−Removed: As a pioneering clinical-stage immunotherapy company, we are focused on harnessing the power of the innate immune system by using its natural killer cells, or NK cells, to treat cancer and viral infectious diseases.
−Removed: NK cells are the body’s first line of defense due to their innate ability to rapidly seek and destroy abnormal cells, such as cancer or virally infected cells, without prior exposure or co-activation by other support molecules, typically required to train and activate adaptive immune cells such as T‑cells.
+Added: We are a pioneering clinical-stage immunotherapy company focused on harnessing the power of the innate immune system by using our natural killer cells, or NK cells, to treat cancer and viral infectious diseases.
+Added: NK cells are the body’s first line of defense due to their innate ability to rapidly seek and destroy abnormal cells, such as cancer or virally infected cells, without prior exposure or co-activation by other support molecules that are typically required to train and activate adaptive immune cells such as T‑cells.
A critical aspect of our strategy is to invest significantly in innovating new therapeutic candidates, based upon our proprietary activated NK, or aNK, cell platform, and conducting clinical testing and scale manufacturing of our most promising biologic product candidates.
−Removed: We hold the exclusive right to commercialize aNK cells, a commercially viable natural killer cell line, and a wide range of genetically modified derivatives capable of killing cancer and virally infected cells.
−Removed: We own corresponding United States, or U.S., and foreign composition and methods-of-use patents and applications covering the cells, improvements, methods of expansion and manufacture and use of aNK cells and their improvements as therapeutics to treat a spectrum of clinical conditions.
−Removed: We also license exclusive commercial rights to a high-affinity CD16 receptor expressing enhancement of our aNK cell platform , covered in a portfolio of U.S.
−Removed: and foreign composition and methods - of - use patents and applications covering both the clinical use as a therapeutic to treat cancers in combination with antibody products , as well as the non-clinical use in laboratory testing of monoclonal antibodies .
−Removed: We believe our proprietary NK cell platform, coupled with our integrated discovery ecosystem, positions us to implement precision cancer medicine by taking advantage of the advances that have evolved during the past decade and addressing newly discovered challenges of cancer.
−Removed: Cancer is only recently understood to be a complex of rare diseases, with hundreds of cancer specific proteins.
−Removed: We believe proteins, selectively expressed on the cancer cells and not on the essential normal tissue, represent large untapped targeting opportunities for immune effector cell products derived from our aNK cell platform.
+Added: We believe our aNK cell is capable of being manufactured as a cell-based “off-the-shelf” therapy that can be molecularly engineered in a variety of ways to boost its killing capabilities against cancers and virally infected cells.
+Added: We retain worldwide commercial rights to clinical and research data, intellectual property and know-how developed with our aNK cells, as well as clinical grade master and working cell bank s of aNK , haNK and t ‑ haNK cell lines .
+Added: Agreement and Plan of Merger with ImmunityBio, Inc.
+Added: On December 21, 2020, NantKwest and ImmunityBio, Inc.
+Added: (ImmunityBio) entered into an Agreement and Plan of Merger (the Merger Agreement), pursuant to which NantKwest and ImmunityBio agreed to combine their businesses.
+Added: The Merger Agreement provides that a wholly owned subsidiary of NantKwest will merge with and into ImmunityBio (the Merger), with ImmunityBio continuing as the surviving company and being renamed NantCell, Inc., upon the terms and subject to the conditions therein.
+Added: At the effective time of the Merger (the Effective Time), NantKwest’s name, as the parent of NantCell, Inc., will be changed to “ImmunityBio, Inc.”
+Added: At the Effective Time, each share of ImmunityBio common stock issued and outstanding immediately prior to the Effective Time, subject to certain exceptions as set forth in the Merger Agreement, will be converted automatically into a right to receive 0.8190 shares of NantKwest common stock.
+Added: At the Effective Time, each share of NantKwest common stock issued and outstanding immediately prior to the Effective Time, will remain an issued and outstanding share of the combined company.
+Added: At the Effective Time, each outstanding option, warrant or restricted stock unit to purchase ImmunityBio common stock will be converted (using the merger exchange ratio of 0.8190) into an option, warrant or restricted stock unit, respectively, on the same terms and conditions immediately prior to the Effective Time, to purchase shares of common stock of the combined company.
+Added: Upon consummation of the Merger, on a fully-diluted basis, ImmunityBio stockholders and NantKwest stockholders will own approximately 72% and 28%, respectively, of the outstanding shares of common stock of the combined company.
+Added: It is estimated that, immediately following the closing date, Dr.
+Added: Patrick Soon‑Shiong, our Executive Chairman and principal stockholder, and his affiliates will beneficially own, in the aggregate, approximately 82% of the common stock of the combined company.
+Added: Following consummation of the Merger, shares of common stock of the combined company are expected to be listed on the Nasdaq Global Select Market under the symbol “IBRX”.
+Added: Under the terms and subject to the conditions set forth in the Merger Agreement, the closing of the Merger depends on a number of conditions being satisfied, including approval of the Merger by holders of a majority of the outstanding shares of NantKwest common stock as of the NantKwest record date (excluding all shares of NantKwest common stock beneficially owned by Dr.
+Added: Patrick Soon‑Shiong and his affiliates Cambridge Equities, LP and Chan Soon‑Shiong Family Foundation or any of their respective controlled affiliates or any of the directors or executive officers of NantKwest or ImmunityBio).
+Added: On February 1, 2021, our Registration Statement on Form S-4, which was filed with the Securities and Exchange Commission (SEC) in connection with the Merger, was declared effective by the SEC.
+Added: A special meeting of the stockholders of NantKwest will be held on March 8, 2021 to consider and vote on a proposal to approve the issuance of shares of common stock of NantKwest to security holders of ImmunityBio, and to consider and vote on a proposal to approve the Merger.
+Added: Only holders of record of NantKwest common stock at the close of January 29, 2021, will be entitled to notice of and to vote at the special meeting.
+Added: We expect the Merger to close in the first quarter of 2021, subject to receipt of the requisite stockholder approvals and satisfaction of other customary closing conditions.
+Added: The Merger is expected to be accounted for as a transaction between entities under common control as Dr.
+Added: Patrick Soon‑Shiong is the controlling stockholder of each of NantKwest and ImmunityBio.
+Added: Upon the closing of the Merger, the net assets of ImmunityBio will be combined with those of NantKwest at their historical carrying amounts and the companies will be presented on a combined basis for all historical periods presented.
+Added: Our Off-the-Shelf Approach
Multiple Modes of aNK Directed Tumor Cell Killing.
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Innate Killing , whereby all of our NK platforms, aNK, haNK, taNK and t‑haNK, recognize the abnormal proteins typically found on the surfaces of metabolically stressed cells, which upon binding, release toxic granules to immediately kill their targets;
−Removed: Antibody-Mediated Killing with our haNK and t‑haNK platforms, which are aNK cells engineered to express antibody receptors that can bind to therapeutically administered antibody products or to antibodies naturally produced in the body, thereby enhancing the cancer cell killing effects of those antibodies through Antibody Dependent Cellular Cytotoxicity, or ADCC;
+Added: Antibody - Mediated Killing with our haNK and t ‑ haNK platforms , which are a NK cells engineered to express antibody receptors that can bind to therapeutically administered antibody products or to antibodies naturally produced in the body, thereby enhancing the cancer cell killing effects of those antibodies through Antibody Dependent Cell ular Cytotoxicity, or ADCC;
CAR-Directed Killing with our taNK and t ‑ haNK platforms, which are aNK cells engineered to express chimeric antigen receptors, or CARs, that target tumor-specific proteins commonly found only on the surfaces of cancer cells and upon binding, induce cell death through the release of toxic granules directly into their targets and by the release of cytokines and chemokines, which recruit additional innate and adaptive immune responses, including the recruitment of cytotoxic T‑cells.
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Our primary target therapeutic area is cancer, with a heavy emphasis on solid tumors.
−Removed: According to the National Cancer Institute, there was an estimated 1.7 million newly diagnosed cases of cancer in the U.S.
−Removed: in 2019, adding to the 16.9 million already living with cancer.
+Added: According to the National Cancer Institute, almost 1.9 million new cancer cases are expected to be diagnosed in the U.S.
+Added: during 2021, adding to the 16.9 million already living with cancer.
In addition, we plan to advance therapies for hematologic malignancies and virally induced infectious diseases.
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They do so through the recognition and binding of stress-proteins that are overexpressed on the surfaces of
−Removed: rapidly growing cancer cells due to oxidative and metabolic stress, nutrient deprivation and waste accumulation typical when cell growth outpaces the capacity of local circulation;
−Removed: virally infected cells where the cellular machinery is hijacked to produce an abundance of viral proteins and virons.
−Removed: Our aNK cells can also deliver a more lethal blow to their target by delivering a larger payload of lytic enzymes and cytokines responsible for both direct and indirect killing when compared to other natural killer cells isolated from healthy donors.
+Added: rapidly growing cancer cells due to oxidative and metabolic stress, nutrient deprivation and waste accumulation that typically occurs when cell growth outpaces the capacity of local circulation;
+Added: virally infected cells where the cellular machinery is hijacked to produce an abundance of viral proteins and virions.
+Added: Our aNK cells are also designed to deliver a more lethal blow to their target by delivering a larger payload of lytic enzymes and cytokines responsible for both direct and indirect killing when compared to other natural killer cells isolated from healthy donors.
This is due to the higher density of lytic granules and larger cell volume possessed by aNK cells when compared to that of donor-derived natural killer cells.
We believe that our aNK cells can be produced at commercial scale as a ‘living drug’ using our proprietary manufacturing and distribution processes to adequately address select global cancer markets.
−Removed: Several phase I safety studies with aNK cells have been conducted in a variety of bulky hematological cancers and solid tumors , enrolling 46 patients in a range of dose levels and schedules with encouraging evidence of single-agent activity and a durable remission, including complete responses in liquid tumors.
+Added: Several phase I safety studies with unmodified aNK cells have been conducted in a variety of bulky hematological cancers and solid tumors, enrolling 46 patients in a range of dose levels and schedules with encouraging evidence of single-agent activity and a durable remission, including some complete responses in liquid tumors.
Based on these earlier clinical trials, we have further modified our aNK platform through virus-free molecular engineering designed to leverage additional modes of killing available to aNKs, including antibody-mediated killing, the haNK platform, and both antibody-mediated and CAR-directed antigen targeted killing, the t‑haNK platform.
Antibody-Mediated Killing—the haNK Platform.
−Removed: We have genetically engineered our aNK cell platform to overexpress high-affinity CD16 receptors, which bind to antibodies.
+Added: We have genetically engineered our aNK cell platform using a virus-free method to overexpress high-affinity CD16 receptors, which bind to antibodies.
These antibody-targeted haNK cells 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 natural killer cells that can kill cancer cells through ADCC.
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Food and Drug Administration, or FDA, approved antibody products such as avelumab, trastuzumab, cetuximab and rituximab.
−Removed: Current Good Manufacturing Practice, or cGMP, master and working cell banks of our haNK product candidate have been successfully established and will serve as our source for product for our clinical trials and commercialization going forward.
−Removed: We have optimized our haNK product manufacturing process partly through the successful development of a product that does not require IL‑2 cytokine supplementation to the growth media every few days, thereby enabling us to overcome a technically challenging and costly limitation that many other natural killer cell-based therapies face.
+Added: Current Good Manufacturing Practice, or cGMP, master and working cell banks of our haNK product candidate have been successfully established and will serve as our source for product for our clinical trials and, if approved, commercialization going forward.
+Added: We have optimized our manufacturing process partly by designing our haNK product candidate to not require IL‑2 cytokine supplementation to the growth media every few days, thereby enabling us to overcome a technically challenging and costly limitation that many other natural killer cell-based therapies face.
We have also successfully established processes for large-scale production, cryopreservation and long-term storage of final dose forms, thereby optimizing production efficiencies and allowing for on-demand availability with minimal handling at the infusion sites.
−Removed: Our cryopreserved haNK product has been approved for clinical testing in several phase Ib/II clinical trials, including our phase II Merkel cell cancer study.
+Added: Our cryopreserved haNK product candidate has been cleared for clinical testing in several phase Ib/II clinical trials, including our phase II Merkel cell cancer study.
CAR-Directed Killing—the taNK Platform.
We have genetically engineered our aNK platform to express CARs that target tumor-specific antigens found on the surfaces of cancers and virally infected cells.
−Removed: Our taNK cells are designed to bind directly to these surface antigens and induce cell death through the release of toxic granules directly into the tumor cells and release cytokines and chemokines to recruit additional innate and adaptive immune responses, including the recruitment of cytotoxic T‑cells.
−Removed: These tumor antigens encompass four categories of proteins, all of which can be targeted individually by our engineered taNK products:
−Removed: Checkpoint ligands, such as PD‑L1 and B7‑H4;
−Removed: Well-established tumor proteins such as HER2 and CD19;
−Removed: Novel surface antigens associated with cancer stem cells, such as CD123 and IGF‑R1;
−Removed: Newly discovered proteins, or neoepitopes, from individual patient tumor samples.
−Removed: Preclinical evidence has been mounting which demonstrates that taNK cell activation through the binding of its CAR receptors to these cancer specific proteins is potent enough to override many of the pre-existing inhibitory signals and immunosuppressive factors present in the tumor microenvironment that may be responsible for tumor resistance.
+Added: Our taNK cells are designed to bind directly to these surface antigens and induce cell death through the release of toxic granules directly into the tumor cells and release of cytokines and chemokines to recruit additional innate and adaptive immune responses, including the recruitment of cytotoxic T‑cells.
+Added: These tumor antigens include checkpoint ligands, such as PD‑L1 and B7‑H4 as well as well-established tumor proteins such as CD19, HER2 and EGFR, all of which can be targeted individually by our engineered taNK products.
+Added: Preclinical evidence has been mounting which indicates that taNK cell activation through the binding of its CAR receptors to these cancer specific proteins may be potent enough to override many of the pre-existing inhibitory signals and immunosuppressive factors present in the tumor microenvironment that may be responsible for tumor resistance.
CAR-Directed and Antibody-Mediated Killing—the t‑haNK Platform.
Our newest and most promising platform for the development of therapeutic product candidates is an innovative, bioengineered combination of our haNK and taNK platforms that incorporates all the features of our haNK platform together with a CAR.
−Removed: The resulting line of products under this platform avails itself to all three modes of killing:
+Added: The resulting line of product candidates under this platform avails itself to all three modes of killing:
innate , antibody-mediated and CAR-directed killing .
−Removed: These products also include one or more additional expression elements such as functional cytokines, chemokines and trafficking factors, making them amongst the most versatile in our portfolio.
−Removed: These products 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.
−Removed: In addition to our two t‑haNK product candidates, PD‑L1.t‑haNK, recently cleared to commence phase II testing, and CD19.t‑haNK, authorized to commence phase I testing, a pipeline of prominent CARs for t‑haNK, including HER2, which is nearing IND submission, and EGFR, which is advancing through human enabling studies, among others will enable us to address an even broader range of cancers as part of a chemotherapy-free combination regimen.
+Added: These product candidates also include one or more additional expression elements such as functional cytokines, chemokines and trafficking factors, making them amongst the most versatile in our portfolio.
+Added: 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.
+Added: In addition to our two t‑haNK product candidates, PD‑L1.t‑haNK, currently in phase II testing, and CD19.t‑haNK, cleared to commence phase I testing, we believe a pipeline of prominent CARs for t‑haNK, including HER2 and EGFR, which are nearing IND submission, and others that are advancing through clinical enabling studies, will enable us to potentially address an even broader range of cancers as part of a chemotherapy-free combination regimen.
The Nant Cancer Vaccine.
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NCV consists of an initial tumor-conditioning regimen followed by a molecularly-informed immunologic conditioning therapy.
−Removed: More specifically, NCV combines tumor and peripheral blood genomic and transcriptomic data derived from our affiliates NantOmics’ and NantHealth Labs’ sequencing and analytical services with the novel delivery of metronomic, albumin-bound low-dose chemotherapy in conjunction with certain other agents, followed by a sequenced administration of tumor-associated antigen vaccines and a unique IL ‑15 cytokine , all of which potentiate our NK cell therapy to potentially drive immunogenic cell death while avoiding the ravages of toxic high-dose chemotherapy.
+Added: More specifically, NCV combines the novel delivery of metronomic, albumin-linked low-dose chemotherapy in conjunction with certain other agents, followed by a sequenced administration of tumor-associated antigen vaccines and an IL‑15 superagonist fusion protein, all of which potentiate our NK cell therapy to potentially drive immunogenic cell death while avoiding the ravages of toxic high-dose chemotherapy.
By inducing immunogenic cell death and enhancing a patient’s innate and adaptive immune system, NCV is designed to attain a long-term, durable response in multiple cancer types with a potential for lower toxicity and improved efficacy and quality of life in comparison with current standards of care.
−Removed: We believe ultimately that employing our NK cell therapy in the context of NCV w ill be a highly effective combination for long term clinical success over available standards of care that employ maximum tolerated dose, tolerogenic cell death and immune system compromise.
−Removed: Our Integrated Discovery Ecosystem for Precision Medicine.
−Removed: In order to effectively target newly discovered neoepitopes, we plan to eventually integrate the following ecosystem to help drive the utility of our NK cell therapies against these unique cancer markers, including the use of our haNK platform in conjunction with cancer vaccines that induce in vivo antibody formation directed against these mutated proteins, as well as the development of t‑haNK cells that directly target these mutated proteins:
−Removed: a high-speed supercomputing infrastructure to help identify both known antigens on the surface of tumor cells and neoepitopes in clinical patients suffering from cancer, in a timely manner and at large scale;
−Removed: a next-generation genomic and transcriptomic sequencing infrastructure to verify the expression of the neoepitopes in the tumor cell, developed by our affiliate entity NantOmics;
−Removed: delivering the neoepitope via an adenoviral or yeast platform developed by an affiliate entity to induce production of IgG1-type antibodies in the body, which would in turn combine with our haNK cells to accelerate ADCC tumor killing;
−Removed: a diverse library of human antibodies from which to interrogate and extract an antibody to construct a CAR for genetic incorporation into our t‑haNK platform;
−Removed: CAR‑targeted t‑haNK cells potentially capable of being produced as a scalable cell-based “off-the-shelf” therapy, without the need for patient compatibility matching.
−Removed: We expect to regularly add newly discovered neoepitopes and novel antibody/CAR targets from our discovery engine and we believe the thousands of newly discovered antigens selectively expressed on the cancer cells and not on the essential normal tissue will provide us with the ability to create new libraries of cancer-specific antibodies and their corresponding CARs to be potentially delivered as living drugs for selective targeting of metastatic cancer cells and cancer stem cells.
+Added: We believe ultimately that employing our NK cell therapy in the context of NCV will be a highly effective combination for long term clinical success over available standards of care that employ maximum tolerated dose, tolerogenic cell death and immune system compromise.
Potential Advantages of Our aNK Platform Over T‑Cell and Other Current Immunotherapies
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This is largely due to the unique versatility of our cell products, which more closely approximates the characteristics of a drug rather than a transplant.
−Removed: Most cell-based immunotherapies are limited to one or a constrained number of doses due to product limitations and cost burdens, thereby driving the need for immune-ablative therapies and reliance on long-term engraftment to achieve clinically meaningful results.
+Added: Most cell-based immunotherapies are limited to one or a constrained number of doses due to product limitations and cost burdens, thereby
+Added: driving the need for immune-ablative therapies and reliance on long-term engraftment to achieve clinically meaningful results.
