectations regarding the potential benefits of our strategy and technology; • our ability to forecast operating results and make period-to-period comparisons predictive of future performance due to fluctuations in warrant and derivative values; • our expectations regarding the operation and effectiveness of our product candidates and related benefits; • our ability to utilize multiple modes to induce cell death; • our beliefs regarding the benefits and perceived limitations of competing approaches, and the future of competing technologies and our industry; • details regarding our strategic vision and planned product candidate pipeline; • our beliefs regarding the success, cost and timing of our product candidate development activities and current and future clinical trials and studies, including study design and the enrollment of patients; • the timing of the development and commercialization of our other product candidates; • our expectations regarding our ability to utilize the Phase 1/2 aNK and haNK ® clinical trials data to support the development of our product candidates, including our taNK, t‑haNK ™ , MSC, and M-ceNK ™ product candidates; • our expectations regarding the development, application, commercialization, marketing, prospects and use generally of our product candidates, including hAd5 constructs, and PD-L1 t‑haNK and M-ceNK; • the timing or likelihood of regulatory filings or other actions and related regulatory authority responses in the U.S. and jurisdictions outside of the U.S., including any planned IND, BLA, NDA or MAA or similar filings or pursuit of accelerated regulatory approval pathways or orphan drug status and Breakthrough Therapy, Fast Track or RMAT designations and any designation’s eventual impact on BLA submission or approval timing and or approval probability; • our ability to implement an integrated discovery ecosystem and the operation of that planned ecosystem, including being able to regularly add neoepitopes and subsequently formulate new product candidates; • the ability and willingness of strategic collaborators to share our vision and effectively work with us to achieve our goals; 1 Table of Conten t s • the ability and willingness of various third parties to engage in research and development activities involving our product candidates, and our ability to leverage those activities; • our ability to attract additional third-party collaborators; • our expectations regarding the ease of administration associated with our product candidates; • our expectations regarding patient compatibility associated with our product candidates; • our beliefs regarding the potential markets for our product candidates and our ability to serve those markets; • our expectations regarding the timing of enrollment and submission of our clinical trials, and protocols and timing of data read-outs related to such trials; • our ability to produce a cytokine fusion protein, a DNA or recombinant protein vaccine, or a cell therapy; • our beliefs regarding the potential manufacturing and distribution benefits associated with our product candidates, and our third-party CMOs’ abilities to follow cGMP standards to scale up the production of our product candidates; • our plans regarding our manufacturing facilities and our belief that our manufacturing is capable of being conducted in‑house; • our belief in the potential of our cytokine fusion proteins, DNA or recombinant protein vaccines, or cell therapies, and the fact that our business is based upon the success individually and collectively of these platforms; • our belief regarding the magnitude or duration for additional clinical testing of our cytokine fusion proteins, DNA or recombinant protein vaccines, or cell therapies, along with other product candidate families; • even if we successfully develop and commercialize specific product candidates, our ability to develop and commercialize our other product candidates either alone or in combination with other therapeutic agents; • the ability to obtain and maintain regulatory approval of our approved product and to obtain and maintain regulatory approval of any of our other product candidates, and any related restrictions, limitations and/or warnings in the label of any approved product candidate; • our ability to successfully commercialize ANKTIVA or any future approved products; • the rate and degree of market acceptance of any approved products; • our ability to attract and retain key personnel; • the accuracy of our estimates regarding our future revenue, as well as our future operating expenses, capital requirements and needs for additional financing; • our ability to obtain, maintain, protect, and enforce patent protection and other proprietary rights for our approved product and our other product candidates and technologies; • the terms and conditions of licenses granted to us and our ability to license additional intellectual property relating to our product, product candidates and technology; • our expectations regarding the results of market access initiatives and coverage under medical reimbursement policies; • shelf life of ANKTIVA drug substance and drug product and availability of product supply; • our global expansion efforts; • any government shutdown or budget disruption, which could adversely affect the U.S. and global economies, and materially and adversely affect our business and/or our future BLA submissions; • the impact on us, if any, if the CVRs held by former Altor stockholders become due and payable in accordance with their terms; and • regulatory developments in the U.S. and foreign countries. 2 Table of Conten t s Forward-looking statements include statements that are not historical facts and can be identified by terms such as “anticipates,” “believes,” “continues,” “goal,” “could,” “estimates,” “scheduled,” “expects,” “intends,” “may,” “plans,” “potential,” “predicts,” “indicate,” “projects,” “seeks,” “should,” “will,” “would,” “strategy,” and variations of such words or similar expressions. and the negatives of those terms. In addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. Statements of past performance, efforts, or results of our preclinical and clinical trials, about which inferences or assumptions may be made, can also be forward-looking statements and are not indicative of future performance or results. These statements are based upon information available to us as of the date of this Annual Report, and although we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted a thorough inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain, and investors are cautioned not to unduly rely upon these statements. This Annual Report also contains estimates, projections and other information concerning our industry, our business, and the markets for certain diseases, including data regarding the estimated size of those markets, and the incidence and prevalence of certain medical conditions. Information that is based on estimates, forecasts, projections, market research or similar methodologies is inherently subject to uncertainties and actual events or circumstances may differ materially from events and circumstances reflected in this information. Unless otherwise expressly stated, we obtained this industry, business, market, and other data from reports, research surveys, studies, and similar data prepared by market research firms and other third parties, industry, medical and general publications, government data, and similar sources. Forward-looking statements involve known and unknown risks, uncertainties, and other factors that may cause our actual results, performance, or achievements to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. We discuss these risks in greater detail in Item 1A. “ Risk Factors ” of this Annual Report. Given these uncertainties, you should not place undue reliance on these forward-looking statements as a representation or warranty by us or any other person that we will achieve our objectives and plans in any specified time frame. Also, forward-looking statements represent our management’s beliefs and assumptions only as of the date of this Annual Report. Except as required by law, we assume no obligation to update these forward-looking statements, or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, even if new information becomes available in the future. You should read this Annual Report completely and with the understanding that our actual future results may be materially different from what we expect. ImmunityBio, ImmunityBio Care, ANKTIVA, ThAnktiva, haNK, taNK, ceNK, NK-92, Nant Cancer Vaccine, NANT 001, NANT XL, NANT 001 and Design, QUILT, Outsmart Your Disease, Smart Therapies for Difficult Diseases, NantKwest, VivaBioCell, and Infacell are trademarks or registered trademarks of ImmunityBio, Inc., its subsidiaries and affiliates. ANKTIVA has been approved by the U.S. FDA for use with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors. Other than as set forth in such specific approved label, our product candidates, including N-803, are investigational agents that are restricted by federal law to investigational use only, and safety and efficacy have not been established by any agency, including the FDA. This Annual Report contains references to our products and trademarks and products and trademarks belonging to other entities. Solely for convenience, trademarks and trade names referred to in this Annual Report, including logos, artwork, and other visual displays, may appear without the ® or TM symbols, but such references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights or the rights of the applicable licensor to these trademarks and trade names. We do not intend our use or display of other companies’ products or trade names or trademarks to imply a relationship with, or endorsement or sponsorship of us, by any other companies. 3 Table of Conten t s Founder’s Vision for Next-Generation Immunotherapy A Message from Patrick Soon-Shiong, M.D., Founder of ImmunityBio, Inc. Founder’s Vision My 35-Year Quest to Change the Paradigm of Cancer Care by Activating the Body’s Immune System and Natural Killer Cells. Founder’s Hypothesis For the past 35 years, through my experience at UCLA treating both diabetic patients with pancreas transplants, and pancreatic cancer patients with pancreatic surgery (Whipple’s), I realized that the body had opposing immune systems: on the one hand, cytotoxic systems to reject the transplanted pancreas and on the other hand immuno-evasion systems to allow pancreatic cancer to grow. By 1990, I came to realize that the common denominator was the NK cell which on the one hand interacted with killer T cells to reject a transplanted organ and on the other hand, the killer NK and T cells were blocked by the tumor, allowing the tumor cells to grow. At that time, I realized that the very therapy patients were receiving (high-dose chemotherapy and radiation) aided in the destruction of the very cells patients needed to cure cancer. Of concern was the realization that the standards-of-care physicians were pursuing were based on the assumption that killing the tumor and achieving a short-term response would win the war against cancer. In fact, a short-term battle would be won by observing a response rate, but the war lost because of the destruction of important cells called lymphocytes by our chemotherapy and radiation treatment, preventing the formation of memory T cells and long-term duration of response – duration matters, T cell memory matters. Thus began the hypothesis that if we could harness the activity of lymphocytes – specifically NK and killer T cells, the potential existed to outsmart the immuno-evasion of cancer and unleash the body’s immune system to treat cancer with immunotherapy for long-term overall survival and indeed even prevent cancer in patients with high risk. However, I faced the challenge of 50 years of standards of care which relied on high-dose chemotherapy and radiotherapy. The notion that the standard-of-care would rapidly destroy these lymphocytes, the very cells needed to kill the tumor and establish T and NK cell memory, was difficult to convince the medical establishment and regulatory authorities. The possibility that our standard-of-care was indeed responsible for preventing long-term complete remissions by the inadvertent process of destroying the very system engineered in our bodies to protect against cancer and infectious disease, was the quest that required challenging. That is the mission of ImmunityBio and the recent recognition in 2025 by the FDA that ANKTIVA and PD-L1 t-haNK was granted a Regenerative Medicine Advanced Therapy (RMAT) designation for the reversal of lymphopenia in patients receiving chemotherapy and radiation therapy is a turning point for this paradigm change in cancer care. The destruction of the NK and T cells resulting in lymphopenia (low levels of lymphocytes) correlated with poor prognosis of overall survival across multiple tumor types. With our increasing knowledge of the immune system, including the discovery of T cells, NK cells and dendritic cells, and their role in cancer suppression (immuno-surveillance) and cancer growth when the tumor develops mechanisms to hide from the cytotoxic effects of NK and T cells (immune evasion), it became time to re-visit immunotherapy. Most are familiar with the breakthrough of CPI therapy, represented by antibodies that target either PD-1, PD-L1, or other molecules that act to inhibit immune cell (specifically T cell) responses to cancer. But even the efficacy of CPI therapies can be undermined by lymphopenia (lack of T cells), making the rescue of lymphopenia an overarching goal of my approach to cancer therapy. 4 Table of Conten t s This vision, which I have pursued for decades, is the transformation in the paradigm for cancer care by treating the host and activating the immune system (NK cell and killer T cell) resulting in immunogenic cell death and inducing long-term duration of response with the generation of memory T cells and memory NK cells. On the other hand, standards of care have been addressing the tumor itself (rather than the host immune system) with high-dose chemotherapy for short-term response gains. A paradigm change would be to address the host’s immune system by activating the host immune system by utilizing the tumor in the body as an antigenic source to generate a long-term durable response to the activated NK cell, T cell and memory T cell. In this way, a therapeutic cancer vaccine could be developed. Along this journey, it has been difficult to convince academia, medical cancer centers, the FDA and even the pharmaceutical industry that existing treatment paradigms for cancer are based on misplaced assumptions utilizing high-dose chemotherapy and radiotherapy by “winning the battle but losing the war.” In 2017, I proposed a General Investigational Plan to study a potential therapeutic cancer vaccine applicable to all tumor types to the FDA and was given an audience with the Oncology Centers of Excellence by the FDA leadership. The hypothesis, including the request for RMAT designation presented in the plan was as follows: “A paradigm change in cancer care is required in which a modernized treatment is based on the biology of the tumor independent of anatomy, utilizing molecular and immunological insights as to the dynamic state of the cancer in its evolution (elimination, equilibrium, and escape) and specifically tailored to the patient’s cancer altered genome, to reinstate the patient into equilibrium. The notion that the tumor tissue itself could act as a source of both antigenicity and adjuvanticity is exploited by the NANT Cancer Vaccine – a universal therapeutic cancer vaccine that acts through the orchestration of the innate and adaptive immune system across all tumor types. We hypothesize that the normal physiological protective immune system of Elimination can be reinstated by the NANT Cancer Vaccine, first by overcoming the immunosuppressed Escape state, followed by induction of immunogenic cell death and activation of effector immune cells, with restoration of the patient to a state of Equilibrium, a paradigm change in cancer care.” The leadership at the FDA listened to this presentation and subsequently while denying RMAT designation, authorized my request to pursue this hypothesis by performing Phase 1 and Phase 2 clinical trials I termed “QUILT” QU antum I ntegrative L ifelong T rial across certain indications including first-line and second-line NMIBC, second-line and third-line MCC, second-line and third-line metastatic pancreatic cancer, second-line or greater GBM, third-line metastatic TNBC and third-line metastatic head & neck cancer. I also coined the term “Quantum Oncotherapeutics” to highlight the concept that the TME is dynamic and very rapid changes occur based on the therapy we administer. This authorization was seminal in my journey to prove the importance of NK and T cells and the need to orchestrate molecules which would induce the innate and adaptive immune system to result in durable overall survival and complete remissions. Over the course of the past 8 years, the findings I describe below provide support that my hypothesis was correct and a universal therapeutic cancer vaccine may be possible. For the first time in 50 years, oncologists may now have a reason to pay more attention to a complete blood count analysis of lymphocytes (NK & T cells) as the RMAT designation – granted on February 27, 2025 for ANKTIVA and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer – is developed. Below is a summary of this journey. It is my hope that the concept of ALC will begin to be recognized by oncologists and the ratio of ANC to ALC will become a key biomarker of the current status of a patient with cancer and a predictor of outcome. The Breakthrough of NK and T Cell Rescue by IL-15 Receptor Superagonist – Overcoming Lymphopenia The standard analysis performed by oncologists following chemotherapy is the evaluation of the CBC with the differential subset of cells that make up the circulating blood levels. The focus of oncologists today in the review of the differential are red blood cells, platelet count and neutrophils. Remarkably, very little to no attention is given to lymphocyte count – the very cells (killer T cells and NK cells) that are critical for killing the tumor. Instead, in addition to platelet counts, oncologists today focus on the following subset of cells in the CBC: • Red Blood Cells (RBCs) – to determine anemia as a consequence of the chemotherapy • Neutrophils (ANC) – to determine the neutrophil level to avoid infection as a consequence of the chemotherapy 5 Table of Conten t s Oncologists are familiar with monitoring RBCs and neutrophils since therapies are available to mitigate the consequences of anemia and neutropenia by administration of, for example, EPOGEN to manage anemia and NEUPOGEN to manage neutropenia. Yet there is little focus on the cells of importance in the blood system that are directly involved in the killing of the tumor, lymphocytes (NK and T cells ), as reflected by the lymphocyte count and percentage of lymphocytes relative to the neutrophils. It is likely that attention was rarely given to the lymphocyte count and the neutrophil to lymphocyte ratio (NLR) by caregivers managing cancer patients because no therapy existed to mitigate lymphopenia. Now, we believe our IL-15 receptor superagonist ANKTIVA (also known as N-803; molecular name nogapendekin alfa inbakicept-pmln, which has been approved for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors), provides a potential treatment for lymphopenia. We believe that NAI may be the answer to the challenge oncologists have faced for the last 50 years, that is, how to address lymphopenia. The efficacy of immune CPIs, while a major step forward in cancer care, depends on the presence of T cells as well as the presence of the receptor to T cells on tumors (MHC-I and MHC-II). It stands to reason that with lymphopenia (low T cells) or MHC-I loss, T cell activity would be inhibited, and CPI therapy would fail. However reversing lymphopenia and overcoming low NK and T cell activity could result in the rescue of T cells and CPI failures. Just as EPOGEN and NEUOPOGEN are used across all tumor types regardless of the anatomy, we believe that NAI (proposed as ANKTIVOGEN in this potential indication), due to its ability to rescue lymphopenia by proliferation and activation of NK and T cells, has the potential to, if approved, overcome lymphopenia across all tumor types. We believe the FDA authorization of RMAT designation for NAI and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer places ImmunityBio on the path to a potential paradigm change in cancer care. 6 Table of Conten t s Lymphopenia in cancer and its effects on response rates to chemo and immunotherapy have been studied in detail. Studies performed in large patient populations with advanced cancers confirm that regardless of histological subtype and treatment, global and CD4+ lymphopenia are powerful independent predictors of risk of high-grade toxicity to chemotherapy. In addition, peripheral lymphopenia, pre-existing or induced by therapies in patients with metastatic solid tumors, strongly impacts their survival and CD4+ lymphopenia is a powerful marker of reduced survival. Different published studies exploring the impact of global lymphopenia or NK and T cell subsets on relapse-free survival and overall survival in patients with solid tumors show lymphocyte thresholds (% lymphopenia) generally <1,000 per microliter of blood leading to elevated relative risk scores for both relapse-free survival (1.35-3.81) and overall survival (1.25-7.70). We believe the FDA approval of ANKTIVA with BCG for treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors in 2024 and the recent RMAT designation with ANKTIVA and PD-L1 t-haNK provides the opportunity for the first FDA-approved cancer therapy (ANKTIVA in BCG Unresponsive NMIBC CIS) to be extended in patients receiving standard-of-care chemotherapy and radiotherapy, that has the potential to reverse lymphopenia – meaning the ability to resuscitate and rescue NK and T cells – the very cells of critical importance for immunogenic cell death and long-term memory against the tumor. Through its mechanisms of action to proliferate NK and T cells (as described on its label) and therefore rescue lymphopenia, I believe ANKTIVA has the potential to be the backbone of my vision for ‘Immunotherapy 2.0’ that could launch a new era and paradigm change in the treatment of cancer across all tumor types by driving memory T and NK cells with durable remission of the disease. 7 Table of Conten t s ANKTIVA overcomes tumor evasion by mitigating both the loss of T cells (lymphopenia) and the loss of the ligand to T cells on the tumor (MHC-I loss). The mechanism of potentially overcoming cold tumors will be discussed in detail further below. ABRAXANE – Immunogenic Cell Death in the Tumor Microenvironment (2005: FDA Approval) As the first step in my quest to change the paradigm of cancer care previously based on toxic high-dose chemotherapy and/or radiation, I left academia (UCLA) to develop the nation’s first albumin-bound nanoparticle of paclitaxel (nab-paclitaxel), ABRAXANE, and to institute the concept of LDMC to elicit a vaccine-like effect. LDMC is chemotherapy not used at the MTD to kill the tumor, but rather to stress the tumor and elicit release of antigens to allow the killer cells surrounding the tumor (macrophages, T cells and NK cells), to induce immunogenic cell death. Even today, the concept of albumin-bound therapy to concentrate drug at the tumor site is not always fully appreciated by the oncology community. ABRAXANE was developed to exploit the biology of the concept of transcytosis whereby the transport of albumin-bound paclitaxel across the endothelial blood vessel layer to the TME is accomplished through the gp60 receptor and the Caveolin pathway leading to entry of paclitaxel in the TME and the production of stress molecules in the tumor (DAMPs), while at the same time activating the killer macrophages (M2 suppressive macrophages to M1 killer macrophages). ABRAXANE was approved by the FDA in 2005 for the treatment of breast cancer after failure of combination chemotherapy for metastatic diseases or relapse within six months of adjuvant chemotherapy and now also has FDA approval for patients with lung and pancreatic cancer in certain indications. 8 Table of Conten t s ANKTIVA – IL-15 Receptor Superagonist Rescuing Lymphocytes and Overcoming MHC-I Loss (2024: FDA Approval) With ABRAXANE as the first pillar in this quest to change the paradigm of care, I then turned my attention to addressing lymphopenia and unleashing the “triangle offense” via the IL-15 receptor superagonist ANKTIVA. In 2024, ANKTIVA with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors was approved by the FDA, who authorized the description of the mechanism of action in the label as: Nogapendekin alfa inbakicept-pmln is an IL-15 receptor agonist. IL-15 signals through a heterotrimeric receptor that is composed of the common gamma chain (γc) subunit, the beta chain (βc) subunit, and the IL-15-specific alpha subunit, IL-15Rα. IL-15 is trans-presented by the IL-15 receptor α to the shared IL-2/IL-15 receptor (βc and γc) on the surface of CD4+ and CD8+ T cells and NK cells. Binding of nogapendekin alfa inbakicept-pmln to its receptor results in proliferation and activation of NK, CD8+, and memory T cells without proliferation of immuno-suppressive T-reg cells. In vivo, intravesicular nogapendekin alfa inbakicept-pmln alone or in combination with BCG showed anti-tumor activity when compared to BCG alone, in a carcinogen-induced model of bladder cancer in immunocompetent rats. I believe this potentially universal therapeutic vaccine, sometimes referred to as NCV (U.S. Patent #US11071774-B2), could be able to coordinate the release of antigens from tumor cells (DAMPs/neoantigens and/or shared tumor-associated antigens, TAAs) or provision of vaccine antigens with support for immune-cell activity, including cells of both the innate and adaptive immune systems, to achieve a vaccine-like effect. ANKTIVA, due to its mechanism of proliferating and activating innate (macrophages, NK cells, dendritic cells) and adaptative (T cells, iNKT cells, and memory T cells) immune cells provides the vital stimulus needed to establish immune memory. 