In comparison, our NK cell based therapies can be re-dosed regularly throughout the year and at much higher dose levels without the same product limitations, cost burdens, reliance on long-term engraftment and potential exposure to long-term toxicities.
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Ease of administration.
−Removed: aNK platform products may be administrable in outpatient facilities, offering physicians the flexibility to re-dose therapy in the ambulatory setting for extended periods and in large practices.
+Added: aNK platform products have been administered in outpatient facilities, potentially offering physicians the flexibility to re-dose therapy in the ambulatory setting for extended periods and in large practices.
Virtually universal patient compatibility.
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Since the founding of our company in 2002, we have assembled a team of proven, experienced and visionary leaders in biotechnology.
−Removed: Our team is led by Patrick Soon-Shiong, M.D., FRCS (C), FACS, our Chairman and Chief Executive Officer, or CEO.
+Added: Our team is led by Patrick Soon‑Shiong, MBBch, FRCS (C), FACS, who has served as our Chairman since March 2015.
Soon‑Shiong was first introduced to us in 2007 when our technology was at a very early stage of development and he provided us with advice and scientific development strategies, including demonstration of activity in the clinical setting following irradiation of the cells and demonstration of safety and activity following multiple infusions in patients with both end-stage solid and liquid tumors.
−Removed: Soon-Shiong made an equity investment in our company in December 2014, joined as our Chief Medical Officer in January 2015, and became our Chairman and CEO in March 2015.
+Added: Soon‑Shiong made an equity investment in our company in December 2014 and joined as our Chief Medical Officer in January 2015.
+Added: Soon‑Shiong became our Chairman in March 2015 and served as our Chief Executive Officer, or CEO, from March 2015 until October 2020.
+Added: Effective October 2020, Dr.
+Added: Soon‑Shiong has served as our Executive Chairman of the board of directors.
Soon‑Shiong, a renowned surgeon and scientist, has pioneered novel therapies for both diabetes and cancer, published over 100 scientific papers in the U.S., and has been issued over 230 worldwide patents on groundbreaking advancements spanning a myriad of fields.
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Soon‑Shiong was founder, Chairman and CEO of American Pharmaceutical Partners (sold to Fresenius SE for approximately $4.6 billion in 2008), Abraxis BioScience (sold to Celgene Corporation for approximately $3.8 billion in 2010), and NantWorks, an ecosystem of companies to create a transformative global health information and next generation pharmaceutical development network.
+Added: Richard Adcock was appointed as our C EO in October 2020.
+Added: Prior to joining NantKwest, Mr.
+Added: Adcock served as CEO of Verity Health from January 2018 to September 2020.
+Added: Verity Health was previously affiliated with Dr.
+Added: Soon ‑ Shiong until 2018.
+Added: Prior to Verity Health, Mr.
+Added: Adcock served in various capacities at Sanford Health, including as its Chief Innovation Officer, President, Executive Vice President and Director from 2004 to 2017.
+Added: Prior to Sanford Health, Mr.
+Added: Adcock served as Global Engineering Director at GE Healthcare from 1999 to 2003.
Barry Simon, M.D., our President and Chief Administrative Officer, who was our CEO from May 2007 until March 2015 and our President and Chief Operating Officer from March 2015 to December 2016, brings decades of drug development and executive leadership experience from Roche Labs, F.
Hoffmann‑La Roche, Connetics Corp.
−Removed: and Immunomedics, having successfully contributed to Biologics License Applications, or BLAs, and drug launches for Xeloda, Pegasys, Kytril, Fortovase, Valcyte, Fuzeon and Tamiflu.
−Removed: Since 2015, we have recruited seasoned executives to lead manufacturing, clinical development, regulatory affairs, medical affairs, quality and other critical staff as we continue to build our management and manufacturing infrastructure.
+Added: and Immunomedics, having successfully contributed to Biologics License Applications, or BLAs, and commercial drug launches for Xeloda, Pegasys, Kytril, Fortovase, Valcyte, Fuzeon and Tamiflu.
+Added: We have experienced executives leading our research and development, manufacturing, preclinical and clinical development, regulatory and medical affairs, finance and other critical areas of our business, and we continue to build our manufacturing and administrative infrastructure.
Company Vision
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Pursuit of both accelerated regulatory pathways and large market opportunities.
−Removed: We are pursuing a comprehensive clinical development plan designed to maximize the commercial potential of our haNK and t‑haNK platforms as the backbone in the treatment of cancers in a streamlined combination with a PD‑L1 checkpoint inhibitor and a highly selective and molecularly enhanced IL‑15 cytokine immunotherapy.
+Added: We are pursuing a comprehensive clinical development plan designed to maximize the commercial potential of our haNK and t‑haNK platforms as the backbone in the treatment of cancers in a streamlined combination with a PD‑L1 checkpoint inhibitor and a highly selective and molecularly enhanced IL‑15 superagonist fusion protein.
We intend to pursue accelerated regulatory approval pathways and seek indications that can lead to orphan drug status and breakthrough therapy designation, as well as pursue large market opportunities in select solid tumors in the shortest feasible timeframe.
−Removed: Progress our lead haNK product through phase II and registration trials.
−Removed: We are leveraging the combined human safety and activity data accumulated to date on haNK therapy to conduct our multi-center phase II trial in patients with Merkel cell carcinoma who have relapsed on checkpoint therapy.
Advance our next-generation t‑haNK products towards phase II and registration trials.
−Removed: Our broadly applicable t‑haNK product, PD‑L1.t‑haNK, is expected to conclude phase I clinical testing by June 30, 2020, and the first phase II trials in pancreatic and PD‑L1 expressing non-small cell lung cancers have recently been filed with the FDA, with an additional phase II trial submission in lung cancer with concurrent chemotherapy in preparation for submission.
+Added: Our broadly applicable t‑haNK product, PD‑L1.t‑haNK, is currently undergoing testing in a phase II trial in pancreatic cancers and has received FDA authorization to begin testing in non-small cell lung cancers with an additional phase II trial submission in triple negative breast cancers with concurrent chemotherapy in preparation for submission.
Additionally, our CD19.t‑haNK IND application has been approved by the FDA for a dose escalation phase I study in patients with CD19 expressing diffuse large B-cell lymphomas and our HER2.t‑haNK IND application is nearing completion and being readied for submission with the FDA during the first half of 2021.
−Removed: Additions to our pipeline of IND-ready t‑haNK product candidates may include EGFR and BCMA t‑haNK products during the second half of 2020.
+Added: Additions to our pipeline of near-term IND-ready t‑haNK product candidates include an EGFR t‑haNK product during the second half of 2021.
+Added: Progress our lead haNK product candidate through phase II and registration trials.
+Added: We are leveraging the combined human safety and activity data accumulated to date on haNK therapy to conduct our multi-center phase II trial in patients with Merkel cell carcinoma who have relapsed on checkpoint therapy.
Leverage our exclusive co-development agreement with ImmunityBio for N-803.
As with the emergence of dozens of CAR ‑T companies following the success of a select few, more and more natural killer cell therapy companies are forging ahead into the cancer immunotherapy space.
−Removed: Due to the lack of market access to suitable companion products for co-development, such as cytokine therapies, many natural killer cell therapy developers are following the path of CAR‑T sponsors in the use of myeloablative therapies that support engraftment, but at the same time suppresses immune recruitment and the recipient’s ability to mount an adaptive immune response.
−Removed: N‑803 is an experimental IL‑15 superagonist, currently in late stage registration trials by ImmunityBio, Inc., an affiliated entity.
+Added: Due to the lack of market access to suitable companion products for co-development, suc h as cytokine therapies, many natural killer cell therapy developers are following the path of CAR ‑T sponsors in the use of myeloablative therapies that support engraftment, but at the same time suppresses immune recruitment and the recipient’s ability to mount an adaptive immune response.
+Added: N ‑803 is an experimental IL ‑15 superagonist fusion protein , currently in late stage registration trials by ImmunityBio, Inc., an affiliated entity.
Our utilization of N ‑803 in combination with our NK therapies across our clinical program affords us an additional distinction and competitive advantage where we combine systemic activation of recipient natural killer and T ‑cells with chemotherapy-free treatment regimens for maximal immune response and memory T ‑cell formation.
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Establish low-cost, scalable manufacturing capabilities to support late-stage clinical trials and global commercialization.
−Removed: We believe our aNK platform products offer unique advantages of a simplified, on-demand manufacturing process that is relatively easy to scale and requires minimal handling at the site of infusion.
−Removed: We opened our state-of-the-art commercial production facility in El Segundo, California, at the beginning of 2019 and transferred all of our manufacturing operations from our pilot facility in Culver City, California.
−Removed: We believe this new facility is capable of producing clinical product for all our clinical trials for multiple product lines and well into commercialization.
+Added: We believe our aNK platform product candidates offer unique advantages of a simplified, on-demand manufacturing process that is relatively easy to scale and requires minimal handling at the site of infusion.
+Added: We opened our second state-of-the-art commercial production facility in El Segundo, California at the beginning of 2021 and transferred all of our t‑haNK manufacturing operations from our first facility in El Segundo.
+Added: We believe this new facility is capable of producing clinical product for all our clinical trials for multiple product lines.
We have developed novel manufacturing methods, including the use of proprietary equipment that employs state-of-the-art optics, as well as proprietary media, designed to maximize the attributes of our NK product lines.
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Extend our NK platform to address diseases beyond cancer.
−Removed: We believe our aNK platform has the potential to address diseases beyond cancer such as viral infectious diseases because of the innate ability of natural killer cells to kill virally infected cells.
+Added: We believe our aNK platform has the potential to address diseases beyond cancer such as viral infectious diseases because of the in nate ability of natural killer cells to kill virally infected cells.
Preclinical studies in HIV, HCV, EBV and Ebola viruses demonstrate this capability.
−Removed: Preclinical efforts are underway to evaluate the role of haNK in combination with select broadly neutralizing antibody, or bNAb, candidates in clearing HIV reservoirs as part of a novel immunotherapy combination regimen.
−Removed: Additionally, exploratory efforts are proceeding with the evaluation of haNK cells, as well as other variants, in the treatment of moderate to severe respiratory infections due to Coronaviruses, such as SARS‑CoV‑2.
+Added: Pre clinical e fforts are underway to evaluate the role of h aNK in combination with select broadly neutralizing antibody , or bNAb, candidates in clearing HIV reservoirs as part of a novel immunotherapy combination regimen.
Our Therapeutic Platforms
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We have developed a pre-clinical portfolio of t‑haNK products based on the combined attributes of our existing haNK and taNK platforms.
−Removed: We have also advanced our haNK product into clinical trials across several solid-tumor types, which incorporates a comprehensively orchestrated tumor and immune-conditioning regimen known as the Nant Cancer Vaccine, or NCV, and generated compelling safety and activity data.
−Removed: We now plan to advance our lead clinical candidates from the haNK and t‑haNK platforms into checkpoint inhibitor and IL‑15 combination trials in select cancer indications.
+Added: We have also advanced our haNK product candidate into clinical trials across several solid-tumor types, which incorporates a comprehensively orchestrated tumor and immune-conditioning regimen known as the Nant Cancer Vaccine, or NCV, and generated compelling safety and activity data.
+Added: We now plan to advance our lead clinical candidates from the haNK and t‑haNK platforms into checkpoint inhibitor and IL‑15 superagonist fusion protein combination trials in select cancer indications.
Our aNK Platform is the Foundation for Our haNK, taNK and t‑haNK Product Candidates.
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In the taNK and t‑haNK cell lines, the activation signaling that results from the binding of the CARs to the tumor-specific antigens can be strong enough to overcome both cancer escape mechanisms and suppressive factors present in the tumor microenvironment.
−Removed: These tumor antigens encompass four categories of proteins, all of which can be targeted individually by our engineered taNK products:
+Added: These tumor antigens encompass three categories of proteins, all of which can be targeted individually by our engineered taNK products:
Checkpoint ligands, such as PD‑L1 and B7‑H4;
−Removed: Well-established tumor proteins such as HER2 and CD19;
−Removed: Novel surface antigens associated with cancer stem cells such as CD123 and IGF‑R1;
−Removed: Newly discovered proteins, or neoepitopes, from individual patient tumor samples.
+Added: Well-established tumor proteins such as CD19, HER2 and EGFR;
+Added: Novel surface antigens associated with cancer stem cells.
The table below is a partial list of CAR modified aNK products in the literature and their intended tumor types.
1 unchanged sentence
a Compelling Case for Virus-Free t‑haNK-Based Therapies.
−Removed: We are preparing a novel lineup of virus-free t‑haNK product candidates that are cryopreserved, CAR expressing cell lines based on our haNK cell therapeutic, one of which is progressing towards phase II clinical trials.
+Added: We are preparing a novel lineup of virus-free t‑haNK product candidates that are cryopreserved, CAR expressing cell lines based on our haNK cell therapeutic, one of which is progressing through a phase II clinical trial.
Our rapid advancement of the virus-free t‑haNK platform has enabled us to discontinue all use of viral vectors as a means to genetically enhance our platforms.
These next-generation products avoid the safety concerns associated with the use of retro- and lentivirus sequences, incorporate the high-affinity CD16 receptor for enhanced antibody-mediated killing, as well as IL‑2 for IL‑2 growth independence, which can potentially reduce production costs and enhance clinical efficacy.
−Removed: Clinical Experience With Our Unmodified aNK Platform as a Cell Therapy Candidate
−Removed: Our clinical experience with single and multiple intravenous infusions of aNK monotherapy across a range of relapsed and refractory solid and hematological malignancies has been consistently encouraging from both a safety and activity standpoint.
−Removed: We have demonstrated single-agent safety with dose escalations in both single and repeat dosing schedules to doses as high as 1 x 10 10 cells/m 2 and as many as 18 infusions over a six-month period, corresponding to a cumulative dose of as high as 15 x 10 10 cells in an individual patient.
−Removed: Infusion-related toxicities remained generally mild across all studies and dose levels, with the exception of one grade 3 fever and one grade 4 hypoglycemic episode, neither of which resulted in dose reduction or study discontinuation.
−Removed: A minority of subjects that proceeded with additional testing were found to have detectable levels of anti-HLA antibodies, but none were required to withdraw from study and some continued to receive additional infusions without sequelae.
−Removed: While many cell-based adaptive immunotherapy trials impose heavy pre-screening protocols to cherry-pick likely responders, our subjects were not pre-selected, but rather we accepted all-comers after meeting simple eligibility criteria, including patients who had very advanced disease, having failed multiple rounds of standard chemotherapy, radiation, surgery and even stem cell transplantation.
−Removed: Additionally, none of these patients received lympho-depleting or pre-conditioning regimens in order to enhance therapeutic effects.
−Removed: Although aNK is not intended as a monotherapy, clinical activity was recorded in all studies conducted to date:
−Removed: Among the three Merkel cell cancer patients receiving aNK cell monotherapy, one subject achieved a radiologic complete response.
−Removed: Among the four lung cancer patients treated, three subjects had clinically significant responses including one with a resolved supraclavicular lymph node metastasis, the second with a nearly resolved mediastinal lung metastasis and the third with a 23-month disease stabilization with thoracic pain resolution.
−Removed: Among 12 patients with advanced melanoma and renal cell carcinoma, one melanoma patient went on to have a mixed response with several lesions resolving, and five renal cell carcinoma patients achieved disease stabilization after having breakthrough progression on their prior therapies.
−Removed: Among 12 subjects with advanced hematological malignancies, two subjects , one with Hodgkin’s lymphoma and the other with multiple myeloma, achieved a complete response.
−Removed: A third subject achieved a partial response , another subject achieved a clinical-transient response, and a fifth subject achieved a mixed-transient response.
−Removed: Among six patients with acute myeloid leukemia, one subject achieved a significant reduction in percentage of blasts and two subjects achieved a stable percentage of blasts present in their peripheral blood.
−Removed: Additional detail on each of these studies follows:
−Removed: Merkel Cell Carcinoma:
−Removed: QUILT 3.009 (NantKwest Sponsored)
−Removed: This completed multi-center, nonrandomized, open-label phase II study was conducted in patients 18 years and older with histologically confirmed stage IIIB or stage IV inoperable Merkel cell carcinoma.
−Removed: The primary endpoint was a four month progression-free survival rate, and the secondary endpoints were overall response rate, time to disease progression, median overall survival, safety, and quality-of-life assessment.
−Removed: The study employed a Simon’s two-stage design where upon if at least one patient from the first stage of treatment with aNK monotherapy achieved progression-free survival for 16 weeks or more, the second stage would initiate and proceed to full enrollment.
−Removed: Shortly after the first patient reached the 16 week progression-free survival metric, the protocol was amended such that all second stage patients would receive aNK in combination with N‑803.
−Removed: The aNK dose of 2 × 10 9 cells/m 2 was administered intravenously on two consecutive days every two weeks (one cycle).
−Removed: N‑803 was administered subcutaneous at 10 µg/kg on the first day of every aNK infusion (prior to aNK infusion) every two weeks.
−Removed: Patients were withdrawn from the trial if there was evidence of disease progression at any time after the fourth cycle.
−Removed: A total of three subjects received treatment with aNK monotherapy and a total of four subjects were treated with aNK plus N ‑803, all having previously received and failed treatment with multiple lines of therapy that included checkpoint inhibitors.
−Removed: There were no serious adverse events of grade 3 or higher that were considered to be related to treatment with the study drugs.
−Removed: All adverse events that may have been related to study drug administration were grade 2 or milder and included chest tightness, chills, fatigue, upper respiratory infection, strep throat, redness at the injection site, hypokalemia, hypotension, anorexia, mucosal infection, and hyponatremia.
−Removed: As reported at the November 2019 Society for Immunotherapy Conference and subsequently updated, of the seven subjects enrolled, three having received aNK monotherapy and four having received aNK plus N-803, three experienced a clinical benefit.
−Removed: The objective response rate was 29%, with two of seven patients experiencing a complete response or partial response:
−Removed: One heavily pretreated patient that progressed on pembrolizumab, received aNK monotherapy and achieved and maintained a radiologic complete response until progressive disease was confirmed by biopsy at eight months.
−Removed: Re-challenge with pembrolizumab after aNK therapy resulted in an ongoing durable complete response at 44 months.
−Removed: A second patient receiving aNK plus N‑803 experienced pseudo-progression at three and a half months after initially responding and was taken off therapy with no subsequent intervention.
−Removed: This patient subsequently went on to experience a durable partial response with more than 86% tumor regression that is still ongoing at 29 months.
−Removed: A third patient experienced an ongoing stable disease, now beyond five and a half months.
−Removed: Intriguing changes were noted clinically in superficial tumors in several patients within hours of aNK infusion.
−Removed: Three of the remaining four patients showed progressive disease at the first imaging assessment.
−Removed: The final patient was discontinued from treatment due to clinical disease progression prior to the first imaging assessment.
−Removed: Results from this study show that treatment with aNK and N‑803 is well-tolerated, as no treatment-related serious adverse events were associated with aNK monotherapy or with aNK plus N‑803 combination therapy.
−Removed: Treatment with both aNK monotherapy and aNK plus N‑803 combination therapy were associated with anticancer activity as evidenced by increased antigen presentation, IFN‑γ and other immune response gene expression, as well as CD8+ and CD4+ immune cell infiltration in the tumor microenvironment in addition to measurable tumor responses.
−Removed: Moreover, evidence that aNK cell treatment may reverse refractoriness to immune checkpoint inhibitors was observed with a patient that previously progressed while on pembrolizumab, only later to experience a durable complete response to pembrolizumab re-challenge after completing aNK cell therapy.
−Removed: These results suggest treatment with aNK and N‑803 at doses sufficient to elicit tumor regression is associated with manageable and relatively modest adverse events and provides a foundation upon which to investigate the use of our “off-the-shelf” haNK product in QUILT 3.067, a phase II trial investigating a chemotherapy-free combination of haNK, N‑803 and the checkpoint inhibitor avelumab.
−Removed: Advanced Solid Tumors (Investigator Sponsored) 1
−Removed: This phase I, single-arm, open-label, dose-escalation study conducted at the University Hospital in Frankfurt, evaluated the safety and efficacy of aNK cell monotherapy in 15 pediatric and adult patients with advanced cancer resistant to standard therapies.
−Removed: The objectives of the study were to evaluate safety and clinical outcomes.
−Removed: The three aNK dose levels were 1 × 10 9 cells/m 2 , 3 × 10 9 cells/m 2 , and 1 × 10 10 cells/m 2 (1 × 10 10 cells/m 2 was administered in adults only).
−Removed: Two infusions of aNK were administered intravenously on days one and three.
−Removed: All infusions were well tolerated by all patients, even at the highest dose level, with the exception of one patient whose second transfusion was discontinued after he reported lower back pain.
−Removed: No effect on bone marrow function was observed in any patient as stable blood cell counts observed were over the first four weeks after aNK treatment.
−Removed: Likewise, no changes in renal and hepatic functions were noted.
−Removed: One of seven tested patients had an antibody response to HLA antigens expressed by aNK at the time of testing, one- and four-weeks after aNK infusions;
−Removed: this patient had received blood transfusions after aNK infusion with potential transmission of antibodies.
−Removed: Tonn et al, Cytotherapy.
−Removed: 2013 Dec;15(12):1563-70
−Removed: Three patients with advanced lung cancer had clinically significant re sponses after two doses of aNK:
−Removed: One patient had a diagnosis of non-small cell lung cancer with multiple lung metastases resistant to conventional chemotherapy, radiation and surgery.
−Removed: After treatment with two infusions of 1 × 10 10 cells/m 2 , the patient experienced stable disease.
−Removed: Four months after receiving two initial infusions, the patient received four additional infusions of aNK cells (5 × 10 9 to 1 × 10 10 cells/m 2 ) over a period of six months, with no adverse events from either the initial or subsequent treatments.
−Removed: The patient had an overall survival of 23 months after receiving the initial two infusions of aNK.
−Removed: One patient had a diagnosis of small cell lung cancer with a supraclavicular lymph node metastasis, also resistant to conventional chemotherapy, radiation and surgery.
−Removed: After treatment with two infusions of 3 × 10 9 cells/m 2 , the patient’s lymph node metastasis could no longer be detected.
−Removed: This patient experienced a mixed response and went on to have an overall survival of nearly 18 months.
−Removed: Another patient had a diagnosis of small cell lung cancer with multiple metastases in the liver and a one inch single metastasis in the lung just behind the sternum.
−Removed: After two infusions of 3 × 10 9 cells/m 2 , there was significant regression in the lung metastasis as verified by lateral imaging before and 14 days after aNK treatment with no regression of the liver metastases.
−Removed: This patient was recorded as having a mixed response and an overall survival of eight months.
−Removed: Such beneficial effects of aNK cell therapy in three of four lung cancer patients may not be surprising as we better understand aNK biodistribution upon intravenous administration.
−Removed: After circulating through the right heart and pulmonary vasculature, murine models of aNK trafficking reveal that the cells demarginate and reside in the lungs within the first hours after infusion before circulating systemically to distant organs, including spleen, kidney, bladder and peripherally implanted tumor.
−Removed: This could potentially make tumors of the lung the most readily accessible among solid tumors to serial infusions of aNK cells and provide a foundation upon which to investigate the use of our “off-the-shelf” PD‑L1.t‑haNK product in QUILT 59, a late-stage trial investigating a chemotherapy-free combination of PD‑L1.t‑haNK, N‑803 and a checkpoint inhibitor.
−Removed: NantKwest, Klingemann H., et al., data on file
−Removed: Advanced Melanoma or Renal Cell Carcinoma (Investigator Sponsored) 3
−Removed: This phase I, open-label, single-arm, single-center, dose-escalation study, conducted at Rush University Medical Center, Chicago, evaluated the feasibility and safety of a single cycle consisting of three infusions of aNK monotherapy administered on days one, three and five in 12 patients 18 years and older with measureable refractory or relapsed advanced renal cell carcinoma and melanoma.
−Removed: The primary endpoints were the feasibility and safety of aNK cells.
−Removed: The four dose levels were 1 × 10 8 cells/m 2 , 3 × 10 8 cells/m 2 , 1 × 10 9 cells/m 2 , and 3 × 10 9 cells/m 2 administered intravenously.
−Removed: Three patients developed grade 1 fever and one patient developed grade 3 fever, all possibly related to aNK infusions.
−Removed: One patient with renal cancer, who had extensive liver metastases, developed a transient grade 4 hypoglycemia possibly related to aNK.
−Removed: The patient responded to a 5% dextrose intravenous infusion, and went on to receive two subsequent infusions of aNK uneventfully.
−Removed: Four adverse events were considered not related to aNK and included three exacerbations of tumor pain (grade 2 neck pain, grade 2 chest pain, and grade 3 back pain) and one grade 2 rheumatoid arthritis pain.
−Removed: There were no serious infections reported for patients at the one-year follow-up.
−Removed: Six patients had elevations in lactate dehydrogenase enzymes, and four patients had elevated cytokines, potentially due to tumor lysis reaction.
−Removed: Six of the 12 patients, or 50%, experienced a clinical benefit in this single-course dose escalation study in a dose-dependent fashion with:
−Removed: Zero of three experiencing a clinical benefit in the lowest dose cohort,
−Removed: One of three at the second dose cohort,
−Removed: Two of three at the third dose cohort, and finally
−Removed: Three of three at the highest dose cohort.
−Removed: Two patients had a mixed response, four patients had stable disease, and six patients had progressive disease, all assessed four weeks post-infusion.
−Removed: Of note, the one patient with renal cell carcinoma that had a mixed response was observed to have a significant reduction in lung masses, but progressed in the mediastinum.
−Removed: Also, the one patient with advanced melanoma that had a mixed response had a striking reduction in a target lesion in the upper neck on CT imaging noted at two weeks post-infusion.
−Removed: Overall survival in the patients achieving stable disease ranged from seven to 35 months.
−Removed: These encouraging results became the basis to further investigate repeat course therapy at a recommended phase II dose.
−Removed: Arai et al, Cytotherapy.
−Removed: 2008;10(6):625-32
−Removed: Hematologic Malignancies (Investigator Sponsored) 4
−Removed: This phase I, open-label, single-arm, single-center, dose-escalation study conducted at the Princess Margaret Hospital in Toronto, evaluated the safety of aNK monotherapy in patients 18 years and older with histologically confirmed, refractory hematologic malignancies who relapsed after autologous hematopoietic cell transplantation.
−Removed: The primary endpoint was safety and the secondary endpoints were efficacy, immune responses to aNK, and kinetics of infused aNK.
−Removed: The three aNK dose levels were 1 × 10 9 cells/m 2 , 3 × 10 9 cells/m 2 , and 5 × 10 9 cells/m 2 administered intravenously on days one, three, and five of each cycle of treatment.
−Removed: Patients could receive up to six monthly cycles, for a total of 18 infusions.
−Removed: A total of 12 patients were enrolled in the study and included Hodgkin’s, mantle cell and diffuse large B‑cell lymphoma, chronic lymphocytic leukemia with Richter’s transformation and multiple myeloma.
−Removed: Some patients experienced grade 1 fever, chills, fatigue, blurry vision, and nausea.
−Removed: There was a single grade 2 adverse event of fever and chills that occurred during an aNK infusion.
−Removed: No grade 3 or 4 adverse events were observed.
−Removed: There were no clinically significant alterations in hemoglobin, platelets, white cell counts, creatinine, or liver function tests.
−Removed: Six patients developed either class I or II anti‑HLA antibodies, typically after the second cycle of aNK, however, this did not interfere with repeat dosing, with most receiving 15 or more infusions without incident.
−Removed: Cytokine release was not observed in any of the patients, although there was a transient rise in IL‑10 and IL‑6 in two patients.
−Removed: Five of 12 patients had responses to aNK cell therapy:
−Removed: two durable complete responses, one partial response, one clinical-transient response, and one mixed-transient response.
−Removed: One complete response was observed in a patient with relapsed, refractory Hodgkin’s lymphoma, which was maintained for more than ten years with no subsequent therapy.
−Removed: The second complete response was observed in a patient with IgA kappa myeloma who received concomitant lenalidomide-dexamethasone therapy during and after aNK cell infusions, and this patient remains on maintenance therapy with an ongoing complete response two years after aNK cell therapy.
−Removed: An additional three patients experienced partial or transient responses.
−Removed: One patient diagnosed with Hodgkin’s lymphoma had a partial response after one cycle of aNK cell infusion.
−Removed: This patient elected to undergo allotransplantation and subsequently died of allotransplant-related complications.
−Removed: A patient diagnosed with chronic lymphocytic leukemia showed clinical improvement and subsequently progressed after completing six monthly cycles of aNK infusion.
−Removed: A patient with diffuse large B‑cell lymphoma, or DLBCL, also showed a transient clinical improvement that was followed by progressive disease.
−Removed: Williams et al, Oncotarget.
−Removed: 2017 Jul 12;8(51):89256-89268
−Removed: Results from this trial demonstrated that it was feasible to safely administer to patients serial dosing of aNK in excess of 7 x 10 10 cells across 18 infusions administered over a six month timeframe.
−Removed: Interestingly, both of the complete responses occurred in the lowest dose cohort, though these patients received 15 or more doses of aNK, indicating that dose-exposure over time could potentially overcome shortcomings a smaller individual dose may have.
−Removed: These observations helped to lay the foundation for subsequent phase Ib/IIa trials with modified aNK cells in combination with an immuno-conditioning regimen that includes N‑803 and a checkpoint inhibitor, with repeat NK cell dosing out to 12 months or for as long as the patient is responding to treatment.
−Removed: Acute Myeloid Leukemia:
−Removed: QUILT 3.018 (NantKwest Sponsored) 5
−Removed: This phase I, open-label, single-arm, dose-escalation/de-escalation study evaluated the safety in patients 18 years and older with refractory or relapsed acute myeloid leukemia, or AML.
−Removed: The primary endpoints were the maximum tolerated dose and safety of aNK monotherapy and the secondary endpoints were therapeutic efficacy and aNK cell phenotype, cytotoxic activity, presence in bone marrow, and effects on patient immune systems.
−Removed: Two dose levels of aNK were used:
−Removed: 1 × 10 9 cells/m 2 and 3 × 10 9 cells/m 2 .
−Removed: One course of aNK treatment comprised a total of two intravenous infusions of the same cell dose with each intravenous infusion administered 24 hours apart (i.e., days one and two).
−Removed: Patients underwent bone marrow biopsy 21 days after each course of therapy.
−Removed: Patients who had stable disease or a reduction of leukemia blasts after the initial course were eligible to receive additional aNK infusions.
−Removed: Seven patients were enrolled in the study with three having received the lower dose level and the remaining patients received the higher dose level of aNK cells.
−Removed: None of the seven patients experienced a dose-limiting toxicity during administration of the aNK cell infusions or during the 21-day observation period post-infusion.
−Removed: There were no grade 3 or grade 4 toxicities related to aNK cell infusions.
−Removed: One patient developed grade 2 fever and chills following each aNK infusion that resulted in inpatient observation.
−Removed: These known aNK-related effects were reversible with supportive care.
−Removed: Of the six patients that were evaluable for response 21 days after therapy, three experienced clinical benefit.
−Removed: One patient had a reduction of the percentage of blasts from 70% to 48% and went on to receive a second course.
−Removed: The other two patients achieved disease stabilization, one of which went on to receive two additional courses.
−Removed: This trial demonstrates early evidence of single agent activity and safety in heavily pretreated relapsed or refractory AML patients and serves as a basis to study modified aNK cell therapy in combination with an immuno-conditioning regimen that includes N‑803 and a checkpoint inhibitor, with repeat NK cell dosing for as long as a clinical response is maintained.
−Removed: Boyiadzis et al, Cytotherapy.
−Removed: 2017 Oct;19(10):1225-1232
−Removed: Our Clinical Pipeline
−Removed: haNK Product Candidate
−Removed: Our haNK cell therapeutic is a molecularly engineered variant of our aNK cell platform, which incorporates both the expression of
−Removed: A natural, high-affinity antibody engager, FcγRIIIa/CD16 receptor, which binds to therapeutically administered cancer-targeting antibodies, resulting in destruction of the cancer targets through a mechanism widely referred to as ADCC, and
−Removed: The IL‑2 support cytokine, whose expression is retained within the cell where it can exert its maximum effects of supporting growth and killing function while sparing leakage into the extracellular surroundings, where it could result in cytokine-related symptoms.
−Removed: Our internal research efforts have demonstrated that these high affinity CD16 receptors on our haNK cells are cleaved during ADCC-mediated killing of target cancer cells, thereby enabling them to engage in serial killing of multiple cancer targets, rather than remaining bound to the first target cell it encounters, a key drawback of non-cleavable CD16 receptors.
−Removed: Additionally, internal research efforts have demonstrated that high affinity CD16 receptor expression rebounds and recovers more rapidly in haNK cells after attacking its target when compared to other types of natural killer cells.
−Removed: This unique feature distinguishes our haNK cell product as exceptionally well suited for serial killing.
−Removed: Our haNK cell product retains all the innate killing receptors present on aNK, such as NKG2D and NKp44, and therefore preserves the innate ability to detect and bind a diverse range of ligands unique to cancers through this diverse array of receptors, thereby making it a highly versatile killer product suitable for clinical testing.
−Removed: In preclinical studies, the combination of haNK cells with a number of different therapeutic antibody products resulted in significantly enhanced tumor cell killing when compared to the use of the antibody as a single agent, or the antibody in combination with low affinity expressing CD16 receptors, thereby providing strong scientific support for our therapeutic approach of combining haNK plus N‑803 together with a commercially available therapeutic antibody.
−Removed: A growing body of published and internal research on our haNK cells consistently support its continued study as a therapeutic product for the treatment of cancers.
−Removed: Select highlights from this research include:
−Removed: Utilization of haNK over a low-affinity natural killer cell allows for a one-third lower concentration of herceptin to achieve half of its maximal effect.
−Removed: haNK demonstrates impressive CD16 receptor expression stability after innate pathway activation and degranulation when compared to that of healthy donor natural killer cells.
−Removed: haNK also demonstrates CD16 receptor expression stability after chemically induced activation and degranulation whereas healthy donor natural killer cells undergo CD16 depletion and potential exhaustion.
−Removed: haNK cells also demonstrate rapid and full recovery of CD16 expression after ADCC activation, which may be promoted by its endogenous IL-2 production.
−Removed: Irradiated haNK cells have a higher innate killing frequency than healthy donor natural killer cells.
−Removed: Irradiated haNK cells are efficient killers of a wide range of cancer types through their innate killing mechanism without reliance on their ADCC killing mechanisms.
−Removed: Hypoxemic conditions of the tumor microenvironment that abolishes the killing ability of healthy donor natural killer cells can be overcome by haNK cells.
−Removed: Addition of commercial antibody products to haNK cells adds an ADCC mechanism for killing tumors that would otherwise be resistant to innate killing, and does so in a dose dependent manner.
−Removed: Synergy was demonstrated when combining two antibody products together with haNK cells.
−Removed: haNK enhances the killing capacity of the PD‑L1 checkpoint inhibitor, avelumab.
−Removed: haNK and avelumab in combination exhibits potent killing across a variety of cancer types.
−Removed: A compelling rationale for developing our haNK product in combination with approved and late-stage antibody products that utilize the ADCC killing pathway resides in the fact that only a small subgroup of antibody recipients can benefit from the full potential of antibody products due to CD16 gene variations and natural killer cell dysfunction which haNK therapy could potentially abrogate.
−Removed: These findings are further detailed in the ensuing sections.
−Removed: haNK as the Current ‘Gold-Standard’ in Non-Clinical Characterization of Commercial Antibody Products.
−Removed: Our haNK cells have been widely utilized by numerous biopharmaceutical companies, including many well-known large-pharma companies, under non-exclusive licenses for in vitro ADCC testing of their antibodies in development, as well as to release-test their commercially available antibody products.
−Removed: For example, our haNK cells have been adapted for use in commercial assays such as BioTek’s automated Delfia ADCC assay system and Agilent’s xCELLigence system.
−Removed: Utilization of haNK Over a Low-Affinity Natural Killer Cell Allows for a One-Third Lower Concentration of Herceptin to Achieve Half of its Maximal Effect.
−Removed: In the Delfia ADCC assay system it was determined that the concentration of herceptin which achieves the half-maximum response (EC50) is 48% higher for the low-affinity natural killer cells than for haNK, thereby demonstrating how haNK potentiates herceptin in achieving its peak killing capacity.
−Removed: Natural Killer Cell Numbers, Function and CD16 Expression Levels Are Deficient Among Cancer Patients and Correspond with Clinical Outcomes.
−Removed: Immunologic surveillance studies in human subjects have revealed a series of related trends in natural killer cell numbers, function and their CD16 receptor expression levels in cancer patients that undergo antibody - based treatment regimens.
−Removed: One observation is that e vent f ree s urvival in diffuse large B ‑cell lymphoma, or DLBCL , patients corresponded directly with natural killer cell counts at diagnosis, whereas CD4+, CD8+ and B ‑ cell counts did not.
−Removed: 6 Also, when comparing natural killer cells from DLBCL patients with that of healthy donors , fewer natural killer cells from DLBCL patients express CD16 and of those that do, express CD16 at far lower levels and that these cells demonstrate significantly reduced ADCC ‑ mediated degranulation.
−Removed: 7 Another noteworthy observation was seen in DLBCL patients receiving antibody-based treatment regimens where during and within a month of completing therapy, there was a marked depletion of CD16+ natural killer cells and that these cells exhibited markedly diminished ADCC activity.
−Removed: 8 The same diminished ADCC activity was noted in natural killer cells from ovarian 9 and esophageal 10 cancer patients, when compared to that of healthy donor natural killer cells.
−Removed: It is therefore reasonable to conclude that efforts to address the diminished and exhausted population of natural killer cells in the setting of cancer could have broad therapeutic value and is the underlying driver to forge ahead with clinical research on haNK replacement therapy, particularly in combination with the natural killer cell induction agent, N ‑ 803, targeted antibody products and checkpoint inhibitors.
−Removed: haNK Demonstrates Superior CD16 Receptor Stability After Innate Pathway Activation and Degranulation When Compared to That of Healthy Donor Natural Killer Cells.
−Removed: Four hours after co-culture with the feeder cell line, K562, which serves to activate the innate pathway of killing, CD16 expression on natural killer cells from healthy donors dropped precipitously and only partially recovered after resting overnight whereas that of haNK was maintained at peak levels throughout the study duration.
−Removed: haNK Demonstrates CD16 Receptor Expression Stability After Chemically Induced Activation and Degranulation Whereas Healthy Donor Natural Killer Cells Undergo CD16 Depletion and Potential Exhaustion.
−Removed: Using flow cytometric analysis of CD16 expression after employing a more robust chemical induction model of degranulation, natural killer cells from healthy donors were observed to have a 94% drop in CD16 expression compared to 18% in haNK.