9 Table of Conten t s Thus, I believe ANKTIVA has the potential to become the backbone for a cancer vaccine not only to potentially cure cancer (long-term duration free of disease) but also to prevent cancer. An example of the possibility of prevention is in subjects with Lynch Syndrome, a genetic condition that puts them at significantly higher risk for cancer, and with an earlier age of onset. Currently, ANKTIVA plus vaccines that deliver tumor associated antigens via adenovirus, relevant to Lynch Syndrome are being tested in clinical trials with subjects with Lynch Syndrome for their ability to prevent cancer onset. If efficacious, this novel treatment could help support that a universal cancer vaccine is indeed possible. Quantum Oncotherapeutics – A Potential Universal Therapeutic Cancer Vaccine Changing the paradigm and convincing oncologists of the need to avoid high-dose chemotherapy and implement a treatment protocol that activates the patient’s immune system rather than destroying the NK cells and T cells remains a difficult task even today. In 2017, the FDA allowed ImmunityBio (formerly NantKwest and NantCell) to initiate a series of transformative clinical trials in which the concept of inducing immunogenic cell death (ICD) was pursued. These trials entitled “QUILT” QUantum Integrative Lifelong Trials were seminal in the pursuit of a universal cancer vaccine. The clinical protocols shared an approach that followed my vision of inducing DAMPs, avoiding high-dose chemotherapy, educating T cell via dendritic cell activation and inducing NK, CD4+ and CD8+ T cell proliferation in combination with off-the-shelf CAR-NK cell therapy to overcome immunosuppressive T-reg cells and myeloid-derived suppressive cells (MDSCs). The findings from the QUILT trials have confirmed the validity of the NCV approach. In 2022, I was honored to present the concept of “Quantum Oncotherapeutics” providing updates and receiving authorization to proceed with the QUILT trials and by 2025 met with the FDA to present the update of these trials. The Challenges of Checkpoint Failure Facing Oncologists: Immunotherapy 2.0 Beyond Checkpoints By 2024, the FDA had approved the use of CPIs (pembrolizumab, nivolumab, etc.) across 17 different tumor types. However, at the 2024 ASCO Annual Meeting I believe it became apparent that responses to CPIs were frequently fleeting and that CPIs were not effective in so-called “cold tumors.” The cold tumor is defined as lacking sufficient T-cell infiltration or activity of the T cells, even with use of a CPI, in the TME, and the loss of MHC-I, the binding site on the tumor for the T-cell receptor. Thus, the lack of effect in cold tumors is driven by fewer T cells (lymphopenia) and selection of cancer cell clones without the receptor for T cells to bind to MHC-I (MHC-I loss). Given these dynamics, it is not surprising that CPIs alone often fail or elicit only transient responses. Overcoming Tumor Evasion and Converting a Cold Tumor to a Hot Tumor The addition of ANKTIVA not only rescues T cells, but also activates NK cells that have the ability to recognize tumor cells without MHC-I expression and, as a result of increased interferon-γ (IFN-γ) secretion by the activated NK cells, also has the potential to restore MHC-I expression. All of these activities act to rescue CPIs. Thus, the combination of ANKTIVA plus a CPI represents Immunotherapy 2.0. A depiction of how ANKTIVA has the potential to convert a cold tumor to a hot tumor and rescues CPIs is provided below. 10 Table of Conten t s The loss of MHC-I molecules serves as a mechanism for tumor evasion and progression during CPI therapy. This phenomenon can be understood through the lens of Darwinian selection, where tumors that are resistant to either chemotherapy or chemo-immunotherapy emerge due to the loss of MHC-I receptors on tumor cells, which are essential for T cell recognition. These highly selected resistant cells, characterized by MHC-I loss, subsequently become targets for NK cells. NK cells are specifically designed to identify and eliminate cells that lack MHC-I expression, a process known as “missing-self” recognition. 11 Table of Conten t s The evasion of tumors from checkpoint therapy through the loss of MHC-I molecules leads to the generation of MHC-I negative, or “cold” tumors. Initially, the tumor cells are “hot” and recognized by T cells activated by CPIs. However, with the loss of MHC-I, these tumor cells evade T cell detection, becoming “cold” and resulting in checkpoint therapy failure and subsequent tumor progression. An MHC negative cold tumor cell which has evaded T cell detection and hence led to progression despite treatment with CPIs is now the target of NK cells. NK cells cytotoxicity is independent of MHC-I status and independent of PD-L1 status on the tumor cell. Thus, if NK cells could be activated and proliferated, NK cells could kill these Darwinian-selected resistant cancer cells and rescue CPIs. The NK cell recognizes the MHC negative cold tumor and converts the tumor from hot to cold through IFN-γ stimulation. As a consequence, MHC-I and MHC-II are re-expressed on the tumor cell, making the cell recognizable by T cells. This dynamic activity can be enhanced by proliferation of NK, CD4+ and CD8+ T cells through IL-15 stimulation of the IL-15 receptor on NK, CD4+ and CD8+ T cells. 12 Table of Conten t s ANKTIVA, an IL-15 receptor superagonist, stimulates the IL-15 receptor on natural killer cells resulting in proliferation of the NK cell and conversion of the cold tumor to hot by the NK cell recognizing the MHC negative tumor and converting the cold tumor to hot. This activity of reactivating T cells allows the rescue of CPIs against PD-1. SUMMARY: ANKTIVA rescues and restores CD8+ killer T cells and memory T cells by converting MHC negative (cold) to MHC positive (hot) tumors through IL-15 stimulated NK cell activation and IFN-γ secretion with durable response and prolonged overall survival. 13 Table of Conten t s QUILT Studies Validate NCV with ANKTIVA as the Backbone I presented findings from completed QUILT studies during a 2025 program review meeting with the FDA, including the achievement of complete remissions in late-stage and advanced tumors of many types, such as NMIBC, MCC, TNBC, pancreatic cancer and head & neck cancer, validating the concept of eliciting immunogenic cell death rather than the tolerogenic cell death induced by current standards of care. A summary of the complete remissions is shown in the image below. ImmunityBio Platforms - The Development of a Universal Therapeutic Cancer Vaccine Based on the vision of activating the patient’s immune system, the company continues its efforts to demonstrate that a universal cancer vaccine that leverages the power of its platforms – backbone ANKTIVA, off-the-shelf and autologous NK-cell-based therapies, adenovirus-vectored delivered vaccines, and other technologies – provide benefit and hope not only for patients with cancer but also for those with a high risk of developing cancer. 14 Table of Conten t s Select Clinical Development Program 2025+ The future of immunotherapy appears bright and I continue my quest to drive towards a therapeutic vaccine across multiple tumor types where patients do not suffer the adverse events of high-dose chemotherapy and high-dose radiotherapy. We have made and are targeting multiple submissions to the FDA in 2025 and beyond. In February 2025, the FDA authorized an EAP allowing us to provide rBCG developed by Serum Institute to urologists to address the TICE BCG shortage in all settings where TICE BCG is approved. In addition, as announced on February 27, 2025, the FDA has granted ImmunityBio RMAT designation for ANKTIVA and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer. This RMAT designation follows clinical data of ALC and significant overall survival correlations in QUILT trials across multiple tumor types including third-line or greater metastatic pancreatic cancer, checkpoint relapsed NSCLC, and supportive data from healthy volunteers. The reversal of lymphopenia by ImmunityBio’s IL-15 receptor superagonist is consistent with the mechanism of action of ANKTIVA demonstrating proliferation and activation of NK cells, CD4+ T cells, CD8+ T cells, and memory T cells without upregulation of suppressive T reg cells and approved in the ANKTIVA label (approved for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors). ImmunityBio intends to submit a BLA for the indication of reversal of lymphopenia in patients receiving standard-of-care chemotherapy and/or radiation and for the treatment of locally advanced or metastatic pancreatic cancer which includes the first-in-class CAR-NK (PD-L1 t-haNK), and to provide data from fully enrolled clinical trials in metastatic pancreatic cancer (QUILT 88) and in checkpoint relapsed NSCLC (QUILT 3055, NSCLC Cohort) patients, as well as lymphopenia reversal across multiple tumor types (QUILT 3055, all Cohorts), with supportive data of lymphocyte proliferation in healthy volunteers (QUILT 1004). In addition, ImmunityBio intends to file an EAP for ANKTIVA and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy and submit the protocol to the FDA. 15 Table of Conten t s ImmunityBio Business, Strategy and Products Our Business ImmunityBio is a vertically-integrated commercial stage biotechnology company developing next-generation therapies that bolster the natural immune system to defeat cancers and infectious diseases. The company’s range of immunotherapy platforms, alone and together, act to drive an immune response with the goal of creating durable immune memory generating safe protection against disease. We are applying our science and platforms to treating cancers, including the development of potential cancer vaccines, as well as developing immunotherapies and cell therapies that we believe sharply reduce or eliminate the need for standard high-dose chemotherapy. These platforms and their associated product candidates are designed to be more effective, accessible, and easily administered than current standards of care in oncology and infectious diseases. Our Strategy We seek to become a leading global immunological therapeutics company by creating next-generation therapies to address serious unmet needs within urologic and other cancers as well as infectious diseases. To achieve this goal, the key elements of our strategy include: • advancing the commercialization of ANKTIVA as an integral component of immunotherapy combinations, including those with CPIs and cell therapy; • accelerating product candidates generated from our immunotherapy platforms with registrational intent to address difficult-to-treat oncological and infectious disease indications in large market segments; • continuously refining our pipeline and investing in high-value discovery, development, and manufacturing capabilities for our next generation product candidates; • continuing to prospect, license, and acquire technologies to complement and strengthen our platforms and product candidates, both as single agent and combination therapies, in order to optimize responses of the innate and adaptive immune systems to generate cellular memory against multiple tumor types and infectious diseases; and • cultivating new and expanding existing collaborations for our multi-stage pipeline to reach global scale efficiently. Our Approved Product – ANKTIVA Our lead biologic product ANKTIVA is a novel first-in-class IL-15 receptor superagonist antibody-cytokine fusion protein. On April 22, 2024, the FDA approved our product, ANKTIVA with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors (the “approved product”). ANKTIVA was approved with a label indicating an immunological mechanism of action which proliferates and activates NK, CD8+ and memory T cells without the proliferation of immunosuppressive T-reg cells leading to the establishment of memory T cells. We began commercial distribution of our approved product in May 2024. We believe there is potential for ANKTIVA to become a therapeutic foundation across all phases of treatment, including in adjunctive therapy, to amplify, reactivate or extend the efficacy of standard of care. ANKTIVA is being clinically evaluated in multiple oncology indications. We believe that other oncology indications with registration potential for ANKTIVA include other types of NMIBC ( BCG-unresponsive papillary, BCG-naïve CIS and BCG-naïve papillary), lung, colorectal, pancreatic, prostate and ovarian cancers, and GBM and NHL. Data from multiple clinical trials suggest ANKTIVA has potential to enhance the activity of therapeutic mAbs, including CPIs (e.g., pembrolizumab/Keytruda), across a wide range of tumor types, including lung cancer. Further, ANKTIVA has been observed to increase lymphocyte count in healthy adults, making it a potential therapy to rescue lymphopenia. We believe that the FDA authorization of RMAT designation for ANKTIVA and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer may lead to a potential paradigm change in cancer care. We are also exploring or pursuing several other studies of ANKTIVA in combination with our other product candidates, including in prostate cancer (ANKTIVA in combination with hAd5 PSA), colon cancer (ANKTIVA in combination with hAd5 TriAd), and NHL (ANKTIVA in combination with rituximab). We are also exploring ANKTIVA in infectious diseases, including HIV and long COVID. 16 Table of Conten t s Key Catalysts for ANKTIVA The following is a summary of selected significant developments affecting our business that occurred since the filing of our Quarterly Report dated September 30, 2024 with the SEC on November 12, 2024: • ANKTIVA received a J-code (J9028) assigned by the CMS in the U.S. for ANKTIVA (Injection, nogapendekin alfa inbakicept-pmln, for intravesical use, 1 microgram), which became effective on January 1, 2025. • With a permanent J-code awarded in January 2025, our February 2025 ANKTIVA unit sales volume grew 97% over unit sales volume in December 2024 and 67% over unit sales volume in January 2025. • ANKTIVA is now widely accessible to patients through commercial and government insurance programs (VA, DoD, Medicare). To date, commercial and governmental insurance cover over 240 million lives for ANKTIVA. • We completed the submission of MAAs for the treatment of patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors for ANKTIVA in combination with BCG to the MHRA in the UK in November 2024 and to the EMA in the EU in December 2024. The MHRA validated and accepted the MAA for review in February 2025, while the EMA accepted the MAA for review in January 2025. We are in continued dialogue for requests for information from both the MHRA and EMA, with the potential for approval in the UK and EU by 2026. • In collaboration with Serum Institute, and in connection with our exclusive global supply arrangement that we announced during 2024, in February 2025 the FDA authorized an EAP allowing us to provide rBCG developed by Serum Institute to urologists to address the TICE BCG shortage in all settings where TICE BCG is approved, and we are also testing rBCG in an FDA-approved clinical trial in the U.S. Serum Institute’s GMP capacity to manufacture large-scale volumes of rBCG, already tested for safety and efficacy in clinical trials in Europe in subjects with NMIBC, aims to address the shortage of TICE BCG, which we believe will help to ensure a reliable supply for patients in need. This initiative underscores our commitment to addressing critical supply issues and expanding the opportunity for patients and physicians to have access to high quality and quantities of BCG to initialize and maintain treatments for bladder cancer, subject to regulatory approvals. We expect to begin shipments of rBCG pursuant to the EAP during the first quarter of 2025. • In January 2025, we announced a collaboration and supply agreement with BeiGene, Ltd. (to be renamed to BeOne Medicines, Ltd.), a global oncology company, to conduct a confirmatory randomized Phase 3 clinical trial (ResQ201A-NSCLC), combining BeOne’s tislelizumab, a PD-1 CPI, and our ANKTIVA (nogapendekin alfa inbakicept-pmln) product. The Phase 3 ResQ201A-NSCLC study aims to confirm the efficacy and safety of combination ANKTIVA plus CPI therapy previously demonstrated in the QUILT 3055 trial and provide evidence of the potential for these two immunotherapeutic agents to improve overall survival in patients with advanced or metastatic NSCLC who have acquired resistance to immune CPI therapy. • On February 27, 2025, the FDA granted us RMAT designation for ANKTIVA and CAR-NK (PD-L1 t-haNK) in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer. This RMAT designation follows clinical data of ALC and significant overall survival correlations in QUILT trials across multiple tumor types including third-line or greater metastatic pancreatic cancer, checkpoint relapsed NSCLC, and supportive data from healthy volunteers. The reversal of lymphopenia by our IL-15 receptor superagonist is consistent with the mechanism of action of ANKTIVA demonstrating proliferation and activation of NK cells, CD4+ T cells, CD8+ T cells, and memory T cells without upregulation of suppressive T-reg cells and approved in the ANKTIVA label (approved for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors). We intend to submit a BLA for the indication of reversal of lymphopenia in patients receiving standard of care chemotherapy and/or radiation and for the treatment of locally advanced or metastatic pancreatic cancer which includes the first-in-class CAR-NK (PD-L1 t-haNK), and to provide data from fully enrolled clinical trials in metastatic pancreatic cancer (QUILT 88) and in checkpoint relapsed NSCLC (QUILT 3055, NSCLC Cohort) patients, as well as lymphopenia reversal across multiple tumor types (QUILT 3055, all Cohorts), with supportive data of lymphocyte proliferation in healthy volunteers (QUILT 1004). In addition, we intend to file an EAP for ANKTIVA and PD-L1 t-haNK in combination with standard of care chemotherapy/radiotherapy and to submit the protocol to the FDA. 17 Table of Conten t s 2025 Platforms and Indications Our proprietary platforms for the development of biologic products and product candidates include: Our Next-Generation Platforms i. Cytokine Fusion Proteins a. ANKTIVA ii. DNA and Vaccine Vectors a. hAd5 (PSA, Brachyury, CEA, MUC1, HPV [E6/E7], neoantigens, nucleocapsid) iii. Cell Therapies a. CD19 t-haNK b. PD-L1 t-haNK c. M-ceNK (autologous, allogeneic) Indications (Current Prioritized Studies) i. BCG-Unresponsive NMIBC with CIS (approved) ii. BCG-Unresponsive NMIBC Papillary iii. BCG-Naïve NMIBC with CIS iv. rBCG in NMIBC v. Non-Small Cell Lung Cancer vi. Pancreatic Cancer vii. Chemotherapy Radiation Lymphopenia viii. Lynch Syndrome ix. Hematological Malignancies (Liquid Tumors) x. Colon Cancer xi. Glioblastoma Multiforme xii. Non-Hodgkin Lymphoma xiii. Ovarian Cancer xiv. Prostate Cancer xv. HIV xvi. Universal Nucleocapsid Vaccine xvii. Long COVID Our Pipeline Our proprietary platforms for the development of biologic products and product candidates include: (i) cytokine fusion proteins, (ii) vaccine vectors, and (iii) cell therapies. As of December 2024, our platforms have generated nine first-in-human therapeutic agents (including one agent approved by the FDA) that are currently or planned to be studied in clinical trials in liquid and solid tumors. The indications in the table above are among the most frequent and lethal cancer types and where there are high failure rates for existing standards of care or no available effective treatment. We are constantly monitoring and prioritizing clinical development based upon the availability of our resources and the efficacy and market developments of our competitors’ products and product candidates, among other factors. Our platforms and their associated approved product and product candidates are designed to attack cancer and infectious pathogens by activating both the innate immune system, including NK cells, dendritic cells, and macrophages, as well as the adaptive immune system comprising B and T cells, in an orchestrated manner. The goal of this potentially best-in-class approach is to generate immunogenic cell death thereby eliminating rogue cells from the body whether they are cancerous or virally-infected. Our ultimate goal is to overcome the limitations of current treatments, such as CPIs, by turning immunologically cold, MHC-deficient tumors into hot tumors, and/or reducing the need for standard high-dose chemotherapy in cancer by employing a coordinated approach to establish “immunological memory” that confers long-term benefit for the patient. 18 Table of Conten t s Our Next-Generation Platforms Cytokine Fusion Proteins Cytokine fusion proteins, such as ANKTIVA, represent a novel class of biologics that improve immune responses by enhancing the therapeutic potential of cytokines and promoting lymphocyte infiltration at a site of disease. The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of key immune cells—NK and CD8+ killer T cells—that are involved in killing cancer cells. ANKTIVA is a first-in-class IL-15 receptor superagonist IgG1 fusion complex, consisting of an IL-15 mutant (IL-15N72D) fused with an IL-15Rα, which binds with high affinity to IL-15 receptors on NK, CD4+, and CD8+ T cells. This fusion complex of ANKTIVA, which confers stability and longer half-life than recombinant or native IL-15, mimics the natural biological properties of the membrane-bound IL-15Rα, delivering IL-15 by dendritic cells and drives the activation and proliferation of NK cells with the generation of memory killer T cells that have retained immune memory against these tumor clones. By activating NK cells, ANKTIVA overcomes the tumor escape phase of clones resistant to T cells without stimulating immunosuppressive T-reg cells and restores memory T cell activity with resultant prolonged duration of CR. Further, by stimulating the release of interferon-γ, ANKTIVA restores MHC-I expression, making more tumor cells targets for T-cell killing. As evidenced by its ability to increase lymphocyte counts in healthy adults in Phase 1 testing, ANKTIVA also has the potential to rescue lymphopenia, which is associated with poor prognosis in cancer before treatment or as a consequence of chemo- or radiation therapy. ANKTIVA’s mechanisms-of-action make it an ideal ‘backbone’ for combination therapy with the company’s platforms, such as second-generation hAd5 vaccines, off-the-shelf CAR-engineered NK cells, and M-ceNK cells, as well as other therapeutics including BCG, targeted antibodies, and CPIs. Leveraging our success with ANKTIVA, we are developing multi-functional cytokine fusion proteins targeting TGF-ß, PD-L1, CD16, CD20, and comprising IL-12, IL-15, and IL-21, amongst others, to further enhance NK and T cell activation directed to the TME or virally infected cells and to modulate the systemic and local immune response to accelerate immunogenic cell death. DNA and Vaccine Vectors We have developed and/or acquired rights to multiple vaccine delivery technologies for oncology to deliver common TAAs, and neoepitopes (expressed only by cancer cells) and for infectious diseases to target key viruses. These technologies can deliver DNA and protein subunits to induce B and T cell memory through activation of both CD4+ and CD8+ T cells along with antibody (humoral) responses. Adenovirus is a well-established viral vector that can be utilized as a vaccine platform to stimulate the immune system, however there is risk for a treated person to develop adenovirus immunity. Our second generation hAd5 vector has unique deletions in the early 1, (E1), early 2 (E2b) and early 3 (E3) regions (hAd5 [E1-, E2b-, E3-]), which allows it to be effective in the presence of pre-existing adenovirus immunity and lowers the risk of generating de novo vector-directed immunity. We have developed several hAd5 product candidates that have been evaluated in multiple clinical trials as potential vaccines for and treatments of certain cancers and infectious diseases. Importantly, these product candidates have shown an ability to overcome previous adenovirus immunity in preclinical models and in cancer patients. In oncology, we are clinically evaluating hAd5 product candidates in combination with ANKTIVA to yield immunological immunity in colon cancer (hAd5 TAAs CEA, MUC1, Brachyury; collectively the TriAd) and prostate cancer (hAd5 PSA), and as a single agent in HPV-associated cancers (hAd5 TAA [E6/E7]). Cell Therapies We believe that we have one of the most comprehensive clinical-stage cell-based platforms in development. Our engineered NK cells have demonstrated the ability to induce cell death in cancers and virally-infected cells through a variety of concurrent mechanisms including innate killing, antibody-mediated killing, and CAR-directed killing. 