−Removed: Of note, CD16 expression levels in haNK only dropped to average pre-activation levels in healthy donor natural killer cells.
−Removed: Plonquet et al, Ann Oncol.
−Removed: 2007 Jul;18(7):1209-15
−Removed: Danielou-Lazareth et al, Eur J Immunol.
−Removed: 2013 May;43(5):1383-8
−Removed: Cox et al, Oncoimmunology.
−Removed: 2015 Jan 7;4(3):e990773
−Removed: Carlsten et al, J Immunol.
−Removed: 2009 Oct 15;183(8):4921-30
−Removed: Watanabe et al, Dis Esophagus.
−Removed: 2010 Nov;23(8):675-81
−Removed: haNK Demonstrates Rapid and Full Recovery of CD16 Expression by 24 Hours Post-ADCC Activation.
−Removed: The bottom figure on the left shows the percent CD16 expression five hours after ADCC activation in haNK cells using rituximab and deoxyhypusine hydroxylase, or DoHH, cells.
−Removed: We observed that there is only a modest drop in expression at this time point and that it appears to correspond proportionately with the target burden.
−Removed: haNK CD16 levels dropped slightly more than in the IL‑2 dependent haNK-lite cells, possibly due to the greater degree of target killing.
−Removed: The bottom figure on the right shows the shift in CD16 median fluorescence intensity of expression in haNK versus IL‑2 dependent haNK-lite cells from five to 24 hours after ADCC activation.
−Removed: We observed that haNK recovery at 24 hours is nearly complete, whereas haNK-lite recovery requires more time, possibly due to its lack of endogenous IL‑2 production, possessed by haNK cells.
−Removed: Collectively, these findings indicate that our selected haNK clone is a promising candidate to advance into clinical testing.
−Removed: Irradiated haNK Cells Have a Higher Innate Killing Frequency than Healthy Donor Natural Killer Cells.
−Removed: The following graph compares innate killing of target breast cancer cells by healthy donor natural killer cells versus irradiated haNK cells.
−Removed: Irradiated haNK cells have a three-fold higher killing frequency (on a per cell basis) than the average killing frequency of healthy donor natural killer cells, thereby demonstrating substantially greater levels of lysis from irradiated haNK cells across a range of effector-to-target cell ratios.
−Removed: Quantitative analysis of the killing frequency demonstrated that, on average, it took three healthy donor natural killer cells to kill the same amount of tumor target as one irradiated haNK cell, thereby implying serial killing activity.
−Removed: Irradiated haNK Cells are Efficient Killers of a Wide Range of Cancer Types Through Their Innate Killing Mechanism Without Reliance on Their ADCC Killing Mechanisms.
−Removed: In the graphs that follow, irradiated haNK cells exhibit an ability to efficiently kill 13 human tumor cell lines via innate mechanisms such as NKG2D‑NKG2DL receptors, without the addition of antibodies.
−Removed: This was demonstrated in innate killing assays against lung, colon, breast, cervical, ovarian, pancreatic and chordoma cancer lines.
−Removed: With the exception of ASPC‑1, target killing was consistently observed in an effector-to-target, or E:T, dependent manner.
−Removed: Hypoxemic Conditions of the Tumor Microenvironment That Abolishes the Killing Ability of Healthy Donor Natural Killer Cells Can Potentially be Overcome by haNK Cells.
−Removed: 11 Current research on healthy donor natural killer cell function in the hypoxemic tumor microenvironment supports our understanding of the various mechanisms involved in natural killer cell dysfunction:
−Removed: Exposure to hypoxemia decreases surface expression of NKG2D, the primary receptor needed for innate killing;
−Removed: Exposure to hypoxemia decreases surface expression of CD16 receptors, necessary for ADCC-mediated killing;
−Removed: Intracellular perforin and granzyme B levels are also diminished when exposed to hypoxemic conditions, as well as the total percentage of degranulating natural killer cells in a given population;
−Removed: Natural killer cell activation by IL‑2 can restore NKG2D levels and restore cytotoxicity against a number of hypoxemic cancer cell types.
−Removed: By contrast, haNK cells possess several inherent features that impart in-vivo advantages over healthy donor natural killer cells including:
−Removed: haNK produces its own supply of intracellular IL‑2 thereby maintaining itself in a perpetual state of activation;
−Removed: haNK cells are naturally larger in diameter and therefore volume when compared with donor natural killer cells and within that larger volume, pack a greater density of perforin and granzyme containing granules;
−Removed: haNK cells start off with a high density of surface CD16 and NKG2D receptors and since it can be frequently re-dosed with relative ease at a cell number per dose that is equivalent to an average person’s total natural killer cell population, it is feasible to maintain the equivalent of a fully active population of natural killer cells for extended periods to supplement the recipient’s dysfunctional and exhausted resident population of natural killer cells.
−Removed: New research conducted internally and by collaborators confirming that irradiated and cryopreserved haNK cells maintain optimal performance under hypoxemic conditions, is expected to publish in the near term.
−Removed: Addition of Commercial Antibody Products to haNK Cells Adds an ADCC Mechanism for Killing Tumors that would Otherwise Be Resistant to Innate Killing, and Does so in a Dose-Dependent Manner.
−Removed: The graphs that follow depict the increasing ADCC killing activity of haNK cells in the presence of increasing concentrations of either herceptin or rituxan observed in in vitro studies.
−Removed: The comparative killing activity of aNK alone, low-affinity CD16 receptor expressing aNK cells, or laNK, cells, and haNK with a non-relevant antibody as a negative control, are included for direct comparison purposes.
−Removed: In the first graph below, aNK, laNK, and haNK cells were tested separately in killing assays against SKOV‑3 ovarian cancer cells in the presence of logarithmically increasing concentrations of herceptin.
−Removed: The assay was performed by loading the tumor cells with radioactive chromium‑51 and measuring the release by cytotoxicity in a four‑hour assay.
−Removed: haNK cells responded to a lower dose of herceptin (0.001 ug/mL) and exhibited stronger maximal killing response as compared to cells expressing the low affinity 158F variant.
−Removed: Parental aNK cells, which lack CD16 expression, and haNK cells in combination with non-relevant antibody did not exhibit any ADCC response toward the SKOV‑3 cells.
−Removed: Sarkar et al, PLoS One.
−Removed: 2013 May 28;8(5):e64835
−Removed: In the second graph below , haNK cells responded to a lower dose of r ituxan (0.001 ug/mL) and exhibited stronger maximal killing response, as compared to laNK cells.
−Removed: Parental aNK cells, lacking CD16 expression, did not exhibit any ADCC response toward the 721.221 B ‑cell lymphoma cells and haNK cells together with non-relevant antibody did not trigger any ADCC response.
−Removed: 2008 May 1;180(9):6392-401.
−Removed: Synergy Demonstrated When Combining Two Antibody Products together with haNK Cells.
−Removed: The graph below depicts the synergistic activity of the combination of h erceptin and p erjeta (HER2/HER3) to mediate ADCC killing observed in in vitro studies.
−Removed: Through the application of haNK cells to kill HER2 positive gastric carcinoma cells, the activity observed in the combination of h erceptin and p erjeta was significantly greater than with either agent alone.
−Removed: haNK Enhances the Killing Capacity of the PD ‑L1 Checkpoint Inhibitor, Avelumab.
−Removed: I rradiated haNK cells and MDA ‑MB ‑231 (human breast carcinoma) cells were used as a target at an E:T ratio of 7.5:1.
−Removed: haNK innate killing (black bars) and innate + ADCC killing mediated by avelumab (grey bars) are shown in the graphs below.
−Removed: While avelumab alone and control Ab alone show no killing and haNK alone demonstrates some killing via innate mechanisms, the combination of haNK and avelumab yields the highest degree of killing, attributable to targeting the PD ‑L1 checkpoint protein as a target (a) .
−Removed: Separately, it was demonstrated that irradiated haNK cells do not exhibit cytotoxic activity against other haNK cells (fratricide) (b) .
−Removed: haNK and Avelumab Combination Exhibits Potent Killing Across a Variety of Cancer Types.
−Removed: As illustrated in the graphs below, avelumab-mediated ADCC by haNK cells demonstrated enhanced killing against a variety of cancer types in four ‑hour assays, which was even more pronounced in 18 ‑hour assays.
−Removed: Both haNK with isotype control (black squares) and haNK with avelumab (blue circles) mediated lysis of H460 human lung carcinoma cells in an E:T dose dependent manner ( a ).
−Removed: Similar results were also seen with several other human cell lines including cervical cancer CaSki cell ( b );
−Removed: lung carcinoma ( c );
−Removed: lung carcinoma ( d );
−Removed: ovarian carcinoma ( e );
−Removed: MDA ‑MB ‑231:
−Removed: breast carcinoma ( f );
−Removed: bladder carcinoma ( g ).
−Removed: Rationale for Developing O ur haNK in Combination with Approved and Late-Stage Antibody Products That Utilize the ADCC Killing Pathway.
−Removed: In multiple clinical trials conducted by third parties, patients who were homozygous for high-affinity CD16 (158V/V) generally experienced better responses to antibody therap ies than patients who were carriers of at least one low affinity CD16 allele (158F/F or V/F).
−Removed: The illustration from one study below shows the difference in progression-free survival between HER2 positive breast cancer patients treated with h erceptin who have the homozygous high-affinity form of CD16 and those who are carriers for the low affinity form to be far in excess of 20% at 48 months.
−Removed: Data from two additional clinical trials demonstrating th e same point are shown below.
−Removed: The rationale therefore favors combining haNK with r ituxan, h erceptin and e rbitux in patients that carry the low affinity CD16 allele ( both homozygous 158F/F and heterozygous carriers 158 F / V and 158V/F ) in order to improve the killing effect of these antibody products to approximate the results seen in patients that are homozygous ( 158V/V ) for the high affinity alleles.
−Removed: Antibodies are prevalently used and it is estimated that they generate over $100 billion in reported global annual sales.
−Removed: It has been reported that only approximately 10% to 15% of the addressable patient population for antibody therapies carry high-affinity CD16 receptors.
−Removed: This implies that our haNK product candidates may have significant market potential for these and possibly all IgG1-type antibody products that kill via the ADCC pathway as a combination therapy to address a large number of patients who would otherwise have poor responses to their antibody treatments.
−Removed: haNK Single Agent Phase I Trial
−Removed: QUILT 3.028 (NCT03027128) was our open-label, phase I study of haNK for infusion in subjects with metastatic or locally advanced solid tumors.
−Removed: As a first-in-human trial for haNK cells, our aim was to evaluate safety and single agent activity, determine the maximum feasible dose or highest dose with acceptable toxicity of haNK infusions in up to 16 subjects.
−Removed: The study was conducted in two parts, the first being a standard dose escalation protocol using a 3 + 3 design and the second, an expansion of the highest dose level with acceptable toxicity to further characterize safety and activity.
−Removed: The final treatment was administered during the first quarter of 2019, the same quarter that the trial concluded, and the clinical study report is being finalized for April 2020.
−Removed: Solid tumor types included a wide range of cancers including colorectal, ovarian, head and neck squamous cell and adenoid cystic carcinomas.
−Removed: Patients were highly treatment experienced, with up to seven prior courses of therapy and had progressed on their most recent regiment.
−Removed: A preliminary look at the first two cohorts that received repeat haNK infusions revealed no grade 3 or higher toxicities related to haNK and no dose limiting toxicities.
−Removed: Grade 1 or 2 fever, fatigue, nausea, infusion-related reactions and pain have been reported for most patients.
−Removed: One patient experienced grade 3/4 hyponatremia and another reported grade 4 hyperbilirubinemia, but neither was considered to be related to the administration of the study drug.
−Removed: Transient disease stabilizations were observed in half of the patients treated, though with the absence of concurrent antibody treatment, significant responses were not anticipated.
−Removed: A recommended phase II dose level of 2 x 10 9 was determined and utilized in our subsequent phase Ib/II and phase II combination trials.
−Removed: Transition to Cryopreserved haNK Product Candidate.
−Removed: During the QUILT 3.028 study, our haNK product for infusion was changed from fresh irradiated haNK to frozen irradiated, “off-the-shelf” haNK product.
−Removed: The administration of both products was found to be equally safe and tolerable.
−Removed: The early favorable safety profile established from this first-in-human study paved the way for numerous successful IND submissions to the FDA for our phase Ib/II haNK combination trials, which we designated as NCV trials.
−Removed: The Distinction of Exclusively Combining Our NK Therapies with a Systemically Administered IL‑15 Superagonist.
−Removed: An expansive scientifically-based rationale has evolved that justifies the pairing of our NK cell therapeutic platforms with a selective IL‑15 activator of the patient’s own natural killer and T‑cells, while avoiding bystander activation of deleterious inhibitory immune cells.
−Removed: We anticipate that such a combination in conjunction with a tumor conditioning regimen, which promotes tumor immunogenicity, would be most effective at inducing immunogenic cell death, memory immune cells and cancer remissions.
−Removed: We selected N‑803 for use in our combination trials since it is the only IL‑15 superagonist agent that is in late-stage clinical development, has an evolving dossier of clinical safety and has demonstrated consistent synergism when combined with haNK and PD‑L1.t‑haNK cells in in vitro and in vivo experiments both internally and with various research collaborators.
−Removed: It is generally known that natural killer cell counts at the time of cancer diagnosis corresponds directly with event free survival and that existing natural killer cell populations in these patients are both low in number and dysfunctional due to impaired innate and ADCC killing mechanisms.
−Removed: It is also known that cancer patients receiving an antibody therapeutic demonstrate marked depletion of ADCC competent natural killer cells both during and up to one month after completing therapy.
−Removed: The administration of an “off-the-shelf” replacement natural killer cell therapy such as haNK or t‑haNK, at numbers that readily approximate a patient’s normal natural killer cell count over an extended period through repeat dosing, would be expected to make available iterative waves of innate and ADCC competent natural killer cells until the patient’s own immune system is able to reconstitute and defend itself.
−Removed: N‑803 is a stimulating cytokine that promotes the expansion and activation of the patient’s own natural killer and CD8+ T‑cell populations, a finding that has been demonstrated in numerous preclinical and clinical studies in cancer patients.
−Removed: Moreover, cross reactivity with CD4+ T‑regulatory and MDSC cells does not occur with N‑803, thereby sparing patients from the counterproductive immune inhibitory effects of this immunologic compartment.
−Removed: Pairing these features with the finding that N‑803 acts synergistically to enhance the anti-cancer effects of haNK and t‑haNK sets the foundation for our combination approach to innate natural killer therapeutics for cancers, where these agents can form the backbone of any combination cancer regimen.
−Removed: The following graphs illustrate how the lymphocyte compartments i n human recipients respond to N ‑8 03 administration.
−Removed: A recently reported clinical study that investigated the combination of N ‑ 803 and rituximab in indolent non-Hodgkin’s lymphoma patients who relapsed or were refractory to rituximab therapy demonstrated that N ‑ 803 induced expansion of the patient’s own natural killer cell compartment while avoiding regulatory T ‑ cell stimulation.
−Removed: Natural killer cells, which typically represents 10% of the overall lymphocyte population, expanded three fold to approximately 30% in these recipients, reaching absolute counts averaging 750 cells/μL.
−Removed: N‑803 administration also markedly increased the proliferation marker, Ki67+ on natural killer cells over the full three weeks of patient monitoring.
−Removed: Another recent study in patients with metastatic non-small cell lung cancer who received a checkpoint inhibitor, also demonstrated increased numbers of natural killer cells when administered N ‑ 803 therapy.
−Removed: The ability of N ‑ 803 to drive potent expansion of natural killer cells was identified to potentially have particular value as major histocompatibility complex, or MHC , class I is lost on a substantial frequency of non-small cell lung cancer tumors, thereby making these tumors potentially susceptible to natural killer cell - mediated killing .
−Removed: These foundational data suggest that IL‑15-based immunomodulation using N‑803 has broad effect on patient natural killer cells and indicate that combination therapy with our NK cell therapies can potentially deliver more productive natural killer cell driven responses than would be possible with either alone.
−Removed: Combining haNK and Avelumab as a Versatile Treatment for a Wide Range of Cancer Types.
−Removed: Programmed cell death ligand‑1, or PD‑L1, which hinders anti-tumor immunity, has been detected on a wide range of tumor types and contributes to cancer escape.
−Removed: Antibody-mediated PD‑L1 blockade has already demonstrated clinical benefit in metastatic cancers such as non-small cell lung cancer, bladder cancer, melanoma, renal cell and ovarian cancers.
−Removed: The human anti-PD‑L1 antibody, avelumab, is a commercially available IgG1 antibody product with a fully functional Fc segment that can engage CD16 receptors on natural killer cells, thereby mediating ADCC killing of PD‑L1 expressing cancer cells.
−Removed: Avelumab combinations with haNK, the high affinity CD16 and IL‑2 expressing aNK cell line, could therefore be considered an ideal pairing of agents for a number of highly prevalent cancer types.
−Removed: In the graphs below, we see that PD‑L1 is expressed, to the greatest extent, in high-grade meningioma, but also in lung, breast, prostate cancers and chordoma.
−Removed: Additionally, the combination of haNK and avelumab has a synergistic effect at controlling meningioma tumor growth by volume in mouse models, when compared with either agent alone.
−Removed: Not shown, is the finding that the combination of haNK and avelumab extended survival in both orthotopic and subcutaneous meningioma mouse models in conjunction with increased cytotoxic immune infiltration and tumor necrosis.
−Removed: Wrangle et al, Lancet Oncol.
−Removed: 2018 May;19(5):694-704
−Removed: Also , the data below demonstrates that the haNK and avelumab combination more efficiently lysed meningioma cells when compared with healthy donor natural killer cells and avelumab.
−Removed: PD ‑ L1 expression on meningioma cancer cell lines has been shown to increase under conditions of increasing hypoxemia and in the presence of IFN ‑ γ .
−Removed: This can help explain why the observations below were made of heightened ADCC mediated lysis by haNK cells with avelumab under a hypoxemic condition and in the presence of IFN ‑ γ.
−Removed: Combined with our knowledge about haNK’s ability to function in the hypoxemic tumor microenvironment and the ability of haNK to express IFN‑γ, the potential for clinical applications have become increasingly clear.
−Removed: Building a Blueprint for the Nant Cancer Vaccine (NCV) Treatment Program
−Removed: QUantum Immuno-Oncology Lifelong Trial , or QUILT, is a master clinical trial protocol designed under cooperative research and development agreements between pharmaceutical/biotechnology companies and the National Cancer Institute, in accordance with published FDA guidance.
−Removed: QUILT studies are designed to harness and orchestrate all of the elements of the immune system, including natural killer cell, T‑cell and dendritic cell therapies, by testing novel combinations of cell-based immunotherapy (i.e., haNK and t‑haNK), cytokines (i.e., N‑803), immunomodulators, including checkpoint inhibitors, vaccines, metronomic chemotherapy (i.e., abraxane and aldoxorubicin) and low dose radiotherapy as a ‘triangle offense’ in patients who have undergone next generation whole genomic and transcriptomic analysis, with the goal of achieving durable, long-lasting remission for patients with cancer.
−Removed: After demonstrating phase I safety and activity of single and repeat-dosing of fresh aNK monotherapy in several phase I trials, including QUILT 3.018, we demonstrated the same for both fresh and frozen haNK monotherapy in our QUILT 3.028 study.
−Removed: We next demonstrated safety and activity of the combination of fresh aNK with NCV agents in pancreatic cancer patients in our QUILT 3.039 study and demonstrated the same for both fresh and frozen haNK with NCV agents in our QUILT 3.060 study for patients with pancreatic cancer who have progressed on or after standard-of-care therapy.
−Removed: Then we introduced our cryopreserved haNK formulation together with the addition of low-dose aldoxorubicin and a design change to extend the length of each treatment cycle to three weeks, in our QUILT 3.070 study.
−Removed: Based on the encouraging safety and activity findings, we proceeded to implement this refined NCV design in a new program to better assess responsiveness across several tumor types, which included triple negative breast, colorectal, pancreatic and head and neck squamous cells cancers in QUILT 3.067, 3.071, 3.080 and 3.090, respectively.
−Removed: These phase Ib studies all investigated haNK in combination with metronomic chemotherapy, N‑803, cytokine therapy, cancer vaccines, and stereotactic body radiation therapy and continue to have patients in active follow-up.
−Removed: The primary endpoint is to determine safety and activity of the combination treatment.
−Removed: By March 15, 2020, approximately 540 doses of haNK cells have been administered to subjects.
−Removed: No immune-related adverse effects or cytokine release syndrome attributable to haNK have been observed.
−Removed: Transient low-grade fevers have been reported in these haNK recipients when administered in this NCV combination therapy.
−Removed: QUILT 3.067 study of haNK cells in combination with NCV agents in subjects with triple negative breast cancer who have progressed on or after standard-of-care therapy continues to follow two long-term complete responders on maintenance therapy at 15 and 18 months.
−Removed: We have now concluded enrollment for this phase Ib first-generation NCV program, and while we have demonstrated the safety of this approach, we will continue treatment of patients still on study, analyze data and prepare clinical study reports in select indications.
−Removed: t‑haNK Programs
−Removed: Novel, First-in-Class PD‑L1.t‑haNK Product Candidate for Solid Tumors.
−Removed: Introduction.
−Removed: PD‑L1.t‑haNK is a human, allogeneic, stable clonal NK cell line generated from our parental clinical-grade aNK master cell bank.
−Removed: This product combines the potent cell killing mechanism mediated through PD‑L1 CAR targeting with the well-known and potent Fc g RIIIa/CD16 mediated ADCC killing mechanism.
−Removed: Internal research has demonstrated that such a dual expression is not only stable, but that each component contributes synergistically when used in conjunction with the appropriate therapeutic IgG1 therapeutic antibody.
−Removed: Our PD‑L1.t‑haNK product is highly potent and selectively active through the stable expression of three primary proteins:
−Removed: (1) a human PD‑L1–targeted CAR;
−Removed: (2) the high-affinity variant of the human IgG1 Fc receptor, FcγRIIIa/CD16 for enhanced ADCC;
−Removed: and (3) a variant of the human IL‑2 cytokine for enhanced function, IL‑2 growth independence and limited extracellular leakage of IL‑2 for improved safety.
−Removed: In Vitro Research.
−Removed: Our PD‑L1.t‑haNK master cell bank is a uniform cell population that can be easily and stably expanded in continuous culture.
−Removed: It has demonstrated exceptionally potent and specific in vitro activity against PD‑L1–expressing tumors via CAR-directed cytotoxicity.
−Removed: Likewise, it exhibited potent killing through innate mechanisms, including NKG2D and NKp30 receptors.
−Removed: Moreover, since PD‑L1.t‑haNK retains a high expression of the high-affinity CD16 allele, the engineered enhancement of haNK cells, even after irradiation and thawing, it can also mediate antitumor activity via ADCC when administered in combination with a monoclonal antibody.
−Removed: As such, a tri-targeting approach may be more effective at potentiating antitumor activity in all PD‑L1–expressing solid malignancies, particularly when the appropriate IgG1-type antibody is added to the therapeutic regimen.
−Removed: The receptor expression profiles and in vitro killing plots of our PD‑L1.t‑haNK cells against cancer cell lines utilizing CAR, innate and ADCC mechanisms are illustrated in the following slides.
−Removed: Several NCI manuscripts on PD‑L1.t‑haNK from our collaboration disclosing new and compelling in vitro and in vivo data are expected to publish in the very near term.
−Removed: In Vivo Research.
−Removed: Nonclinical testing was performed to determine the pharmacologic and toxicologic effects of PD‑L1.t‑haNK, which may be predictive of its clinical safety and efficacy in humans.
−Removed: The nonclinical in vivo studies employed immunocompromised mouse models in order to mitigate rejection of PD‑L1.t‑haNK cells by the xenogenic host species.
−Removed: Nonclinical pharmacology data demonstrated that PD‑L1.t‑haNK cells possess potent in vivo antitumor efficacy as demonstrated in PD‑L1–positive xenograft models.
−Removed: PD‑L1.t‑haNK administration was able to markedly decrease metastatic disease burden and inhibit tumor growth in these tumor-bearing animals.
−Removed: A repeat-dose biodistribution study evaluated the dispersion and persistence of the PD‑L1.t‑haNK cell line following repeated administration in the presence of PD‑L1‑expressing tumors.
−Removed: PD‑L1.t‑haNK cells were detected at very low frequency in the liver and lungs of PD‑L1 tumor-bearing mice six-hours after dosing and were completely undetectable 48-hours after dosing.
−Removed: This study also indicated that the presence of the PD‑L1-targeted CAR construct does not affect the biodistribution pattern of the PD‑L1.t‑haNK cells.
−Removed: Likewise, the presence of a PD‑L1–targeted CAR does not affect the biodistribution of the cells, which circulate through the blood with accumulation occurring in the liver and lungs, and with limited persistence.
−Removed: A pivotal toxicity study showed that repeat-dose administration of irradiated PD‑L1.t‑haNK cells in an immunocompromised mouse model was well tolerated and did not result in any significant toxicities, pathological changes, or tumor formation.
−Removed: Additionally, no weight loss, distress, or other treatment-related adverse reactions were observed in any animals.
−Removed: Importantly, the tolerability of repeat-dose administration of PD‑L1.t‑haNK cells was comparable to treatment with other aNK-derived cell lines.
−Removed: In summary, the nonclinical data demonstrated a favorable risk-benefit ratio for PD‑L1.t‑haNK.
−Removed: Development Plan.
−Removed: QUILT 3.064 is a phase I, first-in-human, open label study to evaluate safety, preliminary efficacy, determine the maximum feasible dose and designate the recommended phase II dose of PD‑L1.t‑haNK for infusion in subjects with locally advanced or metastatic solid cancers.
−Removed: This study opened mid-2019 and is being conducted in two parts:
−Removed: the first being a standard dose escalation protocol using a 3 + 3 design, and the second, an expansion of the highest dose level with acceptable toxicity to further characterize safety and efficacy.
−Removed: As of March 15, 2020, we have completed the first two dose levels of 2 x 10 9 and 4 x 10 9 cells and are enrolling the fourth patient for our expansion cohort.
−Removed: Since the observation hold period between each patient only applied to the dose escalation potion of the trial, we anticipate study completion during the second quarter of 2020.
−Removed: Patient tumor types so far included head and neck squamous cell carcinoma, breast and triple negative breast cancers, colon cancers, glioblastoma, urothelial cancer and leiomyosarcoma.
−Removed: One-hundred doses at the 2 x 10 9 dose level and fifty-six doses at the 4 x 10 9 dose level have been administered as of March 2, 2020.
−Removed: One dose limiting toxicity was reported at the 4 x 10 9 dose level that did not require dose-reduction and all but one patient are still alive, two stable diseases were noted, one at an early time point and one at four months and several additional patients are scheduled to undergo imaging studies to assess their tumor responses.
−Removed: We anticipate reporting on this trial at the upcoming American Society of Clinical Oncology conference in June 2020.
−Removed: After evaluation of safety and initial activity, we plan to conduct a wide range of additional immunotherapy studies with this agent in simple combinations to address the PD‑L1 molecular marker across select tumor types leading with pancreatic and non-small cell lung cancers.
−Removed: By the conclusion of the study, we believe we will have characterized the pharmacologic profile for PD‑L1.t‑haNK, obtained preliminary estimates of efficacy as a monotherapy in terms of objective response rate, progression-free survival and overall survival, assessed tumor molecular profiles, as well as therapy-induced changes in immune responses and their correlations with subject outcomes.
−Removed: On a related note, a patient with late stage pancreatic cancer was enrolled to a special IND to receive PD‑L1.t‑haNK cells in combination with N‑803 and aldoxorubicin.
−Removed: This patient has been confirmed to have a complete response by Positron Emission Tomography CT at three months.
−Removed: QUILT 88, a phase II/III protocol that was recently filed with the FDA and described in further detail later in this section, will investigate this combination of agents further.
−Removed: Novel, First-in-Class CD19.t‑haNK Product Candidate for Liquid Tumors.
−Removed: Introduction.
−Removed: CD19.t‑haNK is a human, allogeneic, stable clonal NK cell line generated from our parental clinical-grade aNK master cell bank.
−Removed: This product combines the potent cell killing mechanism mediated through CD19 CAR targeting of the B-cell marker CD19 with the well-known and potent FcγRIIIa/CD16 mediated ADCC killing mechanism.
−Removed: Internal research has demonstrated that such a dual expression is not only stable, but that each component contributes synergistically when used in conjunction with the appropriate therapeutic IgG1-type monoclonal antibody.
−Removed: Our CD19.t‑haNK product is highly potent and selectively active through the stable expression of three primary proteins:
−Removed: (1) a CD19–targeted CAR;
−Removed: (2) the high-affinity variant of the human IgG1 Fc receptor, FcγRIIIa/CD16 for enhanced ADCC;
−Removed: and (3) a variant of the human IL‑2 cytokine for enhanced function, IL‑2 growth independence and limited extracellular leakage of IL‑2 for improved safety.
−Removed: In Vitro Research.
−Removed: Our CD19.t‑haNK master cell bank is a uniform cell population that can be easily and stably expanded in continuous culture.
−Removed: It has demonstrated potent and specific in vitro and in vivo activity against CD19-expressing tumors via CAR-directed cytotoxicity.
−Removed: Likewise, it exhibited potent killing through innate mechanisms, including NKG2D and NKp30 receptors.
−Removed: Moreover, since CD19.t‑haNK also expresses the high-affinity CD16 allele, the engineered enhancement of haNK cells, it can also mediate antitumor activity via ADCC when administered in combination with a monoclonal antibody.
−Removed: As such, a tri-targeting approach may be more effective at potentiating antitumor activity in all CD19 expressing liquid tumors, particularly when the appropriate IgG1-type antibody is added to the therapeutic regimen.
−Removed: The in vitro killing plots of our CD19.t‑haNK cells against cancer cell lines utilizing CAR, innate and ADCC mechanisms are illustrated in the following slides.
−Removed: In Vivo Research .
−Removed: An array of in vitro and in vivo pharmacology proof-of-concept studies have been performed with CD19.t ‑haNK.
−Removed: The in vivo antitumor activity was investigated using a CD19-positive lymphoma cancer line in immunocompromised mouse models.
−Removed: Irradiated CD19.t ‑haNK cells were administered intravenously twice per week over a period of three weeks and resulted in statistically significant tumor growth inhibition on and after the first week compared to a control group.
−Removed: In addition, it was observed during necropsy that treatment with CD19.t ‑haNK cell treatments reduced liver metastasis, which was further corroborated by histological evaluation.
−Removed: Furthermore, treatment with CD19.t ‑haNK was able to reduce the number of animal death events, with 100% of the study subjects alive at the end of the study compared to only 50% of the subjects in the control group.
−Removed: Results from this study are indicative of the potential pharmacological effects of CD19.t ‑haNK for infusion in human lymphoma patients.
−Removed: To investigate the in vivo biodistribution and persistence of CD19.t‑haNK cells intravenously administered in CD19‑positive Raji tumor-bearing mice, tissues were analyzed at six- and 48-hours after the final dose.
−Removed: CD19.t‑haNK cells were detected at very low frequency in the liver and lungs at six-hours post-dosing, and none were detected at 48-hours post‑dosing.
−Removed: The results of this study are consistent with previous biodistribution studies performed with haNK cells, indicating that the addition of the CD19 CAR does not affect the biodistribution pattern of the cells and that like haNK cells, CD19.t‑haNK cells do not persist in vivo , a highly favorable feature that may underlie its excellent safety profile without adversely impacting potency.
−Removed: In investigating in vivo toxicity and tumorigenicity of CD19.t‑haNK cells after 28 days of repeat dosing in immunocompromised mice, results showed that all mice receiving product were overall as healthy as the control group throughout the study.
−Removed: There were no mortalities in either of the treatment groups and likewise, no adverse events were observed.
−Removed: Blood and serum samples collected at the end of the study revealed no significant differences between animals receiving drug product and those in the control group.
−Removed: In addition, gross necropsy and macroscopic morphologic examination revealed no tumor masses or organ abnormalities.
−Removed: Subsequent pathological evaluation of harvested tissues confirmed that there was no gross or microscopic evidence of toxicity or tumorigenicity associated with administration of irradiated CD19.t‑haNK cells.
−Removed: We believe the results from this study provide strong support for the safety of cryopreserved, irradiated CD19.t‑haNK cell therapy in human clinical trials.
−Removed: Diffuse Large B-Cell Lymphoma.
−Removed: Diffuse large B-cell lymphoma, or DLBCL, the most common subtype of non‑Hodgkin’s lymphoma , is a heterogeneous disease.
−Removed: The current standard for first-line therapy is a traditional chemotherapy regimen consisting of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.
−Removed: While approximately 50% to 60% of patients respond well to first-line therapy, approximately 15% to 25% of patients suffer from primary refractory disease, approximately 20% to 30% relapse after achieving a complete response, and 5% achieve only a partial response.
−Removed: Patients that relapse or are refractory to first-line therapy can be treated with one of an array of salvage chemotherapy regimens and if responsive, may subsequently proceed to undertake potentially curative stem cell transplantation.
−Removed: However, patients that are refractory or relapse after two or more lines of therapy, especially those that are not eligible for stem cell transplant or CAR‑T cell therapy, have a very poor prognosis.
−Removed: New therapeutic options are critically needed to address this growing patient population.
−Removed: We believe that the combined potential for our CD19.t‑haNK cells to exhibit a robust CAR-directed and ADCC mediated anti-cancer effect against B‑cell malignancies when combined with rituximab or avelumab, given the strong support from our preclinical programs, merits further evaluation in clinical trials to evaluate the safety and preliminary efficacy of CD19.t‑haNK in subjects with relapsed or refractory DLBCL.
−Removed: Development Plan.
−Removed: QUILT 3.061 is an open-label phase I study that will assess the safety and preliminary efficacy of increasing doses of CD19.t‑haNK monotherapy and determine the maximal feasible dose and designate the recommended phase II dose in subjects with diffuse large B‑cell lymphoma who have progressed through two or more lines of therapy and are ineligible for transplant or CAR‑T therapy.
−Removed: This first clinical trial for our CD19.t‑haNK product candidate cleared FDA review last year for study initiation.
−Removed: The study will be conducted in two parts:
−Removed: the first being a standard dose escalation protocol using a 3 + 3 design, and the second, an expansion of the highest dose level with acceptable toxicity, to further characterize safety and efficacy.
−Removed: Results from the trial will help us characterize the pharmacokinetic and pharmacologic profiles for CD19.t‑haNK, generate preliminary estimates of efficacy in terms of objective response rate, progression-free survival, and overall survival, and help us assess tumor molecular profiles, as well as therapy-induced changes in immune responses and their correlations with subject outcomes.
−Removed: Additional study details have been posted to clinicaltrials.gov.
−Removed: Additional Potential t‑haNK Product Candidates.
−Removed: Depending on the results obtained from our current clinical trial strategy, additional t‑haNK product candidates currently advancing through pre-clinical development, including our EGFR and BCMA t‑haNK programs, may be rapidly moved into first-in-human trials followed by disease and molecular marker specific studies.
−Removed: Registration Trials for haNK and PD ‑L1.t ‑haNK
−Removed: Phase II Second Line or Greater Merkel Cell Carcinoma
−Removed: QUILT 3.063 is a phase II, open label, single-arm trial evaluating the novel triple combination of “off-the-shelf” haNK cell therapy with N‑803 and the checkpoint inhibitor avelumab, without chemotherapy in subjects that have progressed after treatment with a checkpoint inhibitor for Merkel cell carcinoma.
−Removed: This trial, which has already started enrolling, will be evaluating the objective response rate using Response Evaluation Criteria in Solid Tumors Version 1.1 based on Blinded Independent Central Review.
−Removed: Additional measures of efficacy by progression-free survival, overall survival, disease-specific survival, duration of response, disease control rate, and quality of life by patient-reported outcomes and measures of safety will also be assessed.
−Removed: Exploratory objectives include the assessment of the pharmacokinetic and immunogenicity profiles, assessment of tumor molecular profiles and therapy-induced changes in immune responses, and molecular changes in cell-free circulating DNA and RNA, and their correlations with subject outcomes.
−Removed: Additional study details have been posted to clinicaltrials.gov.
−Removed: This triple combination of immunotherapies has been safely studied in our NCV trials for other solid cancer indications.
−Removed: The goal of combining these therapies is to synergistically maximize the killing of cancer cells while attempting to spare patients from chemotherapy and its associated adverse side effects.
−Removed: In both in vitro and in vivo studies we conducted, the combination of haNK cells with a number of different therapeutic antibodies, including avelumab, led to enhanced tumor cell killing when compared to the use of the antibody alone.
−Removed: Avelumab, is a checkpoint inhibitor which targets the programmed death‑ligand 1 protein, or PD‑L1, commonly expressed on a wide range of cancers.
−Removed: N‑803 has been shown to synergistically activate natural killer and T‑cells and enhance cancer cell killing in both single agent and combination therapy.
−Removed: When N‑803 is combined with haNK cells, a synergistic response is likewise observed in both in vivo and in vitro models.
−Removed: Merkel Cell Carcinoma.
−Removed: Merkel cell carcinoma, or MCC, is a rare and aggressive skin cancer that arises from uncontrolled growth of cells in the skin.
−Removed: Increasing in incidence, approximately 2,500 new cases are reported in the U.S.
−Removed: Patients with metastatic or locally advanced MCC have an extremely poor prognosis, with less than 20% of patients surviving longer than five years.
−Removed: Typically, these patients are treated with a range of drugs, including chemotherapy, which can result in significant side effects.
−Removed: Although new immune therapies have the potential to improve survival, MCC is still fatal for a majority of patients who have progressed on or after treatment with a checkpoint inhibitor and represents an unmet medical need.
−Removed: Phase II/III Front-Line Maintenance and Second Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer
−Removed: QUILT 88 is a phase II/III open-label, randomized, two-cohort comparative study of PD‑L1.t‑haNK, N‑803 and aldoxorubicin in combination with standard-of-care therapy versus standard-of-care therapy alone for front-line maintenance and second line treatment of subjects with locally advanced or metastatic pancreatic cancer.
−Removed: The two cohorts include:
−Removed: Front-line maintenance therapy in patients that have achieved either a partial response, complete response, or stable disease after first-line standard-of-care therapy;
−Removed: Second or later-line therapy and within each cohort, enrolled subjects will be randomly assigned to receive PD‑L1.t‑haNK, N‑803 and aldoxorubicin with standard-of-care in an experimental arm or standard-of-care only in the control arm.
−Removed: Cohort A will serve as the phase II portion of the trial and will have three experimental arms, which allows for separate assessment of successively adding only aldoxorubicin, aldoxorubicin and N‑803 and aldoxorubicin, N‑803 and PD‑L1.t‑haNK.
−Removed: Cohort B would serve as the phase III potion of the trial.