19 Table of Conten t s Off-The-Shelf Targeted High-Affinity NK Cells NK cells are a type of cytotoxic lymphocyte critical to the innate immune system. NK cells show spontaneous cytolytic activity against cells under stress such as tumor cells and virally-infected cells. After activation, NK cells secrete several cytokines such as interferon- γ (IFN-γ), tumor necrosis factor-α (TNF-α), granulocyte macrophage colony-stimulating factor (GM‑CSF), and chemokines that can modulate the function of other innate and adaptive immune cells. Our proprietary NK-92 cytotoxic cell line (also referred to as aNK) was established from a patient with clonal NK-cell lymphoma. aNK cells can be expanded in culture in the presence of cytokines (IL-2, IL-15). Our “off-the-shelf” aNK cell platform has been molecularly engineered in a variety of ways to boost its killing capabilities against cancers and virally-infected cells. Unlike normal NK cells, our aNK c ells do not express the key inhibitory receptors that diseased cells often exploit to turn off the killing function of NK cells thereby escaping elimination. Further, w e have genetically engineered our aNK cell platform to generate haNK cells engineered to express the high-affinity variant of the Fc γ receptor ( Fc γRIIIA/CD16a 158V) as well as endoplasmic reticulum-retained IL-2 that bind to antibodies with demonstrated enhanced ADCC-mediated antitumor activity (Jochems 2016). These antibody-targeted haNK cel ls are designed to directly bind to IgG1-type antibodies, such as avelumab, trastuzumab, cetuximab, and rituximab, with the intention of enhancing the cancer-killing efficacy of these antibodies by boosting the population of competent NK cells that can kill cancer cells through ADCC. Our most advanced off-the-shelf NK cell platform, CAR-targeted t-haNK cells, enables innovative, bioengineered cell lines that incorporate all the features of our haNK platform together with a CAR, such as PD-L1. Product candidates under this platform have three modes of killing: innate, antibody-mediated, and CAR-directed killing. These product candidates also include one or more additional expression elements such as functional cytokines, chemokines, and trafficking factors. These product candidates are intended to be combined with commercially-available therapeutic antibodies to effectively target either two different epitopes of the same cancer-specific protein or two entirely different cancer-specific proteins. A number of t-haNK cell lines that express CARs have been developed. Findings from a preclinical study performed in collaboration with the NCI demonstrated our PD-L1 t-haNK cells exert potent antitumor effects against MDSC and overcome T cell escape in multiple types of resistant tumors. The contribution of PD-L1 t‑haNK to antitumor efficacy is further evidenced by data reported at the ASCO meeting in June 2022 and updated at ASCO GI in January 2023 from the QUILT 88 trial of patients with advanced pancreatic cancer who were administered PD-L1 t-haNK, and ANKTIVA. The multi-modal therapy resulted in a median overall survival of 6.3 months (95% CI: 5.0, 7.2 months) in patients who had progressed after two prior lines of therapy, more than doubling the historical survival rate. haNK cells engineered with CARs targeting CD19 have shown to be effective against in vitro/in vivo models of lymphoblastic leukemia and lymphoma (Boissel 2013, Muller 2008, Romanski 2016). The CD19 t-haNK cell line combines the engineered enhancements of haNK cells with the expression of a CAR targeting CD19 and thus has potential to demonstrate robust ADCC antitumor activity against cancerous B cells and provide clinical benefit to patients with R/R NHL. Clinical trials to assess o ur t ‑ haNK product candidates have been initiated: PD-L1 t-haNK in a Phase 1 trial in TNBC and a Phase 2 trial in pancreatic cancer; and CD19 t-haNK in a Phase 1 trial in R/R B-Cell NHL. In addition, the FDA recently granted us RMAT designation for ANKTIVA and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer. Autologous and Allogeneic M-ceNK NK persistence and function can be enhanced with cytokine stimulation. Our M-ceNK cells are generated from lymphocytes collected from donors that are then pre-activated ex-vivo by exposure to interleukins -12 (IL-12), -15 (N-803) and -18 (IL-18), which results in differentiation and acquisition of enhanced responses to cytokine re-stimulation. M-ceNK have increased antitumor characteristics, including enhanced IFN-γ production and cytotoxicity against leukemic cell lines. M-ceNK cells are further distinguished by their unique cell-surface marker profile and their highly desirable feature of immune-memory, marked by their pronounced anti-cancer activity for weeks to months in duration, which has made these cells a research focus for more than a decade. We have developed a unique ability to generate a portfolio of distinct M-ceNK cell products through the application of our proprietary technology and cytokines. Also, we can manufacture these cell products for clinical delivery using our proprietary methods and overall expertise in scale manufacturing of NK cell-based products. A Phase 1 first-in-human trial is open and actively enrolling patients to study the M-ceNK platform in solid tumors (QUILT 3076). In addition, M-ceNK is being evaluated in combination with ANKTIVA and gemcitabine in patients with recurrent platinum-resistant high-grade ovarian cancer (ResQ209) and in combination with ANKTIVA and hAd5-PSA in high-risk prostate cancer (ResQ110A-B). 20 Table of Conten t s Indications (Current Prioritized Studies) Bladder Cancer In the U.S., bladder cancer was the sixth most commonly-diagnosed cancer and the fourth most commonly-diagnosed solid malignancy in men in 2024. The American Cancer Society estimates there will be 84,870 new cases and 17,420 deaths from bladder cancer in 2025. NMIBC represents approximately 75% of all bladder cancers. Radical cystectomy is a treatment to control the disease for unresponsive NMIBC; however, the procedure introduces compromise to the quality of life and additional costs. There is an urgent, unmet need to treat NMIBC and avoid radical cystectomy of the bladder in an attempt to control the disease. ANKTIVA received Breakthrough Therapy and Fast Track designations from the FDA for the treatment of BCG-unresponsive NMIBC with CIS (Cohort A) with or without papillary tumors for which we received approval from the FDA in April 2024. ANKTIVA also received Fast Track designation for BCG-unresponsive NMIBC papillary and BCG-naïve NMIBC with CIS. The receipt of such designations may not lead to a faster development process or regulatory review and may not increase the likelihood that our product candidates will receive marketing approval. In our QUILT 3032 trial, as we reported in November 2022 in NEJM Evidence , the primary end points were met for both BCG-unresponsive NMIBC with CIS with a CR rate of 71%, and BCG-unresponsive NMIBC papillary with a 12-month disease-free rate of 55%. As presented at ASCO 2022, the combination of BCG plus ANKTIVA (as measured in BCG-unresponsive NMIBC patients, Cohorts A and B combined) was well-tolerated with 1% treatment-related serious adverse events, 0% immune-related serious adverse events, and 100% bladder cancer-specific overall survival at 24 months. Low-grade treatment-related adverse events include dysuria (22%), pollakiuria (20%), hematuria (17%), fatigue (16%), and urgency (12%), and all other treatment-related adverse events were seen at 7% or less. Seminal patents covering intravesical administration of BCG and ANKTIVA were issued providing term coverage until 2035. BCG-Unresponsive NMIBC with CIS (Cohort A) – QUILT 3032 In our Phase 2/3 open-label multi-center trial of BCG-unresponsive high-grade NMIBC patients with CIS, the patients receive BCG plus ANKTIVA weekly for six consecutive weeks during induction. The patients also receive additional treatment including three weekly maintenance instillations every three months for up to 12 months and then at month 18. Patients with no disease or low-grade Ta disease at months 24, 30, and 36 are eligible for continued BCG plus ANKTIVA (Cohort A) or ANKTIVA alone (Cohort C) treatment (3 weekly instillations), at the principal investigators’ discretion. The primary endpoint of the BCG-unresponsive NMIBC with CIS trial is a CR rate at any time equal to or greater than 30% and the lower bound of the 95% CI must be greater than or equal to 20% for success. CR, or the disappearance of measurable disease in response to treatment, is evaluated at three months or six months following initial administration of BCG plus ANKTIVA (and every three months thereafter until 24 months). This endpoint would be achieved once at least 24 of the 80 patients in the trial achieve a CR. A data cut-off occurred in January 2022, which provided a median follow-up in Cohort A of approximately 24 months. Data published in NEJM Evidence in November 2022 showed a CR in 58 of 82 patients with a 71% CR rate (95% CI: 59.6, 80.3) and a median duration of CR of 26.6 months (95% CI: 9.9, [upper bound not reached]). At 24 months in patients with a CR, the probability of avoiding cystectomy and disease-specific survival was 91.4% and 100%, respectively. Also, at 24 months in all patients in Cohort A, the probability of avoiding cystectomy and of disease-specific survival was 84.1% and 100%, respectively. In December 2024, we provided an update on the full enrollment of 100 patients with BCG-unresponsive NMIBC with CIS as of November 2024 that have been treated with ANKTIVA in combination with BCG, with a 71% CR rate. In these responders, the range of durable response extended to 54 months. This data was submitted to the EMA in an MAA for ANKTIVA in the EU in December 2024. As part of planned analyses, BCG-unresponsive patients in the QUILT 3032 trial of ANKTIVA plus BCG completed PRO questionnaires, which revealed stability of both mean physical function and global health from baseline to 24 months on-study for those participants who had reached the 24-month assessment. Further, at month 6, Cohort A (CIS disease) patients that achieved a CR reported higher physical function scores than those without a CR (P=0.0659). Summary scores for the NMIBC-specific questionnaire also remained stable. These PROs, taken together with efficacy findings from both the NEJM Evidence report and subsequent follow-up, suggest a favorable risk-benefit ratio for the novel therapeutic combination. 21 Table of Conten t s In May 2022, we submitted a BLA to the FDA for our product candidate, ANKTIVA in combination with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors. In May 2023, we received a CRL from the FDA, indicating that the FDA had determined it could not approve the original BLA submission in its initial form, citing deficiencies related to the FDA’s pre-license inspection of our third-party CMOs, among other items and made recommendations to address the issues raised. The CRL that we received in response to our initial BLA submission required us to resubmit the BLA to the FDA addressing the issues in the CRL. On April 22, 2024, the FDA approved our product, ANKTIVA with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors. We are required to comply with certain post-marketing commitments, including completion of our QUILT 3032 clinical trial and annual reporting for up to four years, with a final report submission to the FDA by the end of 2029. We began commercial distribution of our approved product in May 2024. BCG-Unresponsive NMIBC Papillary (Cohort B) – QUILT 3032 In our Phase 2, open-label multi-center trial of BCG-unresponsive high-grade NMIBC papillary patients (Cohort B), the patients are receiving BCG plus ANKTIVA weekly for six consecutive weeks during induction. The patients also receive additional treatment including three weekly maintenance instillations every three months for up to 12 months and then every nine months for up to 24 months. The primary endpoint of the trial is a 12-month disease free rate greater than or equal to 30% and the lower bound of the 95% CI must be greater than or equal to 20% for success. To meet the primary endpoint, 24 out of 80 patients must be disease free at 12 months. A data cut-off occurred in January 2022, which provided a median follow-up in Cohort B of approximately 21 months. Data published in NEJM Evidence in November 2022 showed a 12-month disease-free survival rate of 55% (95% CI: 42.0, 66.8), with median disease-free survival of 19.3 months (95% CI: 7.4, [upper bound not reached]). At the cutoff date 67 of 72 patients, 93.1%, had not progressed to radical cystectomy and the 24-month disease-free survival rate was 97.7%. We are preparing to submit an sBLA in 2025 for our innovative treatment targeting BCG-unresponsive NMIBC in the papillary indication. This immunotherapy of rescuing BCG with ANKTIVA represents a step towards providing therapeutic options in patients with BCG unresponsive NMIBC in papillary disease who currently have limited treatment choices and face radical total cystectomy (removal of bladder). The addition of the BCG-unresponsive NMIBC papillary indication could expand the potential patient population benefiting from this therapy and may allow patients to avoid the high morbidity and mortality associated with radical total cystectomy. BCG-N aïve NMIBC with CIS – QUILT 2005 As discussed above, ANKTIVA received Fast Track designation from the FDA for the treatment of BCG-naïve NMIBC with CIS. We are currently enrolling patients in our Phase 2b blinded, randomized, two-cohort, open-label, multi-center trial of intravesical BCG plus ANKTIVA vs. BCG alone, in BCG-naïve patients with high-grade NMIBC with CIS (Cohort A) and NMIBC papillary (Cohort B ). Planned enrollment for Cohort A (CIS) and Cohort B (papillary) is 366 patients and 230 patients, respectively. As part of our BLA resubmission for ANKTIVA in combination with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors, we provided an update on the long-term follow-up of BCG-naïve patients in QUILT 2005 receiving ANKTIVA plus BCG for CIS± Ta/T1 in the Phase 1b trial, examining the survival of the 9 subjects who entered the trial since 2014. As initially reported in 2021, all 9 patients (100%) achieved a CR, and in an 8-year follow up, the 6 evaluable patients remain disease-free (two were deceased from causes other than bladder cancer and one was lost to follow-up) with bladder preservation over a median survival period of 8.8 years. As part of our Breakthrough Therapy designation submission for BCG-unresponsive NMIBC with CIS with or without papillary tumors described above, the FDA requested an interim analysis of 43 patients in our QUILT 2005 trial which showed an 84% CR rate at nine months in patients receiving ANKTIVA plus BCG. We continue to enroll patients and expect full enrollment in late 2025 to early 2026 with a data readout from the pivotal clinical trial in the second half of 2026. We are targeting a BLA submission to the FDA in late 2026 to early 2027. 22 Table of Conten t s NMIBC – Recombinant BCG as Alternative Source of BCG In May 2024, we announced an exclusive global arrangement with Serum Institute, the world’s largest manufacturer of vaccines by number of doses produced, to supply ImmunityBio with rBCG for use exclusively in combination with ANKTIVA, subject to regulatory approvals. We are responsible, in part, for regulatory submissions, clinical trials and commercialization efforts, and our exclusive rights under the arrangement extend to the scope of the FDA’s approval obtained by us for Serum Institute’s rBCG product in the U.S. Serum Institute’s GMP capacity to manufacture large-scale volumes of rBCG, already tested for safety and efficacy in clinical trials in Europe in subjects with NMIBC, aims to address the shortage of TICE BCG, which we believe will help to ensure a reliable supply for patients in need. In February 2025, the FDA authorized an EAP allowing us to provide rBCG developed by Serum Institute to urologists to address the TICE BCG shortage in all settings where the TICE BCG label is approved, and shipments of rBCG pursuant to the EAP are expected to begin during the first quarter of 2025. In addition, we are testing rBCG in an FDA-approved clinical trial (ResQ133A) of intravesical rBCG in participants with NMIBC eligible to receive TICE BCG. This initiative underscores our commitment to addressing critical supply issues and expanding the opportunity for patients and physicians to have access to high quality and quantities of BCG to initialize and maintain treatments for bladder cancer, subject to regulatory approvals. Lung Cancer According to the American Cancer Society, lung cancer is the second most common cancer in the U.S. In 2025, it is estimated that 226,650 new cases of lung cancer will be diagnosed in the U.S. and 124,730 deaths will be attributed to the disease. NSCLC accounts for about 87% of all lung cancer diagnoses and there are very few successful treatment options for these patients once the cancer spreads beyond the lungs. The development of CPIs in NSCLC has been revolutionary, doubling the median overall survival in some settings; however, patient response may be short lived, due to late response and/or disease progression after achieving an initial response. As with bladder cancer, ANKTIVA enhances the proliferation and activation of NK and T cells critical for targeting and killing lung cancer cells. There is therefore a strong rationale to evaluate ANKTIVA in addition to a PD-1 or PD-L1 CPI for patients with NSCLC who have relapsed after achieving an initial response to PD-1 or PD-L1 CPI therapy. Analysis of pooled data from a Phase 1/2 trial conducted from January 2016 to June 2017 in 23 patients and a subsequent investigator-initiated Phase 2 trial conducted by the Medical University of South Carolina, yielded confirmation of activity of the combination of CPIs and ANKTIVA in relapsed NSCLC relative to historical response rates. In 15 patients with PD-L1 greater than 50%, the overall response rate was 38% and the median overall survival rate was 17.1 months. These preliminary findings were favorable relative to the historical response rates seen in this patient population in the first-line setting with CPI therapy. Non-Small Cell Lung Cancer – QUILT 3055 On the basis of these findings discussed above, we initiated a single-arm Phase 2b multi-cohort basket trial of ANKTIVA and CPI combinations in patients who have previously received treatment with PD-1/PD-L1 immune CPIs per an FDA-approved indication. Patients enrolled in this trial were eligible if actively progressing on CPI therapy. Upon enrollment, patients continued on the same CPI but with the addition of ANKTIVA. Despite progressing on CPI therapy upon entry into the trial, the majority of patients reverted to stable disease and demonstrated durability of stable disease, some extending as long as nine months. Data presented at the ASCO Annual Meeting in 2021 showed that despite the patients’ prior progression on CPI therapy alone, upon entry into the trial the majority of patients experienced clinical benefit either as stable disease (49%) or a partial response (9%). Among 140 patients enrolled in QUILT 3055, the common ANKTIVA attributed grade 1 and 2 adverse events included: injection-site reaction (71%), chills (34%), fatigue (27%), pyrexia (24%), flu-like illness (13%), and decreased appetite (10%). A total of 18 grade 3 and 4 adverse events attributed to ANKTIVA have been reported among 16 patients (12%) in the trial as of February 2021. All reported grade 3 and 4 adverse events occurred at a frequency of 5% or less; two patients reported increased alanine amino transferase, increased aspartate amino transferase or increased blood alkaline phosphatase, anemia, injection-site reaction, or injection-site pain. All other occurrences of grade 3 or 4 adverse events that the clinical trial site investigators reported as suspected as being due to ANKTIVA include: decreased lymphocyte count; weight loss; influenza-like illness; injection-site pruritus; cellulitis; injection-site cellulitis; sepsis; deep vein thrombosis; hypovolemic shock; colitis; diarrhea; delirium; respiratory failure; and maculopapular rash. Based on this relatively well-tolerated adverse event profile, coupled with NK and CD8+ T cell stimulatory effects, we believe that ANKTIVA has the potential to become a standard in combination with other immunotherapies for multiple indications. 23 Table of Conten t s In September 2024, Dr. John Wrangle gave an oral presentation of the updated QUILT 3055 NSCLC pooled data at the World Conference on Lung Cancer, with data through February 2024 from several cohorts of NSCLC patients who have progressed after CPI therapy. These cohorts are: • Cohort 1a – NSCLC patients with initial response on single-agent CPI therapy and subsequently progressed on or after that therapy. • Cohort 2 – NSCLC patients having high PD-L1 expression (tumor proportion score ≥50%) and disease progression on a PD-1/PD-L1 CPI after experiencing an initial response when received CPI as a single-agent for first-line treatment. • Cohort 3 – NSCLC patients with initial response but subsequently relapsed on maintenance PD-1/PD-L1 CPI therapy when initially received CPI therapy in combination with chemotherapy as first-line treatment. • Cohort 4 – NSCLC patients currently receiving PD-1/PD-L1 CPI therapy that progressed after experiencing stable disease for at least 6 months during previous treatment with PD-1/PD-L1 CPI therapy. These results showed a median overall survival of 14.1 months in the 86 patients in the pooled analysis. This is in contrast to the overall survival of 6.1 months (Freeman et al. 2020) for patients who received any therapy post-CPI therapy progression or an overall survival of 7.5 months (Brueckl et al. 2021) for patients who received docetaxel plus ramucirumab after initial failure of first-line chemotherapy plus a CPI. The Phase 2b study demonstrated prolonged overall survival when ANKTIVA was combined with the same CPIs on which patients were progressing, validating the rescue potential of ANKTIVA for T cells and CPIs. The combination of ANKTIVA plus a CPI represents an immunotherapeutic advance for this disease, when compared to the most frequently used chemotherapy docetaxel in this setting, which has an overall survival ranging from 7 to 10 months and which is associated with high toxicities as a chemotherapeutic agent. Overall survival in checkpoint relapsed patients ranged up to 58 months. The long duration of survival is potentially a result of ANKTIVA’s mechanism of action to stimulate and proliferate memory T cells and overcome immune exhaustion or immune escape mediated by MHC-loss in checkpoint relapse via stimulation of NK cells. We plan to submit a BLA in 2025 for second-line and third-line treatment of patients with NSCLC, who are progressing on CPIs. Non-Small Cell Lung Cancer – ResQ201A Following a meeting with the FDA, we launched a pivotal, randomized, open-label Phase 3 clinical trial of ANKTIVA plus tislelizumab (anti-PD-1) and docetaxel vs. docetaxel monotherapy in participants with advanced or metastatic NSCLC who have acquired resistance to immune CPI therapy. A total of 462 patients will be enrolled 1:2 either in a control arm or an experimental arm. • Control arm: Docetaxel (standard of care) N=154. Repeated 3-week cycles with docetaxel. • Experimental arm: ANKTIVA, tislelizumab, N=308. Two 3-week cycles of ANKTIVA, tislelizumab plus docetaxel followed by repeated 3-week cycles of ANKTIVA and tislelizumab (no docetaxel). Participant randomization to either the control or experimental arm will be stratified by geographical region (North America vs. Europe vs. Asia), NSCLC histology (squamous vs. nonsquamous), and actionable genomic alterations. The primary outcome is the comparison of overall survival between the experimental and the control arms. We expect full enrollment in early 2026 and a data readout in the second half of 2027. Colorectal Cancer According to the American Cancer Society, colorectal cancer is the third-leading cause of cancer-related deaths in the U.S. in men and the fourth-leading cause in women, but it is the second most common cause of cancer deaths when numbers for men and women are combined. Colorectal cancer is expected to cause about 52,900 deaths during 2025. 24 Table of Conten t s Lynch Syndrome – QUILT 5015 (NCI) Lynch Syndrome is the most common cause of hereditary colorectal cancer. People with this syndrome harbor mutations in mismatch repair genes that put them at high risk of developing colorectal cancer. Lynch Syndrome causes about 4,300 c olorectal cancers per year. These cancers are more likely to develop at earlier ages, often before the age of 50. If someone has Lynch Syndrome, it means that their close relatives (parents, siblings, and children) have a 50% chance of having the mutation that causes it too. A Phase 2 trial sponsored by the NCI evaluates the ability of ANKTIVA in combination with our TriAd5–a combination of three vaccines targeting TAAs CEA, MUC1, and Brachyury– to reduce the incidence of cancer onset in people with Lynch Syndrome. The trial recently reached full accrual of participants in the first two open-label phases. The randomized controlled portion of the trial is now recruiting with plans to enroll up to 138 participants. Pancreatic Cancer According to the American Cancer Society, pancreatic cancer is the third-leading cause of cancer-related deaths in the U.S. in men and the fourth-leading cause in women, and is also the third most common cause of cancer deaths when numbers for men and women are combined. Pancreatic cancer is expected to cause about 52,000 deaths during 2025, with a five-year survival rate for late-stage cases of only 3%. Advanced Pancreatic Cancer – QUILT 88 Exploratory Phase 1b/2 trials in patients with second-line or greater metastatic pancreatic cancer in which ANKTIVA was combined with off-the-shelf haNK cells, other agents, and SBRT showed encouraging results in patients with advanced disease. The primary endpoints of the Phase 1b and 2 portions of the trials were safety and objective response rate, respectively. In aggregate, 82% of patients (14/17) with advanced pancreatic cancer achieved disease control following combination therapy including ANKTIVA. There were no ANKTIVA-related grade 3 or 4 adverse events reported. On the basis of these exploratory trials, together with the preclinical findings that PD-L1 t-haNK is as active as haNK + anti-PD-L1 mAbs, we initiated a first-line through third-line pancreatic cancer clinical trial that uses PD-L1 t-haNK as described below: • First-line advanced pancreatic cancer (Cohort A) . Combination of ANKTIVA with low-dose chemotherapy plus SBRT with or without PD-L1 t-haNK vs. gemcitabine/Abraxane ® as the standard-of-care control arm in this randomized trial. • Second-line advanced pancreatic cancer (Cohort B) . Combination of ANKTIVA with low-dose chemotherapy plus SBRT + PD-L1 t-haNK vs. 5FU/Onivyde ® as the standard-of-care control arm in this randomized trial. • Third-line and beyond (Cohort C) . Combination of ANKTIVA with low-dose chemotherapy plus SBRT + PD-L1 t-haNK in a single arm cohort of this trial with a primary endpoint of overall survival. In October 2021, we announced that the trial’s Cohort C was fully enrolled. Based on the strength of earlier data and the significant unmet medical need, we submitted an amendment to the FDA to increase enrollment in Cohort C. As of January 2023, as reported at ASCO GI, the median overall survival in this highly advanced group of patients (who failed two to six prior lines of treatment) was 5.8 months (95% CI: 4.9, 6.4 months) exceeding the approximately two- to three-month historical median overall survival. Of the 83 patients, 41 (49.4%) had progressed after two prior lines of therapy. Median overall survival in this group was 6.3 months (95% CI: 5.0, 7.2 months), more than doubling the historical overall survival (survival of three months as reported by Manax et al. ASCO GI 2019). In Cohort C, grade 3 or greater treatment-related adverse events included anemia (32%), neutropenia (25%), thrombocytopenia (13%) and fatigue (7%) while all other grade 3 or greater treatment-related adverse events occurred at a frequency of less than 5%. 