−Removed: Safety and progression-free survival will be compared between the group using Response Evaluation Criteria in Solid Tumors Version 1.1 based on Blinded Independent Central Review.
−Removed: The IND has been filed and study details will be posted to clinicaltrials.gov upon FDA clearance.
+Added: Latest Addition to Our Platforms
+Added: Our GMP-in-a-Box Approach
+Added: NantKwest is leading the efforts to generate allogeneic and autologous-sourced cell based products, the most advanced of which are our cytokine enriched memory-like NK, or ceNK, and mesenchymal stem cell, or MSC, therapeutics.
+Added: We utilize a scalable GMP production process that combines the use of ImmunityBio’s (a related party) semi-automated manufacturing equipment and software, cytokine expansion and activation reagents, including ImmunityBio’s N‑803, and unique user-friendly processing methods, all of which are proprietary.
+Added: We have optimized processes for generating both fresh and cryopreserved clinical dose forms of ceNK cells with 100% purity (in the allogeneic setting) from a variety of sources, including cord blood and allogeneic and autologous peripheral blood.
+Added: We have also optimized processes for generating fresh and cryopreserved clinical dose forms of MSCs from cord blood, cord tissue and allogeneic bone marrow sources.
+Added: We avoid the use of both feeder-layers and feeder-layer derived substances for activation as well as other commonly applied additives that frequently create downstream issues in achieving a high-quality, operator-friendly reproducible final dose form and have been able to generate multiple dose forms from each donor product, both of which are critical features in achieving scalability.
+Added: Cytokine Enriched Natural Killer (ceNK) Cell Platform.
+Added: Cytokine-induced memory-like NK cells are a unique set of lymphocytes that differentiate after a brief pre-activation with interleukin‑12 (IL‑12), IL‑15, and IL‑18 and exhibit enhanced responses to cytokine re-stimulation that include enhanced interferon‑g production and cytotoxicity against leukemic cell lines.
+Added: These cells have been isolated and characterized 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.
+Added: Based on published literature, we believe the ability to generate these memory-like cells at clinically meaningful quantities has been limited to the work performed at Washington University by T.A.
+Added: Fehniger, et al.
+Added: Published data so far has been limited to the acute myeloid leukemia patient population in the post-allogeneic, haploidentical stem cell transplantation setting, for which the Fehniger group has generated enough cells to provide a one-time dose of these cytokine-activated, memory-like natural killer cells.
+Added: Our cytokine enriched natural killer cell program is based on the ability to enrich and expand donor-sourced natural killer cells in a GMP facility to a clinically relevant scale, which allows for the production of a pure cytokine activated and expanded NK cell population that possesses the unique phenotype we specifically refer to as M‑ceNK cells.
+Added: We have developed a unique ability to generate a portfolio of distinct ceNK cell products through the application of ImmunityBio’s proprietary GMP-in-a-Box bioreactors and cytokines and our proprietary methods and overall expertise in scale manufacturing of NK cell based products.
+Added: Mesenchymal Stem Cell (MSC) Platform.
+Added: Bone marrow-derived allogeneic MSCs are considered to be a prominent cell type to treat degenerative diseases and autoimmune disorders.
+Added: MSCs are reported to be immunoprivileged, allowing for transplantation of allogeneic MSCs without the risk of being rejected by the host immune system.
+Added: MSCs have been found to be capable of modulating immune responses, thereby reducing inflammation as well as immunopathology and protecting alveolar epithelial cells during acute respiratory distress syndrome, or ARDS, including that triggered by cytokine storm.
+Added: More importantly, MSCs demonstrated promising activity in reducing the non-productive inflammation and in promoting lung generation in a phase II clinical trial, as well as in patients with ARDS in clinical practice.
+Added: As a result, we believe MSCs have the potential to alleviate the SARS‑CoV‑2-derived cytokine storm and ARDS, and thereby have an effect on the treatment of subsequent chronic respiratory dysfunction and lung fibrosis.
+Added: We have developed and optimized procedures and proprietary protocols to generate multiple dose forms of MSC products from a single bone marrow or cord tissue sample, in a scalable format using ImmunityBio’s GMP-in-a-Box system.
+Added: Development Update on our Product Candidates
+Added: Our leading programs reside in two core disease areas:
+Added: Oncology, which includes our haNK and PD‑L1.t‑haNK programs, and COVID‑19, which includes our joint BM‑Allo‑MSC therapeutic and hAd5 vaccine programs.
+Added: We also have a pipeline of IND-ready t‑haNK and ceNK projects in both solid and liquid cancers.
Pancreatic Cancer
Pancreatic cancer is one of the deadliest cancers for patients in the U.S.
−Removed: Pancreatic cancer is the third leading cause of cancer-related death in the U.S., behind only lung cancer and colorectal cancer, and is expected to become the second-leading cause after lung cancer around 2020.
+Added: Pancreatic cancer is the third leading cause of cancer-related death in the U.S., behind only lung cancer and colorectal cancer, and is expected to become the second-leading cause after lung cancer by the early 2020’s.
The overall five-year survival rate is just 9%.
In 2019, an estimated 56,770 people were diagnosed with pancreatic cancer in the U.S., and approximately 45,750 of those newly diagnosed will die from the disease.
−Removed: Pancreatic cancer is the ninth-most commonly diagnosed cancer in women and the tenth-most commonly diagnosed in men.
+Added: Pancreatic cancer is the ninth-most commonly diagnosed cancer in women and the tenth-most commonly diagnosed cancer in men.
Only about 20% to 30% of cases are found early enough to treat surgically, before the cancer has spread, and surgery gives the only chance that this cancer can be eradicated.
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Pancreatic cancer is uniformly accepted as an area of serious unmet medical need, with five-year relative survival rates by SEER stage at diagnosis of 37% for localized, 12% for regional, 3% for distant, and 9% for all SEER stages combined.
−Removed: Phase IIb Second-Line or Greater Non-Small Cell Lung Cancer
−Removed: QUILT 3.055 is a phase IIb, open label study of PD‑L1.t‑haNK, N‑803 and a checkpoint inhibitor in subjects with non-small cell lung cancer that have confirmed disease progression by investigator assessment per Immune-related Response Evaluation Criteria in Solid Tumors, or irRECIST, during treatment on-study with N‑803 and a checkpoint inhibitor.
−Removed: This is part of a larger trial that initially utilizes N‑803 and a checkpoint inhibitor for subjects who have progressed after an initial response to checkpoint inhibitor therapy.
−Removed: Safety and objective response rate defined as investigator-assessed complete response + partial response per Response Evaluation Criteria in Solid Tumors Version 1.1 based on Blinded Independent Central Review and secondarily per irRECIST will be determined.
−Removed: The IND amendment has been cleared by the FDA and study details will be posted to clinicaltrials.gov in due course.
−Removed: Phase III First and Second-Line Non-Small Cell Lung Cancer
−Removed: QUILT 59 is a phase III open-label, randomized, three-cohort study of standard-of-care therapy in combination with PD‑L1.t‑haNK, N‑803 and a checkpoint antibody versus standard-of-care chemotherapy alone for first and second line treatment of subjects with locally advanced or metastatic squamous and non-squamous non-small cell lung cancer.
−Removed: The three-cohorts include:
−Removed: Squamous first-line therapy;
−Removed: Non-squamous first-line therapy;
−Removed: Squamous and non-squamous second-line therapy.
−Removed: Within each cohort, enrolled subjects will be randomly assigned to receive PD‑L1.t‑haNK, N‑803 and a checkpoint antibody with standard-of-care in the experimental arms or standard-of-care only in the control arms.
−Removed: Safety and progression-free survival will be compared between the group using Response Evaluation Criteria in Solid Tumors Version 1.1 based on Blinded Independent Central Review.
−Removed: Preparations are being made to file this IND and study details will be posted to clinicaltrials.gov shortly after FDA clearance.
−Removed: Non-Small Cell Lung Cancer.
−Removed: Lung cancer is the second most common cancer.
−Removed: About 222,500 new cases will be diagnosed this year.
−Removed: Non-small cell lung cancer, or NSCLC, is often insidious, producing no symptoms until the disease is well advanced.
−Removed: NSCLC makes up about 80% to 85% of all lung cancers.
−Removed: The three main types of NSCLC are squamous cell carcinoma, and non-squamous cell carcinoma, consisting of adenocarcinoma and large cell carcinoma.
−Removed: Adenocarcinoma is the most common form of lung cancer in the U.S, among both men and women.
−Removed: Squamous cell carcinoma, is the second most prevalent, accounting for 25% of all lung cancers.
−Removed: Large cell carcinoma is the smallest, accounting for approximately 10% of NSCLC tumors.
−Removed: Early recognition of symptoms may be beneficial to outcome.
−Removed: At initial diagnosis, 20% of patients have localized disease, 25% of patients have regional metastasis, and 55% of patients have distant spread of disease.
−Removed: Symptoms depend on the location of cancer.
−Removed: The five-year survival rate for NSCLC is 24%.
−Removed: However, it is important to note that survival rates depend on several factors, including the subtype of lung cancer, and the stage of disease.
−Removed: For people with localized NSCLC, which means the cancer has not spread outside of the lung, the overall five-year survival rate is 61%.
−Removed: For regional NSCLC, which means the cancer has spread outside of the lung to nearby areas, the five-year survival rate is approximately 35%.
−Removed: If the cancer has spread to distant parts of the body, called metastatic lung cancer, the five-year survival rate is 6%.
−Removed: But because of new effective treatments, this number is changing, although better therapies are acutely needed.
−Removed: Phase II First and Second Line Locally Advanced or Metastatic Triple Negative Breast Cancer
−Removed: QUILT 3.069 is a phase II randomized, two-cohort study of PD‑L1.t‑haNK, N‑803, aldoxorubicin and a checkpoint inhibitor in combination with standard-of-care therapy versus standard-of-care alone for first and second line treatment of subjects with locally advanced or metastatic triple-negative breast cancer, or TNBC.
−Removed: The two cohorts include:
−Removed: First-line TNBC therapy;
−Removed: Second-line TNBC therapy.
−Removed: Within each cohort, enrolled subjects will be randomly assigned to receive PD‑L1.t-haNK, N‑803 aldoxorubicin and a checkpoint antibody with standard-of-care in the experimental arms or standard-of-care only in the control arms.
−Removed: Safety and progression-free survival per Response Evaluation Criteria in Solid Tumors, or RECIST, Version 1.1, based on Blinded Independent Central Review, or BICR, will be compared across all treatment groups.
−Removed: Preparations are being made to file this IND and study details will be posted to clinicaltrials.gov shortly after FDA clearance.
+Added: QUILT 88 is a phase II, open-label, randomized, three-cohort comparative study of PD ‑L1.t ‑haNK, N ‑803 and aldoxorubicin in combination with standard-of-care therapy versus standard-of-care therapy alone for front-line maintenance, second-line and third-line or greater treatment of 298 subjects with locally advanced or metastatic pancreatic cancer.
+Added: Each of the three cohorts are being conducted as standalone studies:
+Added: as front-line maintenance therapy in patients that have achieved a clinical response after first-line standard-of-care therapy,
+Added: in second-line therapy, and
+Added: in third-line therapy or greater.
+Added: Cohorts A and B will have their own control arms while cohort C will be conducted as a single-arm, open-label study.
+Added: Safety and progression-free survival for cohorts A and B will be compared within the groups using RECIST Version 1.1 criteria based on blinded independent central review.
+Added: Secondary objectives include initial safety and additional efficacy measures, including overall response rate, complete response rate, durability of response, disease control rate, and overall survival.
+Added: All three study cohorts of the trial are open and actively enrolling patients at Hoag Memorial Hospital Presbyterian in Orange County, California, the Immuno-Oncology Clinic, Inc.
+Added: in Los Angeles County, California, and Avera McKennan Hospital and University Health Center in Sioux Falls, South Dakota, the latter serving patients in the tri-state area of Iowa, Nebraska and South Dakota.
+Added: More than 50 patients are currently enrolled in or being evaluated for the trial.
+Added: In our initial Cancer Moonshot QUILT trials of haNK and avelumab (PD‑L1 checkpoint inhibitor) for patients with metastatic pancreatic cancer, we explored the hypothesis that by activating the patient’s own immune system, a paradigm change in cancer therapy could evolve to eradicate cancer cells without high-dose chemotherapy.
+Added: From 2017 to 2020, multiple QUILT clinical trials exploring the combination of haNK cell therapy, immune-modulating antibodies, adenovirus-based cancer vaccines, and low-dose chemotherapy provided preliminary results showing the median survival rate can be more than doubled, compared to historical controls, from three months to eight months.
+Added: In an expanded access program for patients with advanced metastatic pancreatic cancer who had no available approved treatment options, a complete remission was achieved when replacing haNK and PD‑L1 checkpoint inhibitor avelumab with PD‑L1.t‑haNK and four out of five patients are alive 8 to 16 months since beginning treatment on these expanded protocols as of January 12, 2021.
+Added: On the basis of these initial studies, we initiated our QUILT 88 trials in metastatic pancreatic cancer in October 2020.
+Added: While the data are still early study in cohort C, for which the primary endpoint is overall survival, 15 out of 18 (83%) of the patients enrolled with second-line or greater pancreatic cancer remain alive as of January 12, 2021.
Triple Negative Breast Cancer
−Removed: Breast cancer is the most common cancer among women in the U .
−Removed: , the second most common cause of cancer death, and the main cause of death in women ages 45 to 55 years.
−Removed: In 2009, approximately 192,370 women in the U.S.
+Added: Breast cancer is the most common cancer among women in the U.S., the second most common cause of cancer death, and the main cause of death in women ages 45 to 55 years.
+Added: In 2019, the latest year for which incidence data are available, 268,600 women in the U.S.
were diagnosed with breast cancer, and an estimated 41,760 women died of the disease.
−Removed: T NBC accounts for approximately 15% of all breast cancers.
+Added: Triple Negative Breast Cancer, or TNBC, accounts for approximately 15% of all breast cancers.
Of these TNBC cases, about 75% are "basal-like." TNBC is a subtype of breast cancer that lacks expression of the estrogen receptor, or ER, and progesterone receptor, or PR, and does not overexpress the human epidermal growth factor 2 receptor, or HER2, protein.
9 unchanged sentences
These ethnic or menopausal differences are not seen in either the ER+/HER2+ breast cancer subgroup or the ER+/HER2– subgroup.
−Removed: Five-year relative survival rates for triple-negative breast cancer by SEER stage at diagnosis are 91% for localized, 65% for regional, and 11% for distant.
−Removed: Triple-negative breast cancer has fewer treatment options than other types of invasive breast cancer.
+Added: Five-year relative survival rates for TNBC by SEER stage at diagnosis are 91% for localized, 65% for regional, and 11% for distant.
+Added: TNBC has fewer treatment options than other types of invasive breast cancer.
This is because the cancer cells do not have the estrogen or progesterone receptors or enough of the HER2 protein to make hormone therapy or targeted drugs work.
1 unchanged sentence
Chemotherapy might be given first to shrink a large tumor followed by surgery.
−Removed: It might also be given after surgery to reduce the chances of the cancer coming back.
+Added: Chemotherapy might also be given after surgery to reduce the chances of the cancer coming back.
Radiation might also be an option depending on certain features of the tumor.
1 unchanged sentence
In cases where the cancer has spread to other parts of the body (i.e., stage IV) chemotherapy and other treatments that can be considered include PARP inhibitors, platinum chemotherapy, or immunotherapy.
−Removed: NantKwest’s Ongoing Clinical Trials Activities:
−Removed: Potential Development Catalysts for Driving Value:
−Removed: By virtue of parallel development of a range of products derived from our versatile NK cell platform in a variety of disease settings, numerous potential catalysts have emerged as value drivers for our business:
−Removed: Early indicators of efficacy:
−Removed: Merkel cell cancer complete responses to aNK therapy;
−Removed: Lung cancer responses to aNK therapy;
−Removed: Triple negative breast cancer complete responses to haNK therapy;
−Removed: Pancreatic cancer complete response to PD‑L1.t‑haNK therapy.
−Removed: PD‑L1.t‑haNK in phase II and IIb trials for pancreatic cancer, non-small cell lung cancer and triple-negative breast cancer;
−Removed: haNK in phase II for Merkel cell cancer;
−Removed: CD19.t‑haNK in phase I for diffuse large B-cell lymphoma;
−Removed: HER2.t‑haNK IND-ready for HER2 expressing cancers;
−Removed: EGFR.t‑haNK and BCMA.t‑haNK in preclinical for EGFR and BCMA expressing cancers, respectively.
−Removed: Exclusive Commercial License:
−Removed: We are an early investor and shareholder in Viracta Therapeutics, Inc., or Viracta, and an exclusive licensee of its novel class 1 histone deacetylase inhibitor, or HDACi, nanatinostat, which holds both Orphan Drug and Fast Track Designations from the FDA and is currently in a phase II clinical trial in combination with valganciclovir for patients with Epstein-Barr virus associated lymphomas.
−Removed: Being an HDACi, nanatinostat acts as an epigenetic activator, inducing cold tumors to express immunogenic proteins, thereby rendering them as immunologically recognizable by an activated immune system for elimination.
−Removed: As an easy to administer, short-acting oral agent, nanatinostat is potentially an ideal agent to use in combination with our NK therapies.
−Removed: Our worldwide exclusivity includes the conduct of research, development and commercial sale of nanatinostat in combination with NK cell therapies.
−Removed: We plan to explore therapeutic combinations of nanatinostat for patients with EBV, CMV and HPV associated malignancies, including nasopharyngeal, gastric, breast and cervical cancers and diffuse large B-cell lymphoma.
−Removed: Potential Regulatory Catalysts for Driving Value*:
−Removed: Additional information can be found in the corporate slide deck presented at the 38 th annual J.P.
−Removed: Morgan Healthcare Conference on January 14, 2020 at https://ir.nantkwest.com/static-files/77614f06-5c1f-4c42-8761-b4d2f382425c .
−Removed: Coronavirus Related Activities:
−Removed: Global events relating to the spread of SARS‑CoV‑2 infections, which initially emerged late in 2019 and evolved rapidly into a widespread pandemic, has captured our attention as a unique opportunity to assist our state and country with developing therapies for patients with moderate to severe respiratory infections.
−Removed: Since February 2020, we have been formulating what we believe to be the best approach to study one or more of our clinical candidates, with the objective of hastening the resolution of symptoms, shortening the duration of viral shedding, lessening the burden of intensive care demand, advancing our understanding of this disease, and bridging the health care system to a time when we will have an adequate vaccine deployed around the world.
−Removed: As early clinical data on COVID‑19 patients are being published, we are coming to a better understanding of the associated immunology for patients with moderate and severe disease as well as for convalescent patients.
−Removed: A clearer patient narrative has only recently been forming, with clinical presentations of mild to severe disease associated with elevated neutrophil counts and markedly depressed NK and CD8+ T ‑lymphocyte counts that is in direct proportion with the severity of disease.
−Removed: Moreover, analysis of these NK and CD8+ T ‑lymphocytes reveal that they are functionally exhausted, meaning that they could no longer carry out target cell killing in a standardized assay.
−Removed: Interestingly, the natural killer cells also exhibited a high level of expression of the inhibitory receptor, NKG2A, and reduced expression of interferon- γ, or IFN ‑ γ;
−Removed: interleukin ‑2, or IL ‑2;
−Removed: and granzyme B, or GzB;
−Removed: all of which are associated with exhaustion of chronic viral infection.