25 Table of Conten t s On February 27, 2025, the FDA granted us RMAT designation for ANKTIVA and CAR-NK (PD-L1 t-haNK) in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer. We intend to submit a BLA for the indication of reversal of lymphopenia in patients receiving standard-of-care chemotherapy and/or radiation and for the treatment of locally advanced or metastatic pancreatic cancer which includes the first-in-class CAR-NK (PD-L1 t-haNK), and to provide data from fully enrolled clinical trials in metastatic pancreatic cancer (QUILT 88) and in checkpoint relapsed NSCLC (QUILT 3055, NSCLC Cohort) patients, as well as lymphopenia reversal across multiple tumor types (QUILT 3055, all Cohorts), with supportive data of lymphocyte proliferation in healthy volunteers (QUILT 1004). There can be no assurance that we will be successful in targeting the indication. Prostate Cancer According to the American Cancer Society, one in eight men will be diagnosed with prostate cancer with an estimated 313,780 new diagnoses in 2025. Prostate cancer is the second leading cause of cancer death in men with 35,770 deaths expected in 2025. hAd5 PSA has been evaluated in combination with related recombinant hAd5-based cancer vaccines (hAd5 Brachyury and hAd5 MUC1) in a Phase 1 study in participants with mCRPC who had not responded to standard therapies (Bilusic 2021). A total of 18 patients with mCRPC were enrolled and received at least one vaccination. A total of 62 vaccinations were given. The vaccine regimen was found to be well tolerable and safe with no DLTs. The most common adverse events were grade 1 or grade 2 and included injection-site reaction (94.4% of participants), flu-like symptoms (58.8%), and fatigue (38.9%). Treatment-related toxicities were uncommon and included grade 3 decreased lymphocyte count (n=2), grade 2 injection-site reaction (n=7), and grade 2 decreased lymphocyte count (n=1). The recommended Phase 2 dose was determined to be 5×10 11 viral particles per dose. Grade 3 significant adverse events included anemia, dehydration, hypotension, and lung infection. No significant adverse events were related to study treatment. We believe the combination of ANKTIVA, hAd5 PSA, M-ceNK cells, and standard-of-care in prostate cancer offers a unique opportunity to overcome resistance mediated by more than one mechanism, specifically, T cell exhaustion and human leukocyte antigen modulation. The overall goals of the treatment regimen are to maximize immune cell death and augment and maintain the innate and adaptive immune responses against cancer cells. High-Risk Prostate Cancer – ResQ110A We have initiated a clinical trial to evaluate a new immunotherapy combination of ANKTIVA, hAd5 PSA, and M-ceNK in men with high-risk prostate cancer who have not had prostatectomy. Participants will receive immunotherapy pre- and post-surgery. This open-label study will enroll 20 patients and assess primary endpoints of event-free survival and biochemical recurrence-free survival post-surgery immunotherapy. High-Risk Prostate Cancer – ResQ110B We have also initiated a clinical trial to evaluate the immunotherapy combination of ANKTIVA, hAd5 PSA, and M-ceNK in men with high-risk prostate cancer who are ineligible for prostate surgery and receiving external beam radiation therapy. This open-label study will enroll 20 patients and deliver the combination regimen prior to and after radiation therapy. Primary outcomes are complete pathologic response after pre-radiation immunotherapy and prostate-specific antigen levels following post-radiation immunotherapy. Glioblastoma Multiforme According to the American Association of Neurological Surgeons, GBM is the most common malignant brain tumor accounting for approximately 48% of all primary brain tumors. GBM has a low survival rate of approximately 40% in the first year after diagnosis and only 17% in the second year. In a preclinical study, we evaluated the activity of ANKTIVA alone and in combination with an anti-PD-1 antibody or stereotactic radiosurgery in a murine GL261-luc GBM model and demonstrated that ANKTIVA as a monotherapy or combination therapy with an anti-PD-1 antibody exhibits a robust antitumor immune response resulting in prolonged survival including complete remission in tumor bearing mice. In addition, treatment with ANKTIVA resulted in long-term immune memory against GBM tumor rechallenge. 26 Table of Conten t s Recurrent or Progressive GBM – QUILT 3078 A multi-center, open-label Phase 2/3 trial has been initiated to evaluate the safety and efficacy of combination therapy with ANKTIVA, PD-L1 t-haNK, and bevacizumab in patients with recurrent or progressive GBM. In Phase 2, safety of the combination will be assessed prior to Phase 3 wherein participants will be randomized to either combination therapy or bevacizumab monotherapy as the current standard of care. • Pilot (Part A). Enrollment will be initiated with a single-arm study of 10 patients to receive ANKTIVA, PD-L1 t-haNK, and bevacizumab combination therapy. Continued development of the experimental arm in Part B will be based on the overall risk/benefit of the combined treatment regimen observed in Part A. • Randomized Comparison of Combination Therapy vs. Bevacizumab Monotherapy (Part B). Part B will enroll patients to be randomly assigned (1:1) to the experimental arm or to the control arm. The trial has enrolled patients with plans to enroll up to 20 patients. Non-Hodgkin Lymphoma The American Cancer Society estimates that 80,350 people will be diagnosed with NHL and 19,390 deaths will be attributed to the disease in 2025. A Phase 1 trial evaluating ANKTIVA in combination with rituximab, an anti-CD20 mAb therapy, in patients with iNHL, who had relapsed or were refractory after two lines of therapy, was published in Clinical Cancer Research in 2021. The combination regimen of ANKTIVA with rituximab was well tolerated with a single reported grade 4 adverse event and no reported grade 5 adverse events. For patients with anti-CD20 mAb sensitive disease, the overall response rate in the SQ cohort was 78% (7 of 9) with 7 of 7 (100%) responses as complete remission. NHL types can start in B cells or T cells with B cell lymphomas being more common. Most B cell malignancies express high levels of CD19, including the majority of NHLs, such as diffuse large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma. In addition, many leukemias express high levels of CD19, including B cell precursor acute lymphoblastic leukemia, chronic lymphocytic leukemia, and hairy cell leukemia. As such, two CD19-directed CAR-T cell therapeutics are FDA-approved for use in a variety of indications including NHL and ALL. Like T cells, NK cells can be genetically modified to express CARs that recognize tumor-associated cell-surface antigens and mediate specific recognition and lysis of cancer cells. The CD19 t-haNK cell line combines the engineered enhancements of haNK cells with the expression of a CAR targeting CD19 and thus has the potential to demonstrate robust antibody-dependent cellular cytotoxicity antitumor activity against cancerous B cells and provide clinical benefit to patients with relapsed/refractory NHL. Relapsed/Refractory Non-Hodgkin Lymphoma – QUILT 3092 We have initiated an open-label, Phase 1, first-in-human trial to evaluate the safety of CD19 t-haNK as a single agent and the safety and preliminary efficacy of CD19 t-haNK in combination with rituximab only and in combination with rituximab and ANKTIVA in subjects with relapsed/refractory NHL. Ovarian Cancer The American Cancer Society estimates that 20,890 women will be diagnosed with ovarian cancer and 12,730 deaths will be attributed to the disease in 2025. A woman’s risk of getting ovarian cancer in her lifetime is about 1 in 91 and her chance of dying from ovarian cancer is about 1 in 143. Platinum-Resistant Ovarian Cancer – ResQ209 Platinum-based chemotherapy is the standard-of-care for ovarian cancer; however, 20-30% of patients have cancer recurrence following treatment and are considered platinum-resistant. An open-label Phase 2 trial of ANKTIVA plus M-ceNK in patients with platinum-resistant ovarian cancer has been initiated. In this trial, patients with platinum-resistant high-grade ovarian cancer will receive M-ceNK adoptive cell therapy in combination with ANKTIVA and gemcitabine. Participants will undergo mononuclear cell collection for M-ceNK generation, day 8 induction and every 28-day (if M-ceNK are available) maintenance dosing, along with ANKTIVA. Estimated enrollment is 20 participants. Primary endpoints are progression-free survival using RECIST 1.1 criteria, overall survival, overall response rate, duration of response, disease control rate, and CA-125 levels. Safety endpoints are adverse events, treatment-emergent adverse events and significant adverse events, graded using NCI Common Terminology Criteria for Adverse Events Version 5.0. 27 Table of Conten t s Other Oncology Indications In addition to the indications above, findings from completed QUILT studies, including the achievement of complete remissions in late-stage and advanced tumors of many types, such as MCC, TNBC, pancreatic cancer and head & neck cancer, validate the concept of eliciting immunogenic cell death rather than the tolerogenic cell death induced by current standards of care. In addition to the trials listed above, we are exploring or pursuing several other company-sponsored and investigator-initiated studies of our product candidates including in colon cancer (hAd5 CEA, ANKTIVA), prostate cancer (ANKTIVA, hAd5 PSA), head and neck cancer (ANKTIVA, hAd5 CEA, hAd5 MUC1, hAd5 Brachyury), among others. Infectious Disease Indications In addition to the trials listed above in oncology, our approved product and other product candidates are being evaluated in several other company-sponsored and investigator-initiated studies in infectious diseases. HIV HIV affects tens of millions of people globally and while ART has increased the survival of infected HIV individuals, there is currently no cure. One strategy for curing HIV is known as the “kick and kill” approach. The “kick” is to induce HIV out of its latent resting state in T cells, revealing infected cells to the immune system, and the “kill” is to eliminate the infected cells via an immune response or immunotherapy. ANKTIVA is a promising molecule to elicit “kick and kill” because of its ability to activate viral transcription in CD4+ T cells (“kick”) while strongly activating CD8+ effector memory cells and NK cells important for recognizing and killing HIV infected cells (“kill”), as well as directing these cells to sites of viral reservoirs. ANKTIVA is being evaluated in investigator-initiated trials as a single agent and in combination with broadly neutralizing antibodies to control HIV in persons living with HIV and persons with acute HIV infection. Active HIV Infection – University of Minnesota, National Institute of Allergy and Infectious Diseases Based on the hypothesis that CD8+ T cells will migrate to B cell follicles and reduce the frequency of cells with an inducible HIV provirus in HIV-infected individuals treated with ANKTIVA, a Phase 1 proof-of-concept non-randomized, open-label dose-escalation clinical trial sponsored by the University of Minnesota in collaboration with the NIAID was conducted. The primary assessment is the safety of ANKTIVA in ART-suppressed people living with HIV, along with exploratory analysis of effects on the HIV reservoir. In a 2022 report, no significant laboratory adverse events attributable to ANKTIVA were recorded, and ANKTIVA was associated with proliferation and/or activation of CD4+ and CD8+ T cells and NK cells, with a small but significant decrease in the frequency of peripheral blood mononuclear cells with an inducible HIV provirus. A separate small HIV Cure Phase 1 trial evaluating ANKTIVA in combination with haploidentical NK cells in HIV-infected patients was completed in 2023. Reported data from the study validate the hypothesis that ANKTIVA combined with NK cells has the potential to reduce viral load in people living with HIV, showing a marked decrease in HIV-producing cells in lymph nodes. The trial is complete, and results were published in May 2024. The approach was well tolerated with no unexpected adverse events. A follow-on trial is being planned to further investigate the above regimen in additional patients. Active HIV Infection – National Institute of Allergy and Infectious Diseases, Rockefeller University In June 2021, we announced the opening of a Phase 1 clinical trial sponsored by the AIDS Clinical Trials Group and the NIAID (the HIV Cure Study) that will evaluate whether ANKTIVA alone or together with bNAbs can control HIV following interruption of ART. The Phase 1 open-label, randomized trial will enroll 46 people living with HIV whose virus has been suppressed by ART for approximately two years, including at least 30% cisgender women or transgender men. This trial is actively enrolling as of January 2025. An additional and companion Phase 1 trial utilizing ANKTIVA and 2 different bNAbs sponsored by The Rockefeller University opened in December 2022. This trial completed enrollment as of January 2025. 28 Table of Conten t s Acute HIV Infection – Thai Red Cross and the U.S. Military HIV Research Program In April 2021, we announced the launch of a Phase 2 trial sponsored by the Thai Red Cross and the U.S. Military HIV Research Program. The trial enrolled 14 patients and was designed to investigate the safety, tolerability and immunostimulatory effects of administering ANKTIVA during acute HIV infection. ANKTIVA was administered subcutaneously at weeks zero, three and six (for a total of three doses) and was initiated together with antiretroviral therapy in order to determine if the immunostimulatory effects of ANKTIVA will reduce the amount of HIV present during acute infection. The trial duration for individual participants was approximately 12 weeks. It is hypothesized that ANKTIVA initiated with anti-retroviral therapy during acute HIV infection will not result in complications or additional toxicities compared with anti-retroviral therapy alone and may result in a reduced viral load in these patients by inhibiting early establishment of HIV reservoirs in infected individuals. The trial was recently completed, and data analyses are ongoing. Other Infectious Diseases We previously developed COVID-19 vaccine candidates based on our hAd5 platform that delivered DNA for SARS-CoV-2 spike (S) and nucleocapsid (N) proteins that underwent early clinical testing in the U.S. and South Africa. These trials demonstrated the tolerability of the platforms, which elicited no severe adverse events, and provided evidence of effective antigen delivery. We remain interested in forwarding the idea of a universal nucleocapsid vaccine. Studies on long-term immune responses to SARS-CoV-1, a virus very similar to SARS-CoV-2, have shown that T cell responses to the N protein can provide long-term immunity up to at least 11 years after infection. An N-based vaccine would also overcome the problem of the rapid mutation of S, which renders vaccines less effective over time and necessitates continuous re-design. Because of the cross-reactivity to N from SARS-CoV-1 and -2, we believe a ‘pan-SARS-CoV’ vaccine is possible. This strategy is crucial for developing a universal vaccine that can preemptively address the threat of new coronavirus outbreaks, ensuring long-term and wide-ranging immunity. The U.S. Centers for Disease Control and Prevention have described long COVID as a chronic condition that remains a serious public health concern. Given the consistent observation of altered immune cell persistence and function in persons experiencing symptoms of long COVID, we are exploring the potential value of ANKTIVA and our vaccine candidates in restoring immune cell function in the millions of people at risk for long COVID. Current evidence suggests long COVID may be due, in part, to persistence of SARS-CoV-2 virus in tissues and that both NK and T cell function are aberrant, resulting in persistent inflammation, damage to the blood-brain barrier, and long COVID symptoms. If this model is correct, then ANKTIVA-mediated enhancement of innate and adaptive immune responses against virus replication or residual virus-infected cells across tissues could improve long COVID symptoms. Manufacturing and Distribution We have adopted a strategic position to be vertically-integrated and are committed to the goal of developing our products in compliance with the FDA’s GMP standards for large-scale manufacturing, even during Phase 2 clinical trial development. Biological upstream and downstream manufacturing capabilities, with their attendant know-how and regulatory compliance for approval, have long lead times. We have adopted an approach for preparedness to provide our vaccine, immunotherapy, and cell therapy products at a global scale. As such, we have established our own plants and have access to facilities on a global basis. Our ability to create an efficient manufacturing process and supply chain will be important in enabling us to develop novel therapies. Our strategy is to anticipate the needs of our early-stage research and development initiatives for preclinical and eventual clinical product candidates with a focus on rapid capability to produce at scale fusion proteins, hAd5, protein subunits, toll receptor activators, and NK cell products. We believe members of our management team, many of whom have experience in both nanoparticle commercialization and large-scale injectable drug production, are capable of constructing the processes and commissioning the facilities necessary to meet our development and commercialization goals. For well-known processes, we currently work and plan to continue working with established third-party CMOs to produce drug substance and drug products. In addition, we plan to further enhance our in-house manufacturing capabilities for drug substance, drug products, and labeling and packaging. 29 Table of Conten t s Overview of our Manufacturing Model Our manufacturing capabilities include advanced technological facilities to produce and test various drug substances and drug products. Our experienced operations and quality team focuses on internal manufacturing and testing with a commitment to create robust, high quality, efficient and consistent supply that meets target product profiles. We believe our Phase 1 manufacturing process is designed to efficiently scale-up through all phases of clinical development to commercial manufacturing to drive successful commercialization. Commercial cGMP Production On April 22, 2024, the FDA approved our product, ANKTIVA with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors. We have contracted with multiple multi-national biologics manufacturers with several cGMP-compliant facilities in the U.S., Europe and Asia for production of ANKTIVA for commercial sale and for use in our clinical trials. While we believe the overall experience of these multi-national biologics manufacturers is important, the work they perform for us may involve only one of their facilities. We believe the facilities used for our commercial sales and clinical trials have robust process development and validation and quality oversight with high-capacity production suites operating multiple 2,000-20,000L production bioreactors and high-capacity fill lines. We previously received a CRL from the FDA in May 2023 in response to our initial BLA submission citing deficiencies related in part to the FDA’s pre-license inspection of our third party CMOs. We worked with our CMOs to address the issues raised, resubmitted our BLA in October 2023, and the FDA approved ANKTIVA with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors on April 22, 2024. Clinical Trial GMP Antibody and Fusion Protein Production We are committed to the goal of establishing a cGMP-compliant multi-platform facility in California, which includes a large space for the production of antibodies and fusion proteins (including ANKTIVA) to treat cancers and infectious diseases. We plan for this facility to include fully integrated biologic upstream and downstream production suites and a quality assurance/quality control release laboratory for high-capacity antibody and fusion protein production. We may also potentially use CMOs for our fusion protein candidates. Clinical Trial GMP Adenovirus We have established other facilities for adenovirus production in multiple sites in California and a site in Colorado for oncology and infectious diseases. We are committed to the goal of complying with cGMP at these facilities. We believe we possess adequate inventory to supply our ongoing adenovirus-related clinical trial activities for the foreseeable future. We may determine to outsource manufacturing to a third-party CMO beyond the clinical phase. These facilities generally have fully-integrated biologic upstream and downstream production suites and quality assurance/quality control release laboratories for high capacity, continuous, or personalized just-in-time vaccine production. Clinical Trial GMP NK Cell Therapy Production We have established other facilities for NK cell therapy product production in multiple sites in California for oncology. We are committed to the goal of complying with cGMP at these facilities. One of our sites in California is dedicated to our off-the-shelf product candidates (including PD-L1 t‑haNK and CD19), while another is primarily focused on our M-ceNK product candidates, including a training lab for our second-generation offerings. We are in the process of reviewing our expansion efforts for both our t-haNK and M-ceNK manufacturing capacity with the goal to increase our ability to supply our clinical trials and/or EAPs, as applicable. 