−Removed: Convalescent patients were found to have their NK and CD8+ T ‑lymphocyte numbers restored, reduced NKG2A expression and normalized expression of IFN ‑ γ , IL ‑2 and GzB.
−Removed: Similar data was reported in patients with SARS ‑CoV viral infections during the 2003 outbreak.
−Removed: 13 These finding are indicative of a SARS ‑CoV ‑2 induced impairment of the innate immune antiviral response at an early stage of disease.
−Removed: Mechanistic research on both SARS‑CoV, and MERS‑CoV from the 2012 outbreak, paint the picture of a molecular arms race between host innate antiviral response and human coronavirus adaptations of evasion.
−Removed: MERS‑CoV, for instance, induces repressive histone modifications to downregulate specific subsets of interferon-stimulated genes, or ISGs, which are responsible for establishing an ‘antiviral state’ in the cells that is effected through viral-RNA cleavage enzymes and IFN production.
−Removed: Both SARS and MERS CoVs have been reported to suppress IFN production and signaling pathways through these and other mechanisms, particularly in patients with severe diseases.
−Removed: When this was recreated in the laboratory setting and the deficiency in IFN‑α production in CoV-infected cells was remedied by IFN‑α treatment, CoV replication was inhibited.
−Removed: 15 This, together with other accumulated data, leads us to better understand the essential role of interferons in the anti-viral effect against CoV infection.
−Removed: The administration of haNK cells following the infusion of IgG SARS‑CoV‑2-neutralizing antibodies obtained from the serum of convalescent patients could accomplish several things for patients with moderate to severe disease due to SARS‑CoV‑2 infection.
−Removed: Firstly, it could immediately supplement patients with ADCC-competent, ‘non-exhausted’ natural killer cells in numbers that approximate the body’s otherwise normal natural killer cell levels.
−Removed: These natural killer cells are fully capable of expressing and potentially delivering IFN‑γ, IL‑2, and GzB to the site of infected organs to facilitate immune recruitment and adaptive responses.
−Removed: The neutralizing antibodies from convalescent serum could supplement the patient’s humoral response, coat the CoV infected cells and mediate ADCC killing between it and the administered haNK cells.
−Removed: The overall objective is to shift the balance of the molecular arms race in favor of the patient’s innate immune responses, thereby enabling more patients to recover.
−Removed: With our clinical supply of cryopreserved haNK dose forms in storage and available for on-demand clinical research use, we are well positioned to initiate trials rapidly.
−Removed: Zheng, M., et al.
−Removed: Cellular & Molecular Immunology, 2020
−Removed: Am J Clin Pathol, 2004.
−Removed: Wong, L., et al.
−Removed: Virologica Sinica 2016.
−Removed: Achievements in Process Development, Scale-Up Manufacturing and Clinical Supply
−Removed: Manufacturing has continued to be one of our fastest growing functions in 2019.
−Removed: We made significant strides throughout the year in all of our core manufacturing and ancillary operational areas, including process development, scale-up manufacturing, materials sourcing, completion and certification of production facilities, pipeline buildup of cryopreserved and ready to infuse clinical product, all the way through and including clinical trial supply.
−Removed: An extensive patent portfolio of manufacturing methods applications has been filed to protect this body of pioneering work, which will serve as an added layer of protection to our existing patent estate.
−Removed: We have been qualifying, releasing and storing frozen clinical dose forms of haNK from the fourth quarter of 2017 through the fourth quarter of 2018 and PD‑L1.t‑haNK since the first quarter of 2019.
−Removed: Shelf-life stability for frozen haNK now exceeds two years, which has enabled us to accumulate an inventory of product large enough to satisfy in its entirety our QUILT 3.063 phase II Merkel cell carcinoma trial in an immediate, on-demand basis.
−Removed: Upon shipping receipt, clinical sites simply thaw the frozen product in a warming bath prior to infusion.
−Removed: We believe such simple clinical site requirements for product administration would expand patient accessibility well beyond select certified hospital centers into community outpatient practices and potentially into physician’s offices.
−Removed: Developing the capability to freeze and thaw our cell therapy product while preserving optimal viability and potency was a key goal that we both achieved and continue to refine as we further scale our operations.
−Removed: Our therapeutic platform is flexible and thus our investments in developing manufacturing capabilities have been designed with the ability to introduce new variants of our cellular products quickly.
−Removed: Having developed core capabilities for the successful cryopreservation and recovery of our cellular products, we believe we are now well positioned to implement simpler and more cost effective storage and shipping procedures to supply clinical sites that are located thousands of miles from our production facility.
−Removed: We believe we have unique processing and production capabilities that will enable us to leverage our investments in in-house operations to produce our cell therapy products at commercial scale.
−Removed: These capabilities will enable us to reduce our cost of goods sold and realize significant economies of scale.
−Removed: Further, the flexibility of these capabilities to apply to a wide range of new variants of our aNK cells will allow for more rapid scaling of our newly emerging t‑haNK products from our pipeline and the initiation of a new series of clinical programs.
−Removed: The Production Process
−Removed: Our aNK platform production process largely resembles the widely used monoclonal antibody manufacturing process, without the laborious extraction and purification steps at the end, and bears the least resemblance to that of autologous CAR‑T cell manufacturing.
−Removed: The figure below illustrates the key steps involved with master cell bank establishment, often starting with a Chinese hamster ovary, or CHO, cell line, in the case of antibody products and with an aNK cell line in the case of haNK, taNK and t‑haNK products.
−Removed: Both utilize genetic engineering to achieve the desired clones, which after selection, are expanded to create master cell banks.
−Removed: From this point, a culture can be initiated from a single vial from the bank that will eventually be able to fill a bioreactor.
−Removed: In both cases, such a bioreactor can run for months with multiple harvests over the course of the culture.
−Removed: In the case of antibody products, it is the antibody-rich supernatant that must be separated from the cell culture and then purified before making the bulk product.
−Removed: In the case of haNK, taNK and t‑haNK products, the cell culture is itself the product that simply requires centrifugation and washing before making the final dose forms.
−Removed: A single bioreactor can produce a significant number of doses that can be used to treat many patients.
−Removed: The panel below compares the key steps in the manufacture of autologous CAR ‑T therapy with that of haNK, taNK and t ‑haNK.
−Removed: CAR ‑Ts have a high per-unit manufacturing cost due to a series of complex processes, including harvesting T ‑cells from patients in an invasive procedure called leukapheresis.
−Removed: Once the T ‑cells have been adequately collected, they are sent to the manufacturing facility for individualized processing that starts with genetic engineering and expansion in a dedicated cGMP clean room.
−Removed: Then, through an elaborate series of procedures, the cells are selected using bead removal before a single dose form is prepared and returned to the hospital for infusion back into the original patient.
−Removed: By contrast, the manufacture of our allogeneic “off-the-shelf” haNK, taNK and t ‑haNK cells involves a rapid, scalable and cost efficient process where cells from a master cell bank vial are grown in a bioreactor and, once ready to harvest, the cells are centrifuged and washed before placement into final dose forms.
−Removed: One vial from the master cell bank can potentially produce thousands of cryopreserved dose forms that would be available on-demand, without the typical two- to three week delay in orchestrating the logistics and preparation involved when using the CAR ‑T method.
−Removed: Building Out Our Manufacturing Capabilities
−Removed: Over the past year our process and manufacturing teams have worked diligently to further scale our operations to meet the anticipated commercial demand for our therapeutic products ahead of achieving regulatory approvals.
−Removed: The development of this capability has been key to ensure not just sufficient supply for our current and planned clinical trial operations, but also to ensure that we will be able to build an ample inventory of product to meet commercial demand, as well as to realize economies of scale for our pipeline of products being readied for the clinic.
−Removed: While we initially relied upon external manufacturers, we found that to create a scalable product with a reliable and cost effective clinical supply capability, we needed to build a state of the art cGMP facility for the manufacture of all our cellular therapeutics.
−Removed: In order to ensure uninterrupted clinical supply, we implemented a dual-stage strategy.
−Removed: In the initial stage, we established a pilot cGMP manufacturing facility at our Culver City, California, site and for the second stage we simultaneously built out an approximately 24,250 square foot commercial cGMP facility in El Segundo, California.
−Removed: We completed the El Segundo facility buildout in May 2018 and subsequently outfitted and prepared the facility for commercial scale manufacturing and initiated clinical production of PD‑L1.t‑haNK at this facility starting in the first quarter of 2019.
−Removed: Our initial production capabilities involved limited production of the cells in flasks and gas-permeable chambers.
−Removed: By 2016, our company possessed limited laboratory capabilities, as we were still dependent upon university partners and contract manufacturers for all of our cell production capabilities.
−Removed: While these did not yet involve bioreactors, they were sufficient to meet the limited clinical demands for our studies at the time.
−Removed: This foundational work was in part performed using the early production capabilities at Baylor University’s Cell and Gene Therapy Center, in addition to Northwestern University, and a global contract manufacturing vendor.
−Removed: We recognized the serious limitations and inherent risks in relying on external manufacturing sources, including competition for timely slots for external production runs, exorbitant rising costs, reliance on untrained operators, the need to establish contract manufacturing redundancy in the event of a vendor failure and serious limitations in our ability to achieve consistent scale production.
−Removed: We therefore committed to a strategy of in-sourcing this core capability and have long since achieved this goal.
−Removed: We commenced production operations at our pilot facility in Culver City, California in 2017.
−Removed: It was there that we initialized our in-house cGMP small-bioreactor program for our haNK product, as we progressed production from smaller bioreactor batches to larger ones.
−Removed: In tandem with this improvement in manufacturing capacity, we also established and refined a process to cryopreserve our cell product in ready-to-infuse bags and then integrated it with our main process into a single production line.
−Removed: In 2018, we further increased the scale of our operations twice more by utilizing intermediate-sized bioreactor technologies and were able to outpace demand for clinical drug product while building an inventory of frozen product for future use.
−Removed: In anticipation of increased clinical trial enrollment for 2019, in the final months of 2018 we transferred clinical production operations from our pilot facility in Culver City to our new commercial facility in El Segundo.
−Removed: At present, we are operating fully independent of external manufacturing contractors and partners and have since realized significant improvements in quality, cost , time and reliability .
−Removed: In 2019, we implemented our next larger-scale bioreactor technology in El Segundo, the procedures for which were developed and optimized at our process development facility in San Diego, California in 2018.
−Removed: This upgrade substantially improved our economies of scale , with higher production rates within the same footprint , while being less labor intensive, just as demand for clinical drug product increased.
−Removed: We now have the capability to continue to scale up ahead of increasing clinical demands through regulatory approval.
−Removed: We believe that developing even larger capacity bioreactors will allow us to scale well beyond regulatory approval from a central location, while meeting commercial drug product demands nationwide , as well as ultimately on a global scale.
−Removed: Manufacturing of O ur t-haNK Product Candidates
−Removed: In 2018 and 2019, we developed manufacturing processes for our two lead products from our t‑haNK platform, PD‑L1.t‑haNK and CD19.t‑haNK, as well as for Her2.t‑haNK and EGFR.t‑haNK, at our approximately 44,700 square foot process development facility in San Diego.
−Removed: Adding to our already robust patent portfolio, we filed numerous patents protecting innovative methods and modifications to our bioreactor production procedures, media formulations, additives, special cryopreservation procedures and many other components that address the inherent challenges unique to large scale NK cell production.
−Removed: We believe this places NantKwest at a unique competitive advantage as a leader in commercial scale manufacturing of NK cell products.
−Removed: Present Day Manufacturing of Our NK Products
−Removed: This year, we have been in production of our PD-L1.t-haNK product, building a clinical supply of product ahead of anticipated demand from our mid- to late-stage clinical trials and Expanded Access Program.
−Removed: This will ensure that ready-to-infuse clinical dose forms are available on-demand at all our clinical testing centers.
+Added: QUILT 3.067 is a phase II, open-label, single-arm trial evaluating the same novel triple combination of “off-the-shelf” haNK cell therapy with N‑803 and avelumab following a tumor conditioning regimen in subjects that have progressed on or after standard-of-care therapy for TNBC.
+Added: Patient follow-up concluded during the third quarter of 2020 for the long-term responders in the trial and final data is being collated for a final study report.
+Added: We last reported an overall response rate by immune response RECIST criteria in 6 of 9 patients (67%), a complete response rate in 3 of 9 patients (33%) (one unconfirmed), a median progression-free survival by immune response RECIST criteria of 14.3 months and a median overall survival of 20.2 months.
+Added: With the recent FDA approval of sacituzumab in patients with third-line TNBC, based on a 33% overall response rate, we believe that the addition of PD‑L1.t‑haNK and N‑803 may result in meaningful improvements in clinical outcomes.
+Added: As such, we are preparing for an open-label, randomized controlled phase III trial of PD‑L1.t‑haNK and N‑803 in combination with sacituzumab versus sacituzumab alone.
+Added: For the primary objective, we will compare the overall response rate between the two arms using RESIST criteria in solid tumors, Version 1.1.
+Added: Secondary objectives will include assessments of safety, event-free survival, overall survival and durability of response using the same RESIST Version 1.1 criteria.
+Added: The study will contain a safety lead-in phase in which the safety and tolerability of sacituzumab + PD‑L1.t‑haNK + N‑803 will be assessed prior to the Phase III portion of the study.
+Added: We anticipate filing an IND in the first quarter of 2021.
+Added: Non-Small Cell Lung Cancer
+Added: Lung cancer is the second most common cancer.
+Added: The American Cancer Society estimates that about 235,760 new cases of lung cancer will be diagnosed in the U.S.
+Added: in 2021 and an estimated 131,880 patients will die of the disease.
+Added: Non-small cell lung cancer, or NSCLC, is often insidious, producing no symptoms until the disease is well advanced.
+Added: NSCLC makes up about 80% to 85% of all lung cancers.
+Added: The three main types of NSCLC are squamous cell carcinoma, and non-squamous cell carcinoma, consisting of adenocarcinoma and large cell carcinoma.
+Added: Adenocarcinoma is the most common form of lung cancer in the U.S., among both men and women.
+Added: Squamous cell carcinoma, is the second most prevalent, accounting for 25% of all lung cancers.
+Added: Large cell carcinoma is the smallest, accounting for approximately 10% of NSCLC tumors.
+Added: Early recognition of symptoms may be beneficial to outcome.
+Added: At initial diagnosis, 20% of patients have localized disease, 25% of patients have regional metastasis, and 55% of patients have distant spread of disease.
+Added: Symptoms depend on the location of cancer.
+Added: The five-year survival rate for NSCLC is 24%.
+Added: However, it is important to note that survival rates depend on several factors, including the subtype of lung cancer, and the stage of disease.
+Added: For people with localized NSCLC, which means the cancer has not spread outside of the lung, the overall five-year survival rate is 61%.
+Added: For regional NSCLC, which means the cancer has spread outside of the lung to nearby areas, the five-year survival rate is approximately 35%.
+Added: If the cancer has spread to distant parts of the body, called metastatic lung cancer, the five-year survival rate is 6%.
+Added: As a result of new effective treatments, this number is changing, although better therapies are acutely needed.
+Added: QUILT 3.055 is a phase IIb, open-label, multi-cohort study of combination immunotherapy in patients with NSCLC who have previously received treatment with immune checkpoint inhibitors.
+Added: Patients are eligible to enter into the cohort designated to receive third-line combination immunotherapy consisting of PD‑L1.t‑haNK cell therapy, N‑803 and a checkpoint inhibitor after progressing on one of four other treatment cohorts within the study.
+Added: The primary efficacy endpoint of the study is overall response rate per RECIST Version 1.1.
+Added: Secondary endpoints include progression-free survival, overall survival and durability of response using RECIST Version 1.1 criteria.
+Added: The IND amendment to include this third-line study cohort has been authorized by the FDA.
+Added: Observed responses in this trial will guide our plans to conduct a subsequent phase II trial in second-line NSCLC patients.
+Added: Merkel Cell Carcinoma
+Added: Merkel cell carcinoma, or MCC, is a rare and aggressive skin cancer that arises from uncontrolled growth of cells in the skin.
+Added: Increasing in incidence, approximately 2,000 new cases are reported in the U.S.
+Added: Patients with metastatic or locally advanced MCC have an extremely poor prognosis, with less than 20% of patients surviving longer than five years.
+Added: Typically, these patients are treated with a range of drugs, including chemotherapy, which can result in significant side effects.
+Added: Although new immune therapies have the potential to improve survival, MCC is still fatal for a majority of patients who have progressed on or after treatment with a checkpoint inhibitor and represents an unmet medical need.
+Added: QUILT 3.063 is our phase II, open-label, single-arm trial evaluating the novel triple combination of “off-the-shelf” haNK cell therapy with N‑803 and avelumab, without chemotherapy in subjects that have progressed after treatment with a checkpoint inhibitor for MCC.
+Added: This trial is currently open at multiple centers across the U.S.
+Added: As a rare disease, with approximately 2,000 patients being diagnosed in the U.S.
+Added: each year, MCC patients often require regional referral and additional travel to a clinical trial site.
+Added: The ongoing COVID‑19 pandemic has continued to have an impact on enrollment due in part to limitations in travel and study accessibility as well as a significant reduction in patient referrals.
+Added: In response to this, we will continue to implement measures to increase local community awareness of the trial as we add new sites.
+Added: While we remain cautiously optimistic, it may require additional time to reach our interim data readout.
+Added: Additional Oncology Programs Update
+Added: We anticipate pursuing additional indications for our PD‑L1.t‑haNK product candidate, such as in the neoadjuvant setting in combination with N‑803 and a checkpoint inhibitor for newly diagnosed patients with head and neck squamous cells cancers in collaboration with the National Cancer Institute.
+Added: In the near future we also plan to initiate a series of phase I first-in-human trials with our IND-ready t‑haNK products HER2.t‑haNK, EGFR.t‑haNK and the FDA authorized CD19.t‑haNK.
+Added: Likewise, we are nearing an IND filing for a phase I ceNK trial in locally advanced solid cancers.
+Added: COVID‑19 Programs Update
+Added: QUILT‑COVID‑19‑MSC is a randomized, double-blind placebo-controlled phase Ib study to assess the safety of therapeutic treatment with immunomodulatory bone marrow-derived MSC, or BM‑Allo‑MSC, in adults with severe COVID‑19 infection.
+Added: This clinical trial will evaluate the safety and efficacy of BM‑Allo‑MSC versus best supporting care in treating patients with severe disease requiring ventilator support during COVID‑19 infection.
+Added: A total of 45 subjects receiving care in the critical care or ICU setting for COVID‑19 will be enrolled in this study.
+Added: Subjects will be randomized in a 2:1 fashion to the experimental and control arms, respectively.
+Added: Primary endpoints include incidence of adverse events, mortality and number of ventilator-free days within 60 days of randomization.
+Added: All subjects will also be assessed using the standard National Early Warning Score, or NEWS score (Royal College of Physicians 2012).
+Added: A second, more efficient commercial source of MSC cells has been developed in-house, using cord tissue.
+Added: Consequently, we recently filed a second IND for CT‑Allo‑MSC cells using the same trial design and plan to shift our clinical trial effort to this new protocol, which we plan to open at several clinical sites in Southern California, including Hoag Hospital in Newport Beach, California.
+Added: QUILT 4001 is an hAd5 adenoviral COVID vaccine trial operated by our affiliate, ImmunityBio, under a Joint COVID‑19 Collaboration Agreement, described below.
+Added: This phase Ib, open-label study will evaluate the safety, reactogenicity and immunogenicity of prophylactic vaccination with a second generation E1, E2b and E3 deleted human adenovirus‑5 vaccine in normal healthy volunteers.