30 Table of Conten t s cGMP ISO Class 5 Manufacturing Facility On February 14, 2022, we acquired a leasehold interest in the Dunkirk Facility. This facility has construction needs that may require an additional 12 to 18 months to complete in order for it to be used as intended. These construction needs remain as a result of an ongoing dispute with the Dunkirk Facility’s general contractor and a stay in resolving the dispute related to Athenex’s ongoing bankruptcy proceedings. In addition, and related to the delayed completion of the facility as described above, in November 2024 we received written notice from our landlord alleging non-compliance with the initial employee headcount requirement of our lease for the Dunkirk Facility. While we are seeking to resolve this matter expeditiously, there can be no assurance that we will succeed in doing so, and we may lose access to the Dunkirk Facility. See Item 1A. “Risk Factors— We are party to a public-private partnership regarding our manufacturing facility in Dunkirk, New York, and if we or our counterparties fail to meet the obligations of those agreements, it could materially impact our development, operations and prospects ” for more information. We believe this facility has the potential to provide us with a state-of-the-art biotech production center that will substantially expand and diversify our existing manufacturing capacity in the U.S. and the ability to scale production associated with certain of our product candidates. Manufacture of Platform Product Candidates ImmunityBio’s diverse product candidate portfolio and pipeline requires a broad knowledge of various manufacturing and quality assurance methods. We have invested heavily in the processes, systems, and technology to build an extensive range of manufacturing programs spanning various levels of development from IND-enablement through BLA preparation for our other product candidates. We believe our plan to selectively use third-party CMOs for certain of our assets at various stages, coupled with internal development, will give us assurance that any products will have backup manufacturing options. Distribution In connection with the approval of our product, ANKTIVA with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors, by the FDA on April 22, 2024, we engaged a leading third-party logistic provider in a title model to enable commercial distribution. We began commercial distribution of our approved product in May 2024. We have contracted with large specialty distributors and a large specialty pharmacy provider to make our commercial product available across relevant clinics, hospitals, infusion centers, and government entities. Competition We face potential competition from many different sources, including major and specialty pharmaceutical and biotechnology companies, academic research institutions, governmental agencies, and public and private research institutions. Our approved product and other product candidates that we successfully develop and commercialize will compete with current therapies and new therapies that may become available in the future. We believe that the key competitive factors affecting the success of our approved product and other product candidates will include efficacy, safety profile, convenience, cost, market access, commercial efforts, competition, and intellectual property protection. We have focused our efforts on oncology indications, with a primary focus on urology, and secondarily, infectious disease indications that are difficult to treat and with large unmet needs, and we believe our platform will be broadly applicable across multiple tumor types and infections. Based on the breadth and depth of our platforms, we believe our competitors will range from large pharmaceutical companies to emerging novel biotechnology companies. Oncology • Cytokine Fusion Proteins. This platform primarily competes with large pharmaceutical companies marketing CPIs. However, the potential exists for some of these large pharmaceutical companies to seek collaboration for the combination of ANKTIVA with their marketed CPI. In the context of NMIBC, we currently compete with Ferring Pharmaceuticals and Merck & Co., Inc. (Merck), and may compete with CG Oncology Inc., enGene Holdings Inc., Janssen Pharmaceuticals, Inc. (Janssen)/Johnson & Johnson, and UroGen Pharma, Inc. in the future. We believe this platform will also compete across oncological indications with immunotherapy fusion protein companies developing similar approaches, including Nektar Therapeutics, Neoleukin Therapeutics, Inc., Novartis International AG (Novartis), F. Hoffmann-La Roche AG (Roche), Sanofi, S.A., and Xencor, Inc. 31 Table of Conten t s • DNA and Recombinant Protein Vaccines . This platform and the associated product candidates will likely compete with other cancer vaccines. Other potential cancer vaccine competitors include Achilles Therapeutics, BioNTech SE (BioNTech), Geneos Therapeutics, Inc., Hangzhou Neoantigen Therapeutics, Inc., Merck, Moderna, Inc. (Moderna), and Roche. • Cell Therapies. This platform’s product candidates (t‑haNK and M-ceNK) face competition from several companies focused on NK cell-based approaches, including Artiva Biotherapeutics Inc., Catamaran Bio Inc., Century Therapeutics, Inc., Fate Therapeutics, Inc., Gamida Cell, Ltd., INmune Bio Inc., Nkarta Therapeutics, Inc., NKGen Biotech, Inc., and Shoreline Biosciences, Inc. In addition, our NK cell product candidates compete with other cell and molecule-based immunotherapy approaches using or targeting NK cells, NKT cells, T cells, macrophages, and dendritic cells. There are currently seven approved CAR-T cell-based treatments marketed by Autolus Therapeutics, plc (Autolus), Bristol-Myers Squibb Company (BMS) (two marketed products), Gilead Sciences, Inc. (Gilead)/Kite Pharma (two marketed products), Janssen/Johnson & Johnson, and Novartis. Additional companies focused on CAR T-related treatment approaches include Allogene Therapeutics, Inc., BMS, Cellectis SA, Celularity, Inc., Gilead, Janssen, Novartis, Pfizer, Inc. (Pfizer), and Poseida Therapeutics, Inc./Roche. There is also one approved TIL therapy from Iovance Biotherapeutics, Inc. Competitor companies focused on other T cell-based approaches include Adaptimmune Ltd. (with an approved TCR-T cell therapy), Adicet Bio, Inc., Autolus, Beam Therapeutics Inc., BioNTech, GlaxoSmithKline plc. (GSK), Sensei Biotherapeutics, Inc., and Senti Biosciences, Inc. Infectious Diseases Currently in infectious disease, ANKTIVA is being used in investigational trials primarily focused on HIV and, if approved, will likely compete with companies who have approved therapeutics for HIV, including Gilead, ViiV Healthcare Limited (a joint venture between GSK, Pfizer, and Shionogi, Inc.), Merck, BMS, and Janssen/Johnson & Johnson). Additionally, we are exploring the potential value of ANKTIVA and our vaccine candidates in restoring immune cell function in the millions of people at risk for long COVID. These efforts face competition from companies that include Pfizer, Moderna, AIM ImmunoTech, Inc., and Laurent Pharmaceuticals and also efforts to expand the label for approved generic medicines for the treatment of long COVID. Intellectual Property We strive to protect and enhance the proprietary technology, inventions, and improvements that are commercially important to our business, including seeking, maintaining, and defending patent rights, whether developed internally or licensed from third parties. Our policy is to seek to protect our proprietary position by, among other methods, filing patent applications in the U.S. and in jurisdictions outside of the U.S. related to our proprietary technology, inventions, improvements, and product candidates that are important to the development and implementation of our business. We also rely on trade secrets and know-how relating to our proprietary technology and product candidates, continuing innovation, and in-licensing opportunities to develop, strengthen, and maintain our proprietary position in the field of cancer therapeutics and immunotherapy. We expect to rely on data exclusivity, market exclusivity, patent term adjustment and patent term extensions when available, as well as on regulatory protection afforded through orphan drug designations. Our commercial success will depend in part on our ability to obtain and maintain patent and other proprietary protection for our product candidates, technology, inventions, and improvements; to preserve the confidentiality of our trade secrets; to maintain our licenses to use intellectual property owned by third parties; to defend and enforce our proprietary rights, including our patents; and to operate without infringing, misappropriating or otherwise violating the valid and enforceable patents and other proprietary rights of third parties. We have developed, acquired, and in-licensed patents and patent applications across platforms as previously described for activated NK and T cells, and memory T cell activation. With respect to activated NK and T cells, we have developed N-803, an N72D variant IL-15 complexed to a dimeric IL-15Ra/Fc fusion protein and with respect to memory T cell activation, we have developed adenoviral immunotherapies expressing TAAs such as CEA, MUC1, and Brachyury. 32 Table of Conten t s As of December 31, 2024, we own patents and patent applications related to the development and commercialization of N-803 in the U.S. and jurisdictions outside of the U.S. Our owned patent portfolio is directed to compositions of matter of N-803, methods of use of N-803, and combinations with additional therapeutics. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to N-803 are expected to expire from 2028 to 2040. If patents issue from our pending U.S. patent applications, excluding any patent term adjustment and patent term extension, such patents will be expected to expire from 2031 to 2045. For example, these patents and patent applications include claims directed to: • compositions of matter of N-803; • uses of N-803 in methods of treating cancers; • uses of N-803 in treating HIV; and • combination treatments using N-803 and additional therapeutics. In June 2024, we submitted applications to the USPTO for the extension of the patent term of several U.S. patents directed to compositions of matter of N-803, methods of use of N-803 and methods of manufacture of N-803. These applications are currently under review by the USPTO and FDA. As of December 31, 2024, we own, co-own, and in-license patents and patent applications related to the development and commercialization of cell-based therapies in the U.S. and jurisdictions outside of the U.S. Our owned, co-owned, and in-licensed patent portfolio is directed to compositions of matter of NK, haNK, and t-haNK cell lines, methods of use of these cells, and combinations with additional therapeutics. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to these cell therapies, methods of use, and combinations with additional therapeutics are expected to expire from 2025 to 2040. If patents issue from our pending U.S. patent applications, excluding any patent term adjustment and patent term extension, such patents will be expected to expire from 2034 to 2042. For example, these patents and patent applications include claims directed to: • NK cells; • haNK cells; • EGFR t-haNK cells; • CD19 t-haNK cells; • HER2 t-haNK cells; and • PD-L1 t-haNK cells. As of December 31, 2024, we own patents and patent applications related to development and commercialization of multi-functional antibody-based cytokine fusion proteins targeting the IL-12 pathway, the IL-15 pathway, TGF-ß, PD-L1 and CD20 in the U.S. and jurisdictions outside of the U.S. Our owned patent portfolio is directed to compositions of matter and methods of use of these fusion proteins. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to these fusion proteins are expected to expire from 2028 to 2039. If patents issue from our pending U.S. patent applications, excluding any patent term adjustment and patent term extension, these patents will be expected to expire from 2028 to 2044. For example, these patents and patent applications include claims directed to fusions of CPI and TAA binding antibodies and binding molecules with IL-15/IL-15Rα/Fc fusion proteins complexes. As of December 31, 2024, we own patents and patent applications related to development and commercialization of multi-functional cytokine fusion proteins targeting TGF-ß, the IL-15 pathway, the IL-21 pathway, and CD16 in the U.S. and jurisdictions outside of the U.S. Our owned patent portfolio is directed to compositions of matter and methods of use of these fusion proteins. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to these fusion proteins are expected to expire from 2039 to 2041. If patents issue from our pending U.S. patent applications, excluding any patent term adjustment and patent term extension, these patents will be expected to expire from 2039 to 2044. For example, these patents and patent applications include claims directed to fusions of human transforming growth factor receptor and/or IL-15 with tissue factor. 33 Table of Conten t s As of December 31, 2024, we exclusively own, and co-own with and in-license from the HHS, patents and patent applications related to the development and commercialization of adenovirus-based cancer and viral immunotherapies, in the U.S. and jurisdictions outside of the U.S. Our patent portfolio is directed to compositions of matter of adenovirus and methods of use of adenovirus in treating or preventing cancer and viral diseases. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to adenovirus-based cancer and viral immunotherapies are expected to expire from 2028 to 2039. If patents issue from our pending U.S. patent applications, excluding any patent term adjustment and patent term extension, such patents will be expected to expire from 2028 to 2044. For example, these patents and patent applications include claims directed to: • adenovirus vectors and virus particles comprising TAAs; and • uses of adenovirus vectors and virus particles in methods of treating cancers. As of December 31, 2024, we own U.S. patents and pending U.S. patent applications directed to therapeutics for COVID-19. Some of these patent applications are directed to the use of our adenovirus technologies for a COVID-19 vaccine. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to therapeutics for COVID-19 are expected to expire in 2040 and 2042. If any patents issue from our pending U.S. patent applications, excluding any patent term adjustment and patent term extension, such patents will be expected to expire in 2040 and 2042. As of December 31, 2024, we own patents and patent applications related to the development and commercialization of GMP-in-a-Box in the U.S. and jurisdictions outside of the U.S. Our patent portfolio is directed to GMP-in-a-Box. Excluding any patent term adjustment and patent term extension, the issued U.S. patents directed to GMP-in-a-Box are expected to expire from 2030 to 2037. For example, these patents and patent applications include claims directed to methods, bioreactors, and apparatuses for monitoring and culturing cells. The terms of individual patents extend for varying periods of time, depending upon the date of filing of the patent application, the date of patent issuance, and the legal term of patents in the countries in which they are obtained. Generally, patents issued for applications filed in the U.S. are effective for 20 years from the earliest effective filing date of a non-provisional patent application. The patent term may be adjusted to compensate for delayed patent issuance when such delays are caused by the USPTO or successful appeals against USPTO actions. There is no statutory limit on this patent term adjustment, which is generally the length of any such delays caused by the USPTO. In addition, in certain instances, a patent term can be extended to recapture a portion of the term effectively lost as a result of the FDA regulatory review period. The restoration period cannot be longer than five years, the total patent term, including the restoration period, must not exceed 14 years following FDA approval, only one patent applicable to an approved drug may be extended and only those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended. While we are seeking such patent term extensions where applicable, there is no guarantee that the USPTO and/or FDA will agree with our assessment of whether such extensions should be granted, and if granted, the length of such extensions. While we plan to seek such patent term adjustments where applicable, there is no guarantee that the USPTO will agree with our assessment of whether such adjustments should be granted, and if granted, the length of such adjustments. The duration of patents outside of the U.S. varies in accordance with provisions of applicable local law but typically is also 20 years from the earliest effective filing date. However, the actual protection afforded by a patent varies on a product-by-product and country-to-country basis and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country, and the validity and enforceability of the patent. The patent positions of companies like ours are generally uncertain and involve complex legal and factual questions. No consistent policy regarding the scope of claims allowable in patents in the field of immunotherapy has emerged in the U.S. The patent situation outside of the U.S. is even more uncertain. Changes in either the patent laws or their interpretation in the U.S. and other countries may diminish our ability to protect our inventions and enforce our intellectual property rights, and more generally could affect the value of our intellectual property. In particular, our ability to stop third parties from making, using, selling, offering to sell, or importing products that infringe our intellectual property will depend in part on our success in obtaining and enforcing patent claims that cover our technology, inventions, and improvements. With respect to both licensed and owned intellectual property, we cannot be sure that patents will be granted with respect to any current pending patent applications or with respect to any patent applications filed in the future, nor can we be sure that any existing patents or any patents that may be 34 Table of Conten t s granted in the future will be commercially useful in protecting our approved product and other product candidates and the methods used to manufacture our approved product and those other product candidates. Moreover, even our issued patents do not guarantee us the right to practice our technology in relation to the commercialization of our approved product and other product candidates. The area of patent and other intellectual property rights in biotechnology is an evolving one with many risks and uncertainties, and third parties may have blocking patents that could be used to prevent us from commercializing our approved product and other product candidates and practicing our technology. Our issued patents and those that may issue in the future may be challenged, invalidated, or circumvented, which could limit our ability to stop competitors from marketing related products or limit the length of the term of patent protection that we may have for our approved product and other product candidates. In addition, the rights granted under any issued patents may not provide us with protection or competitive advantages against competitors with similar technology. Furthermore, our competitors may independently develop similar technologies. For these reasons, we may have competition for our approved product and other product candidates. Moreover, because of the extensive time required for development, testing and regulatory review of a potential product candidate, it is possible that, before any particular product candidate can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any advantage of the patent. Our registered trademark portfolio currently contains registered trademarks in the U.S. and in foreign jurisdictions and pending trademark applications in the U.S. and in foreign jurisdictions. We may also rely, in some circumstances, on trade secrets to protect our technology. However, trade secrets are difficult to protect. We seek to protect our trade secrets and other proprietary information, in part, by entering into confidentiality agreements with those who have access to our confidential information, including our employees, contractors, consultants, collaborators, and advisors. We also seek to preserve the integrity and confidentiality of our proprietary technology and processes by maintaining physical security of our premises and physical and electronic security of our information technology systems. Although we have confidence in these individuals, organizations, and systems, agreements or security measures may be breached, and we may not have adequate remedies for any breach. In addition, our trade secrets may otherwise become known or may be independently discovered by competitors. To the extent that our employees, contractors, consultants, collaborators, or advisors use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions. See Item 1A. “Risk Factors— Risks Related to Intellectual Property ” and Item 3. “ Legal Proceedings ” of this Annual Report for risks related to our proprietary technology, inventions, improvements, and products. Collaboration and License Agreements We anticipate that strategic collaborations will continue to be an integral part of our operations, providing opportunities to leverage our partners’ expertise and capabilities to gain access to new technologies and further expand the potential of our technologies and product candidates across relevant platforms. We believe we are well positioned to become a leader in immunotherapy due to our broad and vertically-integrated platforms and through complementary strategic partnerships. Agreements shown below have been arranged in alphabetical order. The following description of certain of our collaboration and license agreements is not a comprehensive listing of all such agreements to which we are a party, and the inclusion of a description of any collaboration or license agreement is not an indication that we consider such agreement(s) to be material to our business and operations as a whole, which is a dynamic and evolving analysis and may change over time. Collaboration Agreements National Cancer Institute The company and its subsidiaries began their relationship with HHS, as represented by the NCI of the NIH in 2015. Pursuant to the CRADAs, the NCI provides scientific staff and other support necessary to conduct research and related activities as described in the CRADAs. During the term of the initial and amended CRADAs, we collaborated with the NCI on the preclinical and clinical development of our proprietary adenovirus technology expressing TAAs for cancer immunotherapy. In 2021, the CRADA was amended and the research plan was modified to include the preclinical and clinical development of ImmunityBio’s proprietary adenovirus platform expressing TAAs, proprietary agent ANKTIVA and derivatives, an antibody-based cytokine fusion protein and derivatives and/or TxM product candidates, proprietary recombinant NK cells and mAbs, proprietary adjuvants, and other proprietary agents owned or controlled by ImmunityBio for cancer immunotherapy. The term of the CRADA was extended through May 2026. Under this agreement, we agreed to pay NCI funding totaling $1.3 million per year, payable in semi-annual installments each year through 2025. 35 Table of Conten t s Serum Institute of India Private Limited In May 2024, we announced an exclusive global arrangement with Serum Institute, the world’s largest manufacturer of vaccines by number of doses produced, to supply ImmunityBio with rBCG for use exclusively in combination with our ANKTIVA product, subject to regulatory approvals. We are responsible, in part, for regulatory submissions, clinical trials and commercialization efforts, and our exclusive rights under the arrangement extend to the scope of the FDA’s approval obtained by us for Serum Institute’s rBCG product in the U.S. Serum Institute’s GMP capacity to manufacture large-scale volumes of BCG, already tested for safety and efficacy in clinical trials in Europe in subjects with NMIBC, aims to address the shortage of TICE BCG, which we believe will help to ensure a reliable supply for patients in need. In February 2025, the FDA authorized an EAP allowing us to provide rBCG developed by Serum Institute to urologists to address the TICE BCG shortage in all settings where the TICE BCG label is approved, and shipments of rBCG pursuant to the EAP are expected to begin during the first quarter of 2025. In addition, we are testing rBCG in an FDA-approved clinical trial (ResQ133A) of intravesical rBCG in participants with NMIBC eligible to receive TICE BCG. This initiative underscores our commitment to addressing critical supply issues and expanding the opportunity for patients and physicians to have access to high quality and quantities of BCG to initialize and maintain treatments for bladder cancer, subject to regulatory approvals. BeiGene, Ltd. In January 2025, we announced a collaboration and supply agreement with BeiGene, Ltd. (to be renamed to BeOne Medicines, Ltd.), a global oncology company, to conduct a confirmatory randomized Phase 3 clinical trial (ResQ201A-NSCLC), combining BeOne’s tislelizumab, a PD-1 CPI, and our ANKTIVA (nogapendekin alfa inbakicept-pmln) product. The Phase 3 ResQ201A-NSCLC study aims to confirm the efficacy and safety of combination ANKTIVA plus CPI therapy previously demonstrated in the QUILT 3055 trial and provide evidence of the potential for these two immunotherapeutic agents to improve overall survival in patients with advanced or metastatic NSCLC who have acquired resistance to immune CPI therapy. License Agreements 3M IPC License Agreement We have licensed rights to 3M-052, a synthetic TLR7/8 agonist, 3M-052 formulations and related technology from 3M IPC and its affiliates and AAHI. In November 2021 we obtained nonexclusive rights in the field of SARS-CoV-2 and in June 2022 we modified those rights and expanded the scope of the license to include (1) SARS-CoV-2 and other infectious diseases including malaria, HIV, tuberculosis, hookworm and varicella zoster on an exclusive basis in countries other than LMIC, and (2) oncology applications, when used in combination with our proprietary technology and/or IL-15 receptor superagonists. Adjuvants are either synthetic or naturally occurring molecules that activate TLRs thereby enhancing the humoral and cell-mediated immune response of vaccines. There are 10 human TLRs expressed either on the inside or outside of the immune cell and their function is to recognize foreign substances expressed by pathogens. Once activated, these TLRs stimulate danger signals to the immune cells initiating an immune response. The synthetic imidazoquinolinone 3M-052 is structurally similar to resiquimod. The 3M-052/Alum adjuvant formulation is in Phase 1 trials in the U.S. with an HIV antigen and has been well-tolerated and immunogenic. In consideration for the license, we agreed to make certain periodic license payments, including $2.25 million each year through June 2025. We have also agreed to make payments upon the achievement of certain regulatory milestone events and tiered royalties ranging from the low to high single-digits as a percentage of net sales. Beginning in April 2026, the annual minimum licensing payment is $1.0 million, which can be credited against any royalty payments due under this agreement. We may terminate this license for any reason after providing 3M and AAHI sixty (60) days’ written notice. GlobeImmune, Inc. In 2020, we entered into an exclusive licensing agreement with GlobeImmune, a consolidated entity of the company, pursuant to which we obtained worldwide, exclusive licenses under certain patents, know-how, and other intellectual property to use, research, develop and commercialize products with GlobeImmune’s Tarmogen-based programs and neoepitopes programs in exchange for a license fee for the first two years of the agreement totaling $1.2 million, up to $345.0 million in milestone payments related to the successful completion of clinical and regulatory milestones and up to $240.0 million in total milestone payments based on licensed product net sales milestones, and a royalty on net sales of licensed products, on a product-by-product basis ranging in percentage from the mid-single digits to the mid-teens. We may terminate this agreement, in whole, or on a licensed-product-by-licensed-product and/or country-by-country basis, at any time upon sixty (60) days’ written notice to GlobeImmune. 36 Table of Conten t s Sanford Health In 2017, and as amended in November 2021, we entered into a license agreement with Sanford Health pursuant to which we obtained a worldwide, exclusive license under Sanford’s applicable patent and know-how rights to use, make, have made, sell, offer to sell, export and import products for all uses and applications of polynucleotides encoding mutant E16 antigen (mutant HPV16 E6 antigen + mutant HPV16 E7 antigen) and the encoded mutant E16 antigen, in exchange for consideration that includes the amount equal to the patent prosecution costs incurred by Sanford for the prosecution of the licensed patent rights, milestone payments payable upon the achievement of certain contractual and regulatory milestones of up to $2.0 million, a low single-digit percentage royalty on net sales of the resulting licensed products, and a low to high-teen percentage share of non-royalty sublicensing revenue. Our obligation to pay royalties continues, on a licensed product-by-licensed product and country-by-country basis, until the date on which such licensed product is no longer covered by a valid claim of a patent licensed pursuant to the agreement in such country. We must use commercially reasonable efforts to develop and commercialize the licensed products. Sanford is responsible for the prosecution and maintenance of the patents licensed pursuant to the agreement. We are required to use commercially reasonable efforts to develop and make available the licensed products, which include achieving certain regulatory objectives within certain specific time periods. We have the first right to enforce the patents licensed pursuant to the agreement, subject to Sanford’s ability to exercise such right if we fail to do so. We may terminate this agreement at any time upon 60 days’ written notice to Sanford. Sanford may terminate the agreement in the event of an uncured material breach by us. In June 2023, we filed an IND for QUILT 3100 exploring the use of an hAd5 [E6/E7] construct known as IBRX-042 in a Phase 1 open-label trial to evaluate safety and determine the MTD in subjects with HPV-associated tumors. During the second half of 2023, we received correspondence from the FDA that it was placing the IND on clinical hold and requesting additional toxicology studies. The company submitted a complete response to the hold letter, and the clinical hold was removed in March 2024. The first patient was enrolled in August 2024, satisfying a commercial milestone. Enrollment for the trial continues at three active clinical sites. Shenzhen Beike Biotechnology Co. Ltd. In 2014, Altor entered into a license, development and commercialization agreement with Beike, which agreement was amended and restated in 2017, pursuant to which Altor granted to Beike an exclusive license under certain of its intellectual property rights in order to use, research, develop and commercialize products based on ANKTIVA in China for human therapeutic uses, in exchange for consideration that includes up to $195.5 million in total milestone payments based on the successful completion of regulatory and sales milestones for each resulting product, and a royalty on net sales of licensed products, on a product-by-product basis ranging in percentage from the mid-single digits to the mid-teens. Beike’s obligation to pay royalties continues, on a licensed product-by-licensed product basis, until the later of (i) the date on which such licensed product is no longer covered by a valid claim of a patent licensed pursuant to the agreement in China and (ii) ten years after the first commercial sale of such licensed product in China. Altor has the sole right to prosecute and maintain the patents licensed pursuant to the agreement. Altor has the first right to enforce the patents licensed pursuant to the agreement, subject to Beike’s ability to exercise such right if Altor fails to do so. Altor and Beike each have the right to terminate the agreement in the event of a material breach by the other party. In 2020, we received a Request for Arbitration before the International Chamber of Commerce, International Court of Arbitration, served by Beike asserting breach of contract under our subsidiary Altor’s license agreement with them. See Item 3. “ Legal Proceedings ” for more information. Government Regulation In the U.S., the FDA regulates biopharmaceuticals under the FD&C Act and the PHSA. Biopharmaceuticals also are subject to other federal, state, and local statutes and regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or post-market may subject an applicant to administrative or judicial sanctions. These sanctions could include, among other actions, the FDA’s refusal to approve pending applications, withdrawal of an approval, a clinical hold, untitled or warning letters, product recalls or market withdrawals, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement and civil or criminal penalties. Any FDA or judicial enforcement action could have a material adverse effect on us. Failure to comply with statutory and regulatory requirements subjects a manufacturer to possible legal or regulatory action, including warning letters, the seizure or recall of products, injunctions, consent decrees placing significant restrictions on or suspending manufacturing operations and civil and criminal penalties. CMOs often encounter difficulties involving production yields, quality control and quality assurance, as well as shortages of qualified personnel. Any of these actions or events could have a material impact on the availability of our product candidates. 37 Table of Conten t s The FDA and other regulatory authorities at federal, state, and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring, and post-approval reporting of small molecule and biologics such as those we are developing. We, along with third-party contractors, will be required to navigate the various preclinical, clinical, and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval or licensure of our product candidates. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local, and foreign statutes and regulations require the expenditure of substantial time and financial resources. The process required by the FDA before biopharmaceutical product candidates may be marketed in the U.S. generally involves the following: • completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s GLP guidelines; • submission to the FDA of an IND, which must become effective before clinical trials may begin and must be updated annually or when significant changes are made; • approval from an independent IRB or ethics committee for each clinical site before the clinical trial is begun; • performance of adequate and well-controlled human clinical trials 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 BLA or NDA, after completion of all required clinical trials; • a determination by the FDA within 60 days of its receipt of a BLA/NDA to file the application for review; • satisfactory completion of an FDA Advisory Committee review, if applicable; • satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMP and to assure that the facilities, methods, and controls are adequate to preserve the product candidates’ continued safety, quality, purity and potency or efficacy, and of selected clinical investigational sites to assess compliance with GCP guidelines; • FDA review and approval of the BLA or NDA to permit commercial marketing of the product for particular indications for use in the U.S.; and • compliance with any post-approval requirements, including the potential requirement to implement a REMS, and the potential requirement to conduct post-approval studies. The testing and approval process requires substantial time, effort, and financial resources, and we cannot be certain that any approvals for our product candidates will be granted on a timely basis, if at all. Prior to beginning the first clinical trial with a product candidate, we must submit an IND to the FDA. An IND is a request for authorization from the FDA to administer an IND product to humans. The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical trials. The IND also includes results of animal and in vitro studies assessing toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product; chemistry, manufacturing, and controls information; and any available human data or literature to support the use of the investigational product. An IND must become effective before human clinical trials begin. 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. In such a case, the IND may be placed on clinical hold, and the IND sponsor and 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. 38 Table of Conten t s When a clinical trial using genetically engineered cells is conducted at, or sponsored by, institutions receiving NIH funding for wild-type DNA research, prior to the submission of an IND to the FDA, a protocol and related documentation is submitted to and the study is registered with the OBA pursuant to the NIH Guidelines. Compliance with the NIH Guidelines is mandatory for investigators at institutions receiving NIH funds for research involving wild-type DNA, and many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them. The NIH is responsible for convening the RAC, a federal advisory committee that discusses protocols that raise novel or particularly important scientific, safety, or ethical considerations at one of its quarterly public meetings. The OBA will notify the FDA of the RAC’s decision regarding the necessity for full public review of a protocol. RAC proceedings and reports are posted to the OBA web site and may be accessed by the public. If the FDA allows the IND to proceed, but the RAC decides that full public review of the protocol is warranted, the FDA will request at the completion of its IND review that sponsors delay initiation of the protocol until after completion of the RAC review process. Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCP guidelines, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial. 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. Furthermore, an independent IRB, for each site proposing to conduct the clinical trial, must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site and must monitor the study until completed. Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives. Some studies also include oversight by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy. There are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries. For purposes of BLA or NDA approval, human clinical trials are typically conducted in three sequential phases that may overlap: • Phase 1. The investigational product is initially introduced into healthy human subjects and tested for safety. In the case of some products for severe or life-threatening diseases, the initial human testing is often conducted in patients. • Phase 2. The investigational product is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy or potency of the product for specific targeted diseases and to determine dosage tolerance, optimal dosage, and dosing schedule. • Phase 3. Clinical trials are undertaken to further evaluate dosage, clinical efficacy or potency, and safety in an expanded patient population at geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk to benefit ratio of the product and provide an adequate basis for product labeling. • Phase 4. Companies may voluntarily pursue additional clinical trials after a product is approved to gain more information about the product for that approved indication. In some cases, the FDA may require an additional trial after a product is approved, and these so-called Phase 4 trials may be a condition to approval of the BLA or NDA. Phase 1, Phase 2, and Phase 3 testing may not be completed successfully within a specified period, if at all, and there can be no assurance that the data collected will support FDA approval or licensure of the product. Concurrently with clinical trials, companies may complete additional animal studies and develop additional information about the biological characteristics of the product candidate and must finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. To help reduce the risk of the introduction of adventitious agents with use of biological products, the PHSA emphasizes the importance of manufacturing control for products whose attributes cannot be precisely defined. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final product, or for biologics, the safety, purity and potency. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life. 39 Table of Conten t s BLA/NDA Submission and Review by the FDA Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, nonclinical studies and clinical trials are submitted to the FDA as part of a BLA for a biologic product candidate or an NDA for a small molecule product candidate requesting approval to market the product for one or more indications. Unless agreed to in advance with the FDA, the BLA/NDA must include all data from pertinent preclinical and clinical trials, including negative or ambiguous results, as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things. Data can come from company-sponsored clinical trials intended to test the safety and effectiveness of the use of the product or from a number of alternative sources, including studies initiated by investigators, including government agencies (e.g., NIH). The submission of a BLA/NDA requires payment of a substantial user fee to the FDA, and the sponsor of an approved BLA/NDA is subject to annual product and establishment user fees. These fees typically increase annually. A waiver of user fees may be obtained under certain limited circumstances. Within 60 days following submission of the application, the FDA reviews a BLA/NDA to determine if it is substantially complete before the agency accepts it for filing. The FDA may refuse to file any BLA or NDA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the BLA/NDA must be resubmitted with the additional information. Once a BLA/NDA has been submitted, the FDA’s goal is to review the application within ten months after it accepts the application for filing, or, if the application relates to an unmet medical need in a serious or life-threatening indication, the FDA may review the application six months after the FDA accepts the application for filing. The review process is often significantly extended by FDA requests for additional information or clarification. The FDA reviews a BLA/NDA to determine, among other things, whether a product is safe and effective, or safe, pure, and potent for the proposed indication(s) and the facility in which it is manufactured, processed, packed or held meets standards designed to assure the product’s continued safety, purity and potency or efficacy. The FDA may convene an advisory committee to provide clinical insight on application review questions. Before approving a BLA/NDA, the FDA will typically inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities comply with cGMP requirements and are adequate to assure consistent production of the product within required specifications. If applicable, FDA regulations also require tissue establishments to register and list their human cells, tissues, and cellular and tissue-based products with the FDA and to evaluate donors through screening and testing. Additionally, before approving a BLA/NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP guidelines. If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information. Notwithstanding the submission of any requested additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval. The testing and approval process requires substantial time, effort, and financial resources, and each may take several years to complete. The FDA may not grant approval on a timely basis, or at all, and we may encounter difficulties or unanticipated costs in our efforts to secure necessary governmental approvals, which could delay or preclude us from marketing our product candidates. After the FDA evaluates a BLA/NDA and conducts inspections of manufacturing facilities where the investigational product and/or its drug substance will be produced, the FDA may issue an approval letter or a CRL. An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications. A CRL indicates that the review cycle of the application is complete, and the application is not ready for approval. A CRL may request additional information or clarification. The FDA may delay or refuse approval of a BLA/NDA if applicable regulatory criteria are not satisfied, require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product. If regulatory approval of a product is granted, such approval may entail limitations on the indicated uses for which such product may be marketed. For example, the FDA may approve the BLA/NDA with a REMS plan to mitigate risks, which could include medication guides, physician communication plans, or other restrictions to assure safe use, such as restricted distribution methods, patient registries, and other risk minimization tools. The FDA also may condition approval on, among other things, changes to proposed labeling or the development of adequate controls and specifications. Once approved, the FDA may withdraw the product approval if compliance with pre- and post-marketing regulatory standards is not maintained or if problems occur after the product reaches the marketplace. The FDA may require one or more Phase 4 post-market trials and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization and may limit further marketing of the product based on the results of these post-marketing studies. In addition, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our product candidates under development. 40 Table of Conten t s A sponsor may seek approval of its product candidate under programs designed to accelerate the FDA’s review and approval of new drugs and biological products that meet certain criteria. Specifically, new drugs and biological products are eligible for Fast Track designation if they are intended to treat a serious or life-threatening condition and demonstrate the potential to address unmet medical needs for the condition. For a Fast Track product, the FDA may consider sections of the BLA/NDA for review on a rolling basis before the complete application is submitted if relevant criteria are met. A Fast Track- designated product candidate may also qualify for priority review. Priority review is granted when there is evidence that the proposed product would be a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition. If criteria are not met for priority review, the application is subject to the standard FDA review period. Priority review designation does not change the scientific/medical standard for approval or the quality of evidence necessary to support approval. Under the accelerated approval program, the FDA may approve a BLA/NDA on the basis of either 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. Post-marketing studies or completion of ongoing studies after marketing approval are generally required to verify the product’s clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit. The Food and Drug Omnibus Reform Act made several changes to the FDA’s authorities and its regulatory framework, including, among other changes, reforms to the accelerated approval pathway, such as requiring the FDA to specify conditions for post-approval study requirements and setting forth procedures for the FDA to withdraw a product on an expedited basis for non-compliance with post-approval requirements. In addition, the FDASIA established Breakthrough Therapy designation. A sponsor may seek FDA designation of its product candidate as a Breakthrough Therapy if the product candidate is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the therapy may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. Sponsors may request the FDA to designate Breakthrough Therapy at the time of, or any time after, the submission of an IND, but ideally before an end-of-Phase 2 meeting with the FDA. If the FDA designates Breakthrough Therapy , it may take appropriate actions to expedite the development and review of the application, which may include holding meetings with the sponsor and the review team throughout the development of the therapy; providing timely advice to, and interactive communication with, the sponsor regarding the development of the product candidate to ensure that the development program to gather the nonclinical and clinical data necessary for approval is as efficient as practicable; involving senior managers and experienced review staff, as appropriate, in a collaborative, cross-disciplinary review; assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the sponsor; and considering alternative clinical trial designs when scientifically appropriate, which may result in smaller or more efficient clinical trials that require less time to complete and may minimize the number of patients exposed to a potentially less efficacious treatment. Breakthrough Therapy designation also allows the sponsor to file sections of the BLA/NDA for review on a rolling basis. We may seek designation as a Breakthrough Therapy for some or all of our product candidates. The 21st Century Cures Act established an expedited review program for RMATs, which include cell and gene therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products. This program is intended to facilitate efficient development and expedite review of regenerative medicine therapies, which are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition and qualify for RMAT designation. A sponsor may request that the FDA designate a product candidate as an RMAT concurrently with or at any time after submission of an IND. The FDA has 60 calendar days to determine whether the product candidate meets the criteria, including whether there is preliminary clinical evidence indicating that the product candidate has the potential to address unmet medical needs for a serious or life-threatening disease or condition. A BLA for a product candidate that has received RMAT designation may be eligible for priority review or accelerated approval through use of surrogate or intermediate endpoints reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of sites. Benefits of RMAT designation also include early interactions with the FDA to discuss any potential surrogate or intermediate endpoint to be used to support accelerated approval. A product candidate with RMAT designation that is granted accelerated approval and is subject to post-approval requirements may fulfill such requirements through the submission of clinical evidence from clinical studies, patient registries, or other sources of real world evidence, such as electronic health records; the collection of larger confirmatory data sets; or post-approval monitoring of all patients treated with such therapy prior to its approval. 41 Table of Conten t s Breakthrough Therapy, Fast Track and RMAT designations and priority review do not change the standards for approval. The receipt of such designations may not lead to a faster development process or regulatory review and may not increase the likelihood that our product candidates will receive marketing approval. In addition, the PREA requires a sponsor to conduct pediatric clinical trials for certain drugs and biological products, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration. Under PREA, original NDAs/BLAs and supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver. The required assessment must evaluate the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The sponsor or FDA may request a deferral of pediatric clinical trials for some or all of the pediatric subpopulations. A deferral may be granted for several reasons, including a finding that the product candidate is ready for approval for use in adults before pediatric clinical trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric clinical trials begin. The FDA must send a non-compliance letter to any sponsor that fails to submit the required assessment, keeps a deferral current or fails to submit a request for approval of a pediatric formulation. Orphan Drugs Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biologic intended to treat a rare disease or condition, defined as a disease or condition with a patient population of fewer than 200,000 individuals in the U.S., or a patient population greater than 200,000 individuals in the U.S. and when there is no reasonable expectation that the cost of developing and making available the drug or biologic in the U.S. will be recovered from sales in the U.S. for that drug or biologic. Orphan drug designation must be requested before submitting a BLA or NDA. After the FDA grants orphan drug designation, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. If a product that has orphan drug designation subsequently receives the first FDA approval for a particular active ingredient for the disease for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications, including a full BLA or NDA, to market the same biologic or drug product for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated. Orphan drug exclusivity does not prevent the FDA from approving a different drug or biologic for the same disease or condition, or the same drug or biologic for a different disease or condition. Among the other benefits of orphan drug designation are tax credits for certain research and a waiver of the BLA application user fee. A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that is broader than the indication for which it received orphan designation. In addition, orphan drug exclusive marketing rights in the U.S. may be lost if the FDA later determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition. Post-Approval Requirements Any products manufactured or distributed by us pursuant to FDA approval are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record keeping, reporting of adverse experiences, periodic reporting, distribution, and advertising and promotion of the product. After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also are continuing, annual user fee requirements for any marketed products and the establishments at which such products are manufactured, as well as new application fees for supplemental applications with clinical data. Biopharmaceutical manufacturers and their subcontractors 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, which impose certain procedural and documentation requirements upon us and any third-party manufacturers that we may decide to use. Changes to the manufacturing process are strictly regulated and, depending on the significance of the change, may require prior FDA approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting requirements upon us, and any third-party manufacturers, that we may decide to use. Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance. We cannot be certain that we or our present or future suppliers will be able to comply with cGMP regulations and other FDA regulatory requirements. If our present or future suppliers are not able to comply with these requirements, the FDA may, among other things, halt our clinical trials, require us to recall a product from distribution, or withdraw approval of the BLA or NDA. 42 Table of Conten t s In the U.S., once a drug is approved, its manufacture is subject to comprehensive and continuing regulation by the FDA. FDA regulations require that drugs be manufactured in specific facilities per the BLA or NDA approval and in accordance with cGMP. Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs 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 and other laws. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance. These regulations also impose certain organizational, procedural, and documentation requirements with respect to manufacturing and quality assurance activities. BLA or NDA holders using CMOs, laboratories or packagers are responsible for the selection and monitoring of qualified firms, and, in certain circumstances, qualified suppliers to these firms. These firms and, where applicable, their suppliers are subject to inspections by the FDA at any time, and the discovery of violative conditions, including failure to conform to cGMP, could result in enforcement actions that interrupt the operation of any such facilities or the ability to distribute drugs manufactured, processed, or tested by them. Future FDA and state inspections may identify compliance issues at our facilities or at the facilities of CMOs that may disrupt production or distribution or require substantial resources to correct. In addition, discovery of previously unknown problems with a product or the failure to comply with applicable requirements may result in restrictions on a product, manufacturer, or holder of an approved BLA or NDA, including withdrawal or recall of the product from the market or other voluntary, FDA-initiated or judicial action that could delay or prohibit further marketing. Post-Marketing Requirements Following approval of a new drug, a biopharmaceutical company and the approved drug are subject to continuing regulation by the FDA, including, among other things, establishment registration and drug listing, monitoring and recordkeeping activities, reporting to the applicable regulatory authorities of adverse experiences with the drug, providing the regulatory authorities with updated safety and efficacy information, drug sampling and distribution requirements, and complying with promotion and advertising requirements, which include, among others, standards for direct-to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved labeling, limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet. In the U.S., once a drug is approved, its manufacture is subject to comprehensive and continuing regulation by the FDA. FDA regulations require that drugs be manufactured in specific facilities per the NDA approval and in accordance with cGMP. We rely, and expect to continue to rely, on third parties for the production of clinical and commercial quantities of its drugs in accordance with cGMP regulations. cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP. Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs 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 and other laws. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance. These regulations also impose certain organizational, procedural, and documentation requirements with respect to manufacturing and quality assurance activities. NDA holders using CMOs, laboratories or packagers are responsible for the selection and monitoring of qualified firms, and, in certain circumstances, qualified suppliers to these firms. These firms and, where applicable, their suppliers are subject to inspections by the FDA at any time, and the discovery of violative conditions, including failure to conform to cGMP, could result in enforcement actions that interrupt the operation of any such facilities or the ability to distribute drugs manufactured, processed, or tested by them. Discovery of problems with a drug after approval may result in restrictions on a drug, manufacturer, or holder of an approved NDA, including, among other things, recall or withdrawal of the drug from the market, and may require substantial resources to correct. 43 Table of Conten t s The FDA may also require post-approval testing, sometimes referred to as Phase 4 testing, risk minimization action plans, and post-marketing surveillance to monitor the effects of an approved drug or place conditions on an approval that could restrict the distribution or use of the drug. The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical trials to assess new safety risks; or imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things: • restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls; • fines, warning letters or holds on post-approval clinical trials; • refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product license approvals; • product seizure or detention, or refusal to permit the import or export of products; or • injunctions or the imposition of civil or criminal penalties. The FDA closely regulates the marketing, labeling, advertising and promotion of biological or drug products. A company can make only those claims relating to safety and efficacy, purity and potency that are approved by the FDA and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses. Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties, and exclusion from participation in governmental health programs, like Medicare and Medicaid. Physicians may prescribe legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA. Such off-label uses are common across medical specialties. Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances. The FDA does not regulate the behavior of physicians in their choice of treatments. The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products. 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. 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. However, companies may share truthful and not misleading information that is otherwise consistent with a product’s FDA-approved labelling. Modifications or enhancements to the drug or its labeling or changes of the site or process of manufacture are often subject to the approval of the FDA and other regulators, which may or may not be received or may result in a lengthy review process. Prescription drug advertising is subject to federal, state, and foreign regulations. In the U.S., the FDA regulates prescription drug promotion, including direct-to-consumer advertising. Prescription drug promotional materials must be submitted to the FDA in conjunction with their first use. Any distribution of prescription drugs and pharmaceutical samples must comply with the U.S. PDMA, a part of the FD&C Act. The DSCSA, enacted in 2013, aims to build an electronic system to identify and trace certain prescription drugs distributed in the U.S. The DSCSA mandates phased-in and resource-intensive obligations for pharmaceutical manufacturers, wholesale distributors, and dispensers. The law’s requirements include the quarantine and prompt investigation of a suspect product to determine if it is illegitimate and notifying trading partners and the FDA of any illegitimate product. Drug manufacturers and their collaborators are also required to place a unique product identifier on prescription drug packages. Premarket Clearance and Approval Requirements for Medical Devices Each medical device we seek to commercially distribute in the U.S., including our bioreactors, will require a prior 510(k) clearance, unless it has received a PMA from the FDA. Generally, if a new device has a predicate that is already on the market under a 510(k) clearance, the FDA will allow that new device to be marketed under a 510(k) clearance; otherwise, a PMA is required. Medical devices are classified into one of three classes: Class 1, Class 2, or Class 3, depending on the degree of risk associated with each medical device and the extent of control needed to provide reasonable assurance of safety and effectiveness. Class 1 devices are deemed to be low risk and are subject to the general controls of the FD&C Act, such as provisions that relate to: adulteration; misbranding; registration and listing; notification, including repair, replacement, or refund; records and reports; and good manufacturing practices. Most Class 1 devices are classified as exempt from premarket notification under section 44 Table of Conten t s 510(k) of the FD&C Act and therefore may be commercially distributed without obtaining 510(k) clearance from the FDA. Class 2 devices are subject to both general controls and special controls to provide reasonable assurance of safety and effectiveness. Special controls include performance standards, post market surveillance, patient registries and guidance documents. A manufacturer may be required to submit to the FDA a premarket notification requesting permission to commercially distribute some Class 2 devices. Devices deemed by the FDA to pose the greatest risk, such as life-sustaining, life-supporting or implantable devices, or devices deemed not substantially equivalent to a previously cleared 510(k) device, are placed in Class 3. A Class 3 device cannot be marketed in the U.S. unless the FDA approves the device after submission of a PMA. However, there are some Class 3 devices for which the FDA has not yet called for a PMA. For these devices, the manufacturer must submit a premarket notification and obtain 510(k) clearance in orders to commercially distribute these devices. The FDA can also impose sales, marketing, or other restrictions on devices in order to ensure that they are used in a safe and effective manner. 510(k) Clearance Pathway When a 510(k) clearance is required, we must submit a premarket notification to the FDA demonstrating that our proposed device is substantially equivalent to a predicate device, which is a previously cleared and legally marketed 510(k) device or a device that was in commercial distribution before May 28, 1976. By regulation, a premarket notification must be submitted to the FDA at least 90 days before we intend to distribute a device. As a practical matter, clearance often takes significantly longer. To demonstrate substantial equivalence, the manufacturer must show that the proposed device has the same intended use as the predicate device, and it either has the same technological characteristics, or different technological characteristics and the information in the premarket notification demonstrates that the device is equally safe and effective and does not raise different questions of safety and effectiveness. The FDA may require further information, including clinical data, to make a determination regarding substantial equivalence. If the FDA determines that the device, or its intended use, is not substantially equivalent to a previously cleared device or use, the FDA will place the device into Class 3. There are three types of 510(k)s: traditional; special; and abbreviated. Special 510(k)s are for devices that are modified, and the modification needs a new 510(k) but does not affect the intended use or alter the fundamental scientific technology of the device. Abbreviated 510(k)s are for devices that conform to a recognized standard. The special and abbreviated 510(k)s are intended to streamline review, and the FDA intends to process special 510(k)s within 30 days of receipt. De Novo Classification Medical device types that the FDA has not previously classified as Class 1, 2 or 3 are automatically classified into Class 3 regardless of the level of risk they pose. The Food and Drug Administration Modernization Act of 1997 established a new route to market for low to moderate risk medical devices that are automatically placed into Class 3 due to the absence of a predicate device, called the Request for Evaluation of Automatic Class 3 Designation (or the De Novo Classification Process). This procedure allows a manufacturer whose novel device is automatically classified into Class 3 to request down-classification of its medical device into Class 1 or Class 2 on the basis that the device presents low or moderate risk, rather than requiring the submission and approval of a PMA application. Prior to the enactment of the FDASIA, a medical device could only be eligible for De Novo classification if the manufacturer first submitted a 510(k) premarket notification and received a determination from the FDA that the device was not substantially equivalent. The FDASIA streamlined the De Novo classification pathway by permitting manufacturers to request De Novo classification directly without first submitting a 510(k) premarket notification to the FDA and receiving a not substantially equivalent determination. Under the FDASIA, the FDA is required to classify the device within 120 days following receipt of the De Novo application. If the manufacturer seeks reclassification into Class 2, the manufacturer must include a draft proposal for special controls that are necessary to provide a reasonable assurance of the safety and effectiveness of the medical device. In addition, the FDA may reject the reclassification petition if it identifies a legally marketed predicate device that would be appropriate for a 510(k) or determines that the device is not low to moderate risk or that general controls would be inadequate to control the risks and special controls cannot be developed. Premarket Approval Pathway A PMA application must be submitted to the FDA for Class 3 devices for which the FDA has required a PMA. The PMA application process is much more demanding than the 510(k) premarket notification process. A PMA application must be supported by extensive data, including but not limited to technical, preclinical, clinical trials, manufacturing and labeling to demonstrate to the FDA’s satisfaction reasonable evidence of safety and effectiveness of the device. 45 Table of Conten t s After a PMA application is submitted, the FDA has 45 days to determine whether the application is sufficiently complete to permit a substantive review and thus whether the FDA will file the application for review. The FDA has 180 days to review a filed PMA application, although the review of an application generally occurs over a significantly longer period of time and can take up to several years. During this review period, the FDA may request additional information or clarification of the information already provided. Also, an advisory panel of experts from outside the FDA may be convened to review and evaluate the application and provide recommendations to the FDA as to the approvability of the device. Although the FDA is not bound by the advisory panel decision, the panel’s recommendations are important to the FDA’s overall decision-making process. In addition, the FDA may conduct a preapproval inspection of the manufacturing facility to ensure compliance with the QSR. The agency also may inspect one or more clinical sites to assure compliance with FDA’s regulations. Upon completion of the PMA review, the FDA may: (i) approve the PMA application which authorizes commercial marketing with specific prescribing information for one or more indications, which can be more limited than those originally sought; (ii) issue an approvable letter which indicates the FDA’s belief that the PMA application is approvable and states what additional information the FDA requires or the post-approval commitments that must be agreed to prior to approval; (iii) issue a not approvable letter which outlines steps required for approval, but which are typically more onerous than those in an approvable letter, and may require additional clinical trials that are often expensive and time consuming and can delay approval for months or even years; or (iv) deny the application. If the FDA issues an approvable or not approvable letter, the applicant has 180 days to respond, after which the FDA’s review clock is reset. Clinical trials are almost always required to support PMA and are sometimes required for 510(k) clearance. In the U.S., for significant risk devices, these trials require submission of an application for an IDE to the FDA. The IDE application must be supported by appropriate data, such as animal and laboratory testing results, showing it is safe to test the device in humans and that the testing protocol is scientifically sound. The IDE must be approved in advance by the FDA for a specific number of patients at specified trial sites. During the trial, the sponsor must comply with the FDA’s IDE requirements for investigator selection, trial monitoring, reporting and recordkeeping. The investigators must obtain patient informed consent, rigorously follow the investigational plan, and trial protocol, control the disposition of investigational devices and comply with all reporting and recordkeeping requirements. Clinical trials for significant risk devices may not begin until the IDE application is approved by the FDA and the appropriate IRBs at the clinical trial sites. An IRB is an appropriately constituted group that has been formally designated to review and monitor medical research involving subjects and which has the authority to approve, require modifications in, or disapprove research to protect the rights, safety, and welfare of human research subjects. A non-significant risk device does not require FDA approval of an IDE; however, the clinical trial must still be conducted in compliance with various requirements of FDA’s IDE regulations and be approved by an IRB at the clinical trial sites. The FDA or the IRB at each site at which a clinical trial is being performed may withdraw approval of a clinical trial at any time for various reasons, including a belief that the risks to study subjects outweigh the benefits or a failure to comply with FDA or IRB requirements. Even if a trial is completed, the results of clinical testing may not demonstrate the safety and effectiveness of the device, may be equivocal or may otherwise not be sufficient to obtain approval or clearance of the product. Sponsors of clinical trials of devices are required to register with clinical trials.gov, a public database of clinical trial information. Information related to the device, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is made public as part of the registration. Ongoing Medical Device Regulation by the FDA Even after a device receives clearance or approval and is placed on the market, numerous regulatory requirements apply. These include: • establishment registration and device listing; • the QSR, which requires manufacturers, including third-party manufacturers, to follow stringent design, testing, control, documentation, and other quality assurance procedures during all aspects of the manufacturing process; • labeling regulations and the FDA prohibitions against the promotion of products for uncleared, unapproved or off-label uses and other requirements related to promotional activities; 46 Table of Conten t s • medical device reporting regulations, which require that manufactures report to the FDA if their device may have caused or contributed to a death or serious injury, or if their device malfunctioned and the device or a similar device marketed by the manufacturer would be likely to cause or contribute to a death or serious injury if the malfunction were to recur; • corrections and removal reporting regulations, which require that manufacturers report to the FDA field corrections or removals if undertaken to reduce a risk to health posed by a device or to remedy a violation of the FD&C Act that may present a risk to health; and • post market surveillance regulations, which apply to certain Class 2 or 3 devices when necessary to protect the public health or to provide additional safety and effectiveness data for the device. After a device receives 510(k) clearance, any modification that could significantly affect its safety or effectiveness, or that would constitute a major change in its intended use, will require a new clearance or possibly a PMA. The FDA requires each manufacturer to make this determination initially, but the FDA can review any such decision and can disagree with a manufacturer’s determination. If the FDA disagrees with the determination not to seek a new 510(k) clearance, the FDA may retroactively require the manufacturer to seek 510(k) clearance or possibly a PMA. The FDA could also require the manufacturer to cease marketing and distribution and/or recall the modified device until 510(k) clearance or PMA is obtained. Also, in these circumstances, the manufacturer may be subject to significant regulatory fines and penalties. Some changes to an approved PMA device, including changes in indications, labeling or manufacturing processes or facilities, require submission and FDA approval of a new PMA application or PMA supplement, as appropriate, before the change can be implemented. Supplements to a PMA application often require the submission of the same type of information required for an original PMA application, except that the supplement is generally limited to that information needed to support the proposed change from the device covered by the original PMA. The FDA uses the same procedures and actions in reviewing PMA supplements as it does in reviewing original PMA applications. FDA regulations require us to register as a medical device manufacturer with the FDA. Additionally, some states require us to register as a medical device manufacturer within the state. Because of this, the FDA and similar state agencies may inspect us on a routine basis for compliance with the QSR. In February 2024, the FDA issued a final rule replacing the QSR with the QMSR, which incorporates by reference the quality management system requirements of ISO 13485:2016. The FDA has stated that the standards contained in ISO 13485:2016 are substantially similar to those set forth in the existing QSR. This final rule does not go into effect until February 2026. These regulations require that the manufacturer maintain proper documentation in a prescribed manner with respect to manufacturing, testing and control activities. Further, the FDA requires medical device manufacturers to comply with various FDA regulations regarding labeling. Failure by us or by our suppliers to comply with applicable regulatory requirements can result in enforcement action by the FDA or state authorities, which may include any of the following sanctions: • warning or untitled letters, fines, injunctions, consent decrees and civil penalties; • customer notifications, voluntary or mandatory recall or seizure of our medical device product candidates; • operating restrictions, partial suspension, or total shutdown of production; • delay in processing submissions or applications for new products or modifications to existing products; • withdrawing approvals that have already been granted; and • criminal prosecution. The Medical Device Reporting laws and regulations require medical device manufacturers to provide information to the FDA when they receive or otherwise become aware of information that reasonably suggests the device may have caused or contributed to a death or serious injury as well as a device malfunction that likely would cause or contribute to death or serious injury if the malfunction were to recur. In addition, the FDA prohibits an approved device from being marketed for off-label use. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including substantial monetary penalties and criminal prosecution. 47 Table of Conten t s Newly discovered or developed safety or effectiveness data may require changes to a product’s labeling, including the addition of new warnings and contraindications, and also may require the implementation of other risk management measures. Also, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory clearance or approval of our medical device product candidates under development. Medical device manufacturers are also subject to other federal, state, and local laws and regulations relating to safe working conditions, and laboratory and manufacturing practices. Other Healthcare Laws and Compliance Requirements Manufacturing, sales, promotion, and other activities following drug approval are also subject to regulation by numerous regulatory authorities in addition to the FDA, including, in the U.S., CMS, other divisions of HHS, the Drug Enforcement Administration for controlled substances, the Consumer Product Safety Commission, the FTC, Occupational Safety and Health Administration, the Environmental Protection Agency, and state and local governments. In the U.S., sales, marketing, and scientific/educational programs must also comply with state and federal fraud and abuse laws. Pricing and rebate programs must comply with the Medicaid rebate requirements of the U.S. Omnibus Budget Reconciliation Act of 1990 and more recent requirements in the Patient Protection and Affordable Care Act as amended by the ACA. If drugs are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply. The handling of any controlled substances must comply with the U.S. Controlled Substances Act and Controlled Substances Import and Export Act. Drugs must meet applicable child-resistant packaging requirements under the U.S. Poison Prevention Packaging Act. Manufacturing, sales, promotion, and other activities are also potentially subject to federal and state consumer protection and unfair competition laws. We are subject to numerous foreign, federal, state, and local environmental, health, and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment, and disposal of hazardous materials and wastes. In addition, our leasing and operation of real property may subject us to liability pursuant to certain U.S. environmental laws and regulations, under which current or previous owners or operators of real property and entities that disposed or arranged for the disposal of hazardous substances may be held strictly, jointly, and severally liable for the cost of investigating or remediating contamination caused by hazardous substance releases, even if they did not know of and were not responsible for the releases. The distribution of pharmaceutical drugs is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage, and security requirements intended to prevent the unauthorized sale of pharmaceutical drugs. The failure to comply with regulatory requirements subjects firms to possible legal or regulatory action. Depending on the circumstances, failure to meet applicable regulatory requirements can result in criminal prosecution, fines, or other penalties, injunctions, voluntary recall, or seizure of drugs, total or partial suspension of production, denial or withdrawal of product approvals, or refusal to allow a firm to enter into supply contracts, including government contracts. In addition, even if a firm complies with FDA and other requirements, new information regarding the safety or efficacy of a product could lead the FDA to modify or withdraw product approval. Prohibitions or restrictions on sales or withdrawal of future products marketed by us could materially affect our business in an adverse way. Changes in regulations, statutes, or the interpretation of existing regulations could impact our business in the future by requiring, for example: (i) changes to our manufacturing arrangements; (ii) additions or modifications to product labeling; (iii) the recall or discontinuation of our products; or (iv) additional record-keeping requirements. If any such changes were imposed, they could adversely affect the operation of our business. Our sales, promotion, medical education, clinical research, and other activities following product approval will be subject to regulation by numerous regulatory and law enforcement authorities in the U.S. in addition to the FDA, including potentially the FTC, the Department of Justice, the CMS, other divisions of HHS and state and local governments. Our promotional and scientific/educational programs must comply with the AKS, the FCA, physician payment transparency laws, privacy laws, security laws, and additional federal and state laws similar to the foregoing. If drugs are made available to authorized users of the Federal Supply Schedule of the General Services Administration, additional laws and requirements apply. Drugs must meet applicable child-resistant packaging requirements under the U.S. Poison Prevention Packaging Act. Manufacturing, sales, promotion, and other activities are also potentially subject to federal and state consumer protection and unfair competition laws. Changes in regulations, statutes, or the interpretation of existing regulations could impact our business in the future by requiring, for example: (i) changes to our manufacturing arrangements; (ii) additions or modifications to product labeling; (iii) the recall or discontinuation of our products; or (iv) additional record-keeping requirements. If any such changes were imposed, they could adversely affect the operation of our business. 48 Table of Conten t s The AKS prohibits, among other things, the knowing and willing, direct or indirect offer, receipt, solicitation, or payment of remuneration in exchange for or to induce the referral of patients, including the purchase, order or lease of any good, facility, item or service that would be paid for in whole or part by Medicare, Medicaid or other federal health care programs. Remuneration has been broadly defined to include anything of value, including cash, improper discounts, and free or reduced-price items and services. The AKS has been interpreted to apply to arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers, formulary managers, and beneficiaries on the other. Although there are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution, the exceptions and safe harbors are drawn narrowly. Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchases or recommendations may be subject to scrutiny if they do not qualify for an exception or safe harbor. Failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the AKS. Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all its facts and circumstances. Several courts have interpreted the statute’s intent requirement to mean that if any one purpose of an arrangement involving remuneration is to induce referrals of federal healthcare covered business, the AKS has been violated. The government has enforced the AKS to reach large settlements with healthcare companies based on sham research or consulting and other financial arrangements with physicians. Further, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it to have committed a violation. In addition, the government may assert that a claim including items or services resulting from a violation of the AKS constitutes a false or fraudulent claim for purposes of the FCA. Many states have similar laws that apply to their state health care programs, as well as private payors. Federal false claims and false statement laws, including the FCA, impose liability on persons or entities that, among other things, knowingly present or cause to be presented claims that are false or fraudulent or not provided as claimed for payment or approval by a federal health care program. The FCA has been used to prosecute people or entities that cause the submission of claims for payment that are inaccurate or fraudulent, by, for example, providing inaccurate billing or coding information to customers, promoting a product off-label, submitting claims for services not provided as claimed, or submitting claims for services that were provided but not medically necessary. Actions under the FCA may be brought by the Attorney General, or as a qui tam action by a private individual, in the name of the government. Violations of the FCA can result in significant monetary penalties and treble damages. The federal government is using the FCA, and the accompanying threat of significant liability, in its investigation and prosecution of pharmaceutical and biotechnology companies throughout the country, for example, in connection with the promotion of products for unapproved uses and other illegal sales and marketing practices. The government has obtained multi-million and multi-billion dollar settlements under the FCA in addition to individual criminal convictions under applicable criminal statutes. In addition, certain companies that were found to be in violation of the FCA have been forced to implement extensive corrective action plans and have often become subject to consent decrees or corporate integrity agreements, restricting the manner in which they conduct their business. The HIPAA created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payors; knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services; and willfully obstructing a criminal investigation of a healthcare offense. Like the AKS, the ACA amended the intent standard for certain healthcare fraud statutes under HIPAA such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation. Given the significant size of actual and potential settlements, it is expected that the government will continue to devote substantial resources to investigating healthcare providers’ and manufacturers’ compliance with applicable fraud and abuse laws. In addition, many states have similar fraud and abuse statutes or regulations that may be broader in scope and may apply regardless of payor, in addition to items and services reimbursed under Medicaid and other state programs. Additionally, to the extent that our product candidates, once commercialized, are sold in a foreign country, we may be subject to similar foreign laws. In addition, there has been a recent trend of increased federal and state regulation of payments made to physicians and certain other healthcare providers and teaching hospitals. The ACA, among other things, under the federal Physician Payment Sunshine Act, imposed reporting requirements on certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, for payments or other transfers of value made by them to certain covered recipients, including physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members. Effective January 1, 2022, these reporting obligations with respect to covered recipients have been extended to include payments and transfers of value made 49 Table of Conten t s to non-physician providers such as physician assistants and nurse practitioners. Covered manufacturers are required to collect and report detailed payment data and submit legal attestation to the accuracy of such data to the government each year. Failure to submit required information may result in civil monetary penalties for all payments, transfers of value or ownership or investment interests that are not timely, accurately, and completely reported in an annual submission. Additionally, entities that do not comply with mandatory reporting requirements may be subject to a corporate integrity agreement. Certain states also mandate implementation of commercial compliance programs, impose restrictions on covered manufacturers’ marketing practices and/or require the tracking and reporting of gifts, compensation and other remuneration to physicians and other healthcare professionals. We may also be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business. HIPAA, as amended by HITECH and their respective implementing regulations, impose specified requirements on certain health care providers, plans, and clearinghouses, or collectively, covered entities, and their business associates, relating to the privacy, security and transmission of individually identifiable health information. Among other things, HITECH makes HIPAA’s security standards directly applicable to business associates, which includes independent contractors or agents of covered entities that create, receive, maintain, or transmit protected health information in connection with providing a service for or on behalf of a covered entity. HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce HIPAA and seek attorney’s fees and costs associated with pursuing federal civil actions. In addition, certain states have their own laws that govern the privacy and security of health information in certain circumstances, many of which differ from each other and/or HIPAA in significant ways and may not have the same effect, thus complicating compliance efforts. If our operations are found to be in violation of any of such laws or any other governmental regulations that apply to us, we may be subject to penalties, including, without limitation, civil and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare programs, imprisonment, contractual damages, reputational harm, and diminished profits and future earnings, any of which could adversely affect our ability to operate our business and our financial results. If any of the physicians or other providers, independent contractors, or entities with whom we do business are found to not be in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs and imprisonment, which could affect our ability to operate our business. Further, defending against any such actions can be costly, time-consuming and may require significant personnel resources. Therefore, even if we are successful in defending ourselves against any such actions that may be brought against us, our business may be impaired. In addition to the foregoing health care laws, we are also subject to the FCPA and similar worldwide anti-bribery laws, which generally prohibit companies and their intermediaries from making improper payments to government officials or private-sector recipients for the purpose of obtaining or retaining business. The anti-corruption policy mandates compliance with the FCPA and similar anti-bribery laws applicable to our business throughout the world. However, we cannot assure you that such a policy or procedures implemented to enforce such a policy will protect us from intentional, reckless, or negligent acts committed by our employees, distributors, partners, collaborators or agents. Violations of these laws, or allegations of such violations, could result in fines, penalties or prosecution and have a negative impact on our business, results of operations and reputation. Coverage and Reimbursement Sales of pharmaceutical products depend significantly on the extent to which coverage and adequate reimbursement are provided by third-party payors. Third-party payors include state and federal government health care programs, managed care providers, private health insurers and other organizations. Although we currently believe that third-party payors will provide coverage and reimbursement for our product candidates, if approved, we cannot be certain of this. Third-party payors are increasingly challenging the price, examining the cost-effectiveness, and reducing reimbursement for medical products and services. In the U.S., no uniform policy of coverage and reimbursement for drugs or biological products exists, and one payor’s determination to provide coverage and adequate reimbursement for a product does not assure that other payors will make a similar determination. In the U.S., the principal decisions about reimbursement for new medicines are typically made by the CMS, an agency within the HHS, as the CMS decides whether and to what extent a new medicine will be covered and reimbursed under Medicare. Private third-party payors tend to follow Medicare coverage and reimbursement limitations to a substantial degree but also have their own methods and approval processes apart from Medicare determinations. Significant uncertainty exists as to the reimbursement status of newly approved healthcare products. 50 Table of Conten t s The U.S. government, state legislatures and foreign governments have continued implementing cost containment programs, including price controls, restrictions on coverage and reimbursement and requirements for substitution of generic products. Adoption of price controls and cost containment measures and adoption of more restrictive policies in jurisdictions with existing controls and measures could further limit our revenues and results. We may need to conduct expensive clinical trials to demonstrate the comparative cost-effectiveness of our product candidates. The product candidates that we develop may not be considered cost-effective and thus may not be covered or sufficiently reimbursed. It is time consuming and expensive for us to seek coverage and reimbursement from third-party payors, as each payor will make its own determination as to whether to cover a product and at what level of reimbursement. Thus, one payor’s decision to provide coverage and adequate reimbursement for a product does not ensure that another payor will provide coverage or that the reimbursement levels will be adequate. Moreover, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Reimbursement may not be available or sufficient to allow us to sell our product candidates on a competitive and profitable basis. Healthcare Reform The U.S. and some foreign jurisdictions are considering or have enacted a number of legislative and regulatory proposals to change the healthcare system in ways that could affect our ability to sell our product candidates profitably. Among policy makers and payors in the U.S. and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access. In the U.S., the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives. By way of example, in March 2010, the ACA was signed into law, intended to broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance remedies against fraud and abuse, add new transparency requirements for the healthcare and health insurance industries, impose new taxes and fees on the health industry and impose additional health policy reforms. Among the provisions of the ACA of importance to our potential product candidates are: • an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents, apportioned among these entities according to their market share in certain government healthcare programs; • an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program to 23.1% and 13.0% of the average manufacturer price for branded and generic drugs, respectively; • a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected; • a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 70% (increased pursuant to the Bipartisan Budget Act of 2018, effective as of 2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for a manufacturer’s outpatient drugs to be covered under Medicare Part D; • extension of a manufacturer’s Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations; • expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals and by adding new mandatory eligibility categories for certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability; • expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program; and • a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research. In addition, other legislative changes have been proposed and adopted since the ACA was enacted. These changes include, among others, the Budget Control Act of 2011, which mandates aggregate reductions to Medicare payments to providers of up to 2% per fiscal year effective April 1, 2013, and, due to subsequent legislative amendments, will remain in effect through 2032. In January 2013, President Obama signed into law the ATRA, which, among other things, further reduced Medicare payments to several providers, including hospitals and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. These new laws may result in additional reductions in Medicare and other healthcare funding, which could have a material adverse effect on customers for our product candidates, if approved, and, accordingly, our financial operations. 51 Table of Conten t s Under the American Rescue Plan Act of 2021, the statutory cap on Medicaid Drug Rebate Program rebates that manufacturers pay to state Medicaid programs was eliminated. Elimination of this cap may require pharmaceutical manufacturers to pay more in rebates than they receive on the sale of products, which could have a material impact on our business. Further, in July 2021, an executive order, “Promoting Competition in the American Economy,” was released with multiple provisions aimed at increasing competition for prescription drugs. In August 2022, Congress passed the IRA, which includes prescription drug provisions that have significant implications for the pharmaceutical industry and Medicare beneficiaries, including allowing the federal government to negotiate a maximum fair price for certain high-priced single source Medicare drugs, imposing penalties and excise tax for manufacturers that fail to comply with the drug price negotiation requirements, requiring inflation rebates for all Medicare Part B and Part D drugs, with limited exceptions, if their drug prices increase faster than inflation, and redesigning Medicare Part D to reduce out-of-pocket prescription drug costs for beneficiaries, among other changes. Various industry stakeholders have initiated lawsuits against the U.S. government asserting that the price negotiation provisions of the IRA are unconstitutional. The impact of these judicial challenges, legislative, executive, and administrative actions and any future healthcare measures and agency rules on us and the pharmaceutical industry as a whole is unclear. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our product candidates if approved. Complying with any new legislation and regulatory changes could be time-intensive and expensive, resulting in a material adverse effect on our business. Since the enactment of the ACA, there have been judicial and Congressional challenges to certain aspects of the ACA. In June 2021, the United States Supreme Court held that Texas and other challengers had no legal standing to challenge the ACA, dismissing the case without specifically ruling on the constitutionality of the ACA. Accordingly, the ACA remains in effect in its current form. It is possible that the ACA will be subject to judicial or Congressional challenges in the future. It is unclear how additional challenges and healthcare reform measures will impact the ACA. Complying with any new legislation or changes in healthcare regulation could be time-intensive and expensive, resulting in material adverse effect on our business. At the state level, individual states are increasingly passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including discounts, restrictions on certain product access and marketing cost disclosure and transparency measures. For example, a number of states are considering or have recently enacted state drug price transparency and reporting laws that could substantially increase our compliance burdens and expose us to greater liability under such state laws once we begin commercialization after obtaining regulatory approval for any of our products. For example, the FDA has authorized the state of Florida to develop a program to import certain prescription drugs from Canada for a limited period to help reduce drug costs, provided that Florida’s Agency for Health Care Administration meets the requirements set forth by the FDA. Other states may follow Florida. These measures could reduce the demand for our products, if approved, or impose additional pricing pressures on how much we can charge for our products if approved. We expect that the ACA, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and lower reimbursement and additional downward pressure on the price that we receive for any approved product. Any reduction in reimbursement from Medicare or other government-funded programs may result in a similar reduction in payments from private payors. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability or commercialize our product candidates. Furthermore, the current presidential administration and Congress may continue to attempt broad sweeping changes to the current health care laws. We face uncertainties that might result from modifications or repeal of any of the provisions of the ACA, including as a result of current and future executive orders and legislative actions. The impact of those changes on us and potential effect on the pharmaceutical and biotechnology industries as a whole is currently unknown. However, any changes to the ACA are likely to have an impact on our results of operations and may have a material adverse effect on our results of operations. We cannot predict what other healthcare programs and regulations will ultimately be implemented at the federal or state level or the effect any future legislation or regulation in the U.S. may have on our business. Foreign Regulation In addition to regulations in the U.S., we will be subject to a variety of foreign regulations governing clinical trials and commercial sales and distribution of our product candidates to the extent we choose to develop or sell any product candidates outside of the U.S. The approval process varies from country to country and the time may be longer or shorter than that required to obtain FDA approval. The requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary greatly from country to country. 52 Table of Conten t s Human Capital Our Human Resources talent strategy relies on attracting, retaining and developing top talent that align with our culture and mission to “Outsmart Your Disease.” We promote a culture that is focused on delivering treatments utilizing natural immunities, and we seek to harness our science first focus to deliver solutions to patients and families. As of December 31, 2024, we had 680 employees located across the U.S. and Italy. Among our employees, 41% are focused on research and development, 26% on manufacturing and quality, and 33% on selling, general and administrative functions. We have not been subject to labor action or union activities, and our management considers its relationship with employees to be good. We believe that fostering a workplace that celebrates differences and strengths creates an environment that supports the inclusion and value of diverse thoughts, backgrounds and perspectives. A well-rounded culture allows for ongoing dialogue and discussions that challenge the status quo and create a learning environment that supports diversity, equity and inclusion. As part of our commitment, we continue to encourage a culture where employees can freely ask questions and raise concerns. Our annual performance review process helps support our commitment to develop and retain top talent by providing an opportunity to have open dialogue, establish goals, discuss milestones and continue to engage in opportunities to develop and cultivate the talent. Additionally, we conduct an annual employee engagement survey, and our management team makes themselves available to all employees, including 1:1s, Department Meetings and Town Hall events. Our ongoing success will continue to depend on our ability to attract, engage and retain top talent in an ever growing competitive market. We offer a competitive compensation package to help meet the needs of our employees, incentivize performance and enhance retention. In addition to salaries, these programs include the potential to receive annual bonuses and equity awards, and a 401(k) plan, healthcare and insurance benefits, flexible spending accounts, paid time off, family leave, flexible work schedules, and an employee assistance program, among others. We work to ensure pay equity by assessing our compensation practices and working with external benchmarks and compensation consultants to design and benchmark our programs. Organization and Development of ImmunityBio, Inc. ImmunityBio, Inc. is incorporated in Delaware and its principal executive offices are located in San Diego, California. The company operates in one business and one reportable segment. ImmunityBio, Inc. was established following a series of mergers and name changes. For more information regarding ImmunityBio’s development, see Part I, Item 1. “Business—Organization and Development of ImmunityBio, Inc.” of our Annual Report filed with the SEC on March 19, 2024. Available Information Financial and other information about our company is available on our website at https://www.immunitybio.com. We make available on our website, free of charge, copies of our Annual Report, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and all amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act as soon as reasonably practicable after such reports are electronically filed with, or furnished to, the SEC. All reports we file with the SEC are available free of charge via EDGAR through the SEC website at https://www.sec.gov. We have included the web addresses of ImmunityBio and the SEC as inactive textual references only. Except as specifically incorporated by reference into this Annual Report, information on these websites, including the higher resolution images referred to in the “Founder’s Vision” section of this Annual Report, is not part of this filing. 53 Table of Conten t s