+Added: The test article is an hAd5‑S‑Fusion+N‑ETSD vaccine which encodes for an optimized spike protein (S‑Fusion), to enhance stability and cell surface expression of the receptor binding domain of the SARS‑CoV‑2 spike protein, and a Nucleocapsid protein with an enhanced T‑cell stimulation domain (N‑ETSD) to enhance cell-mediated immunity.
+Added: Two cohorts of ten subjects will receive either 5×10 10 or 1×10 11 virus particles per dose on days 1 and 22 and a third cohort of fifteen patients would receive the highest safe dose administered in the two initial cohorts.
+Added: Safety and activity will be assessed for up to twelve months after the second dose.
+Added: Toxicities will be graded using the Guidance for Industry - Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (2007).
+Added: As a result of the emergence of rapidly evolving resistance mutations in the spike protein, an IND amendment has been filed under the ongoing QUILT 4001 to incorporate a sublingual (SL) formulation of the hAd5 ‑ S ‑ Fusion+N ‑ ETSD vaccine , thereby expanding the trial to a total of 60 patients across six study cohorts .
+Added: In addition, a second IND has been filed to test an oral formulation in a separate phase Ib trial in the U.S.
+Added: This trial, QUILT 4005, will study an additional 40 patients across four cohorts.
+Added: Th e oral formulation employed is stable at room temperatures, which may help alleviate cold-chain logistics issues that have slowed deployment of currently approved COVID ‑19 vaccines .
+Added: Additionally, the oral and SL formulations are designed to enhance IgA secretion and may confer greater protection against infection.
+Added: On February 11, 2021, we announced that the IND amendment for QUILT 4001 and the new IND for QUILT 4005 have been authorized by the FDA.
+Added: These studies are now actively enrolling patients at Hoag Hospital, in Newport Beach, California.
+Added: Once these new formulations have been tested for safety and immunogenicity , we will then proceed with a planned phase II/III trial using the most optimal combination.
+Added: The following table summarizes our current development programs:
+Added: N-803 is an IL-15RαFc Superagonist, a proprietary therapeutic cytokine designed to induce expansion of native NK and CD8+ T‑cells without concurrent stimulation of T‑regulatory cells;
+Added: Aldoxorubicin (Aldox) is a proprietary albumin-bound doxorubicin complex that is designed to preferentially accumulate in a tumor’s low pH environment.
+Added: Both agents are in late-stage clinical development by our affiliate, ImmunityBio, which has exclusive, worldwide rights to the agents.
+Added: Avelumab is an FDA approved checkpoint inhibitor marketed by Pfizer.
+Added: * Program owned by NantKwest and subject to Joint Development Agreement with ImmunityBio.
+Added: † Program owned by ImmunityBio and subject to Joint Development Agreement with NantKwest.
+Added: ‡ QUILT number not yet designated.
+Added: Joint COVID‑19 Collaboration Agreement with ImmunityBio
+Added: On August 21, 2020, we entered into a definitive agreement, which we refer to as the Collaboration Agreement, with ImmunityBio to pursue collaborative joint development, manufacturing and marketing of certain COVID‑19 therapeutics and vaccines.
+Added: The terms of the Collaboration Agreement supersede and replace the terms of the binding term sheet executed on May 22, 2020.
+Added: Through their efforts, the parties agreed to jointly develop ceNK, haNK, MSC, hAd5, and N‑803, a novel IL‑15 superagonist fusion protein, for the prevention and treatment of SARS‑CoV‑2 viral infections and associated conditions in humans, including without limitation, COVID‑19.
+Added: Pursuant to the Collaboration Agreement, we have contributed our ceNK, haNK, and MSC product candidates and certain of our manufacturing capabilities, and ImmunityBio has contributed their hAd5 and N‑803 product candidates.
+Added: hAd5 has been developed as a vaccine, and ceNK, haNK, MSC and N‑803 have each been developed as therapeutics for treating COVID‑19 at various stages of infection.
+Added: From and after the effective date of the Collaboration Agreement, the parties will share equally in all costs relating to developing and manufacturing of the product candidates globally with the exception of certain laboratory equipment purchases that will be borne solely by us.
+Added: With the exception of N‑803, we will be primarily responsible for the manufacture of each product.
+Added: Each party will be responsible for the regulatory affairs and the commercialization relating to its contributed products.
+Added: The global net profits from the collaboration products will be shared 60%/40% in favor of the party contributing the product on which the sales are based except if the parties mutually agree because of certain circumstances.
+Added: All net profits from sales of combined collaboration products will be shared equally.
+Added: This collaboration is supervised by a joint steering committee, which is comprised of an equal number of representatives from both parties.
+Added: The term of the agreement will be five years and it is renewable for an additional five year period upon mutual agreement.
+Added: Each party will also have a right to terminate in the event of material breach, bankruptcy, or insolvency.
+Added: In this Joint COVID‑19 Collaboration, we contributed the following programs:
+Added: MSC cells (as described above) as a therapeutic candidate for patients with severe symptoms of COVID‑19 to modulate the immune system’s excessive response to COVID‑19 infection, thereby potentially reducing the debilitating and sometimes fatal effects of the disease;
+Added: ceNK and haNK cells (as described above) as a therapeutic candidate for moderate-risk, hospitalized adults with moderate to severe symptoms of COVID‑19.
+Added: ImmunityBio contributed the following programs:
+Added: N‑803 as a therapeutic candidate for patients with mild symptoms of COVID‑19 prior to the onset of severe disease by potentially activating natural killer cells to mitigate viral replication;
+Added: Human adenovirus (hAd5) as a vaccine candidate for those individuals in an uninfected state to prevent the onset of COVID‑19.
+Added: In addition to the above programs contributed by each party, we have contributed our manufacturing capabilities in the form of facilities, equipment, personnel and related know-how, including our GMP manufacturing facility in El Segundo, California, and ImmunityBio has contributed certain manufacturing equipment and related technology and know-how.
+Added: To date, NantKwest and ImmunityBio have each prepared a GMP-ready manufacturing plant for COVID‑19 vaccine production, which we and ImmunityBio expect will have a combined estimated capacity to produce sufficient clinical supply for our planned studies in 2021.
+Added: We have prepared one of our GMP manufacturing facilities previously used to manufacture product for our oncology trials to manufacture and produce the hAd5 vaccine candidate and have readied a new, well-equipped location to manufacture and produce clinical products for our oncology trials, which resulted in additional facilities and related facility operating costs starting in the third quarter of 2020.
+Added: We have established a clinical product inventory to continue to supply clinical product for our ongoing oncology trials while this new facility was being readied.
+Added: The new facility will resume clinical product supply for our oncology trial starting in early 2021.
+Added: In addition, we have repurposed some of our personnel overseeing quality of our oncology programs to support the Joint COVID‑19 Collaboration.
+Added: We also expect to hire additional staff to support the Joint COVID‑19 Collaboration.
+Added: We believe the Joint COVID‑19 Collaboration will have no material impact on our current oncology efforts and trials, and we expect that we will be able to continue to manufacture adequate product to continue our ongoing oncology trials.
The biopharmaceutical industry is characterized by intense and dynamic competition to develop new technologies and proprietary therapies.
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The key competitive factors affecting the success of any approved product will include its efficacy, safety profile, pricing, and method of administration, as well as the level of promotional activity invested in it.
−Removed: Our haNK, taNK and t‑haNK product candidates will compete with other cell and molecule-based immunotherapy approaches using and/or targeting natural killer cells, T‑cells and dendritic cells.
−Removed: Competitors focused on CAR‑T related treatment approaches include AbbVie Inc., Atara Biotherapeutics, Inc., Intrexon Corporation, Allogene Therapeutics, Inc., Bristol‑Myers Squibb Company, JW Therapeutics Co., Ltd., Amgen, Inc., Leucid Bio Ltd., Bellicum Pharmaceuticals, Inc., Medisix Therapeutics Pte Ltd., Bluebird Bio, Inc., Mesoblast Ltd., Calibr/Scripps Research, Mustang Bio, Inc., CARsgen Therapeutics, Nanjing Legend Biotechnology Co., Ltd, Cartherics Pty Ltd, Novartis AG, Pfizer, Inc., Cellectis SA, Poseida Therapeutics, Inc., Celularity, Inc., Servier Laboratories, Celyad SA, Takeda/Shire, Fortress Biotech, Inc., TC BioPharm Ltd., Gilead Sciences, Inc., Transposagen Biopharmaceuticals, Inc., Humanigen, Inc., Unum Therapeutics, Inc., Immune Therapeutics, Inc., and Xyphos, Inc.
−Removed: Competitor companies focused on other T‑cell based approaches include Adaptimmune Ltd., Adicet Bio, Inc., Autolus Therapeutics, plc, Cell Medica Limited, GlaxoSmithKline plc., Green Cross LabCell Corp., Immunocore Limited, Iovance Biotherapeutics, Inc., Kiadis Pharma Netherlands B.V., Lion TCR Pte Ltd., MolMed, S.p.A., Precision Biosciences, Inc., Janssen Pharmaceuticals, Inc., Noile‑Immune Biotech, Inc., Anixa Biosciences, Inc., Beam Therapeutics Inc., BioNTech SE, Cartesian Therapeutics, Inc., and Takara Bio, Inc.
−Removed: Competitor companies focused on dendritic cell based approaches include Argos Therapeutics, Inc., Biovest International, Inc., ImmunoCellular Therapeutics, Ltd., Merck & Co, Inc./Immune Design, Inc., Inovio Pharmaceuticals, Inc., Intrexon Corporation, Medigene AG, and Northwest Biotherapeutics, Inc.
−Removed: Competitor companies focused on natural killer cell based approaches include Kiadis Pharma Netherlands B.V./CytoSen Therapeutics, Inc., Dragonfly Therapeutics, Inc., Fate Therapeutics, Inc., Gamida Cell, Ltd., Nkarta Therapeutics, Inc., Onkimmune Ltd., NKMax America, Artiva Biotherapeutics, HebeCell Corp., Vycellix, Inc., oNKo‑innate Pty Ltd., and Ziopharm Oncology, Inc.
−Removed: Competitor companies focused on large molecule immunotherapy approaches include Cytomx Therapeutics, Inc., Innate Pharma SA, and Sorrento Therapeutics, Inc.
−Removed: Other potential immunotherapy competitors include Affimed GmbH, Agios Pharmaceuticals, Inc., Codiak Biosciences, Glycostem Therapeutics BV, Triumvira Immunologics, Century Therapeutics, Incysus Therapeutics, Inc., GammaDelta Therapeutics Ltd., Lyell Immunopharma, Inc., and GT Biopharma, Inc.
−Removed: There are currently two approved T‑cell based treatments which are marketed by Novartis AG and Gilead Sciences/Kite Pharma.
−Removed: There is currently one approved dendritic cell-based cancer vaccine which is marketed by Dendron Pharmaceuticals, LLC for the treatment of metastatic castration resistant prostate cancer.
+Added: Our haNK, taNK, t‑haNK and ceNK product candidates compete with other cell and molecule-based immunotherapy approaches using or targeting natural killer cells, NKT cells, T‑cells, and dendritic cells.
+Added: Competitors focused on CAR‑T related treatment approaches include AbbVie Inc., Atara Biotherapeutics, Inc., Precigen Corporation, Inc., Allogene Therapeutics, Inc., Bristol‑Myers Squibb Company, Beijing Immunochina Pharmaceuticals Co., Ltd., Cellular Biomedicine Group, Inc., iCell Gene Therapeutics LLC, JW Therapeutics Co., Ltd., Amgen, Inc., Leucid Bio Ltd., Bellicum Pharmaceuticals, Inc., Medisix Therapeutics Pte Ltd., Bluebird Bio, Inc., Mesoblast Ltd., Calibr/Scripps Research, Mustang Bio, Inc., Carina Biotech, Inc., CARsgen Therapeutics, CRISPR Therapeutics, Inc., GEMoaB Monoclonals GmbH, Nanjing Legend Biotechnology Co., Ltd, Cartherics Pty Ltd, Novartis AG, Pfizer, Inc., Cellectis SA, Poseida Therapeutics, Inc., Prepromene Bio, Inc., Celularity, Inc., Servier Laboratories, Sorrento Therapeutics, Inc., Celyad SA, Takeda Pharmaceutical Company Limited, Fortress Biotech, Inc., TC BioPharm Ltd., Tessa Therapeutics Pte Ltd, Gilead Sciences, Inc., Tmunity Therapeutics, Inc., Transposagen Biopharmaceuticals, Inc., Humanigen, Inc., Immune Therapeutics, Inc., and Xyphos, Inc./Astellas.
+Added: Competitor companies focused on other T ‑cell based approaches include Adaptimmune Ltd., Adicet Bio, Inc., Autolus Therapeutics, plc, Cell Medica Limited, Eureka Therapeutics, Inc., Formula Pharmaceuticals, Inc., GlaxoSmithKline plc., Green Cross LabCell Corp., Immatics Biotechnologies GmbH, Immunocore Limited, Iovance Biotherapeutics, Inc., Kiadis Pharma Netherlands B.V., Lion TCR Pte Ltd., MolMed, S.p.A., Precision Biosciences, Inc., Janssen Pharmaceuticals, Inc., Noile ‑Immune Biotech, Inc., Anixa Biosciences, Inc., Beam Therapeutics Inc., BioNTech SE, Cartesian Therapeutics, Inc., Marker Therapeutics, Inc., Refuge Biotechnologies, Inc., Repertoire Immune Medicines, Inc., Sensei Biotherapeutics, Inc., Senti Biosciences, Inc., TCR² Therapeutics Inc., TScan Therapeutics, Inc., and Takara Bio, Inc.
+Added: Competitor companies focused on dendritic cell based approaches include Argos Therapeutics, Inc., Biovest International, Inc., ImmunoCellular Therapeutics, Ltd., Merck & Co, Inc./Immune Design, Inc., Inovio Pharmaceuticals, Inc., Precigen Corporation, Inc., Medigene AG, and Northwest Biotherapeutics, Inc.
+Added: Competitor companies focused on natural killer cell based approaches include Acepodia, Inc., Carabou Biosciences, Inc., Catamaran Bio Inc., Celularity, Inc., Century Therapeutics, Inc., Cytovia Therapeutics, Inc., Glycostem Therapeutics BV, Kiadis Pharma Netherlands B.V./CytoSen Therapeutics, Inc., Dragonfly Therapeutics, Inc., Editas Medicine, Inc., EMERcell, Exacis Biotherapeutics, Inc., Fate Therapeutics, Inc., Gamida Cell, Ltd., INmune Bio Inc., Nkarta Therapeutics, Inc., Onkimmune Ltd., Oncternal Therapeutics, Inc., NKMax America, Artiva Biotherapeutics/Merck, HebeCell Corp., Vycellix, Inc., oNKo‑innate Pty Ltd., ONK Therapeutics Limited, Sanofi, S.A., Shoreline Biosciences, Inc., Takeda Pharmaceutical Company Limited, XNK Therapeutics AB, Zelluna Immunotherapy AS, and Ziopharm Oncology, Inc.
+Added: Competitor companies focused on large molecule immunotherapy approaches, including those overlapping the natural killer cell space, include Cytomx Therapeutics, Inc., Compass Therapeutics, Inc., Innate Pharma SA, Nektar Therapeutics, Inc., and Sorrento Therapeutics, Inc.
+Added: Other potential immunotherapy competitors include Affimed GmbH, AgenTus Therapeutics, Inc., Agios Pharmaceuticals, Inc., Codiak Biosciences, Glycostem Therapeutics BV, Kuur Therapeutics Limited, Triumvira Immunologics, Incysus Therapeutics, Inc., GammaDelta Therapeutics Ltd., Lyell Immunopharma, Inc., and GT Biopharma, Inc.
+Added: There are currently four approved T‑cell based treatments that are marketed by Novartis AG, Gilead Sciences/Kite Pharma (two therapeutics), and the Bristol‑Myers Squibb Company.
+Added: There is currently one approved dendritic cell-based cancer vaccine marketed by Dendron Pharmaceuticals, LLC for the treatment of metastatic castration resistant prostate cancer.
+Added: Competitor companies focused on COVID‑19 cell therapy currently include AstraZeneca plc, Athersys, Inc./Healios K.K., Capricor Therapeutics, Inc., CAR‑T (Shanghai) Biotechnology, Cellavita Pesquisa Científica Ltda, Cellenkos, Inc., Cellular Biomedicine Group, Inc., Celularity, Inc., Sorrento Therapeutics, Inc., Chinese Academy of Sciences, Chongqing Sidemu Biotechnology Technology/ImmunCyte Life Sciences, Inc., Enlivex Therapeutics Ltd, Green Cross LabCell Corp., Hope Biosciences, Johnson & Johnson, Mesoblast Limited, Moderna, Inc., NovaVax, Inc., Orbsen Therapeutics Limited, Pfizer, Inc./BioNTech SE, Pluristem Therapeutics, Inc., Rigshospitalet, Tianhe Stem Cell Biotechnologies Inc., University of Minnesota/Fate Therapeutics, Inc., and Xinjiang Medical University.
+Added: In addition, a very large number of companies, government agencies and academic centers around the world are developing COVID‑19 vaccines, and many of these entities are in more advanced stages of development than ImmunityBio, including some that have started Phase II and/or III clinical trials or already have emergency regulatory approval in some regions.
+Added: Even if ImmunityBio’s COVID‑19 vaccine candidate is ultimately approved for marketing, the value of our profit-sharing opportunity would be adversely impacted if other COVID‑19 vaccines are approved earlier or show better efficacy or safety than ImmunityBio’s COVID‑19 vaccine candidate.
Many of our competitors, either alone or with their strategic partners, have substantially greater financial, technical and human resources than we do, as well as significantly greater experience in the discovery and development of product candidates, obtaining FDA and other regulatory approvals of treatments and commercializing those treatments.
64 unchanged sentences
Moreover, even our issued patents do not guarantee us the right to practice our technology in relation to the commercialization of our products.
−Removed: However, 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 patented product
−Removed: candidates and practicing our proprietary technology.
+Added: However, 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 patented product candidates and practicing our proprietary 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 product candidates.
5 unchanged sentences
trademark registrations;
−Removed: (ii) one pending U.S.
+Added: (ii) two pending U.S.
trademark application;
−Removed: (iii) 35 foreign trademark registrations (five of which are Madrid Protocol International registrations);
−Removed: and (iv) five pending foreign trademark applications.
+Added: (iii) 28 foreign trademark registrations, six of which are Madrid Protocol International registrations;
+Added: and (iv) 24 pending foreign trademark applications.
We may also rely, in some circumstances, on trade secrets to protect our technology.
6 unchanged sentences
For risks related to our proprietary technology, inventions, improvements and products, please see Part I, Item 1A, “ Risk Factors – Risks Related to Intellectual Property ” and “ Legal Proceedings ” of this Annual Report.
−Removed: Collaboration Agreements
−Removed: ImmunityBio, Inc.
−Removed: In January 2020, we entered into a Cost Allocation Agreement, or the Agreement, with ImmunityBio, Inc.
−Removed: and its subsidiaries, or ImmunityBio.
−Removed: The Agreement is effective as of October 1, 2019.
−Removed: ImmunityBio is a related party, as it is an affiliate of NantWorks.
−Removed: Simultaneously, we and ImmunityBio entered into Work Order Number One under the Agreement.
−Removed: Under the Agreement and Work Order Number One, the parties agreed to conduct a joint study, the clinical research trial being conducted pursuant to the protocol titled QUILT 3.063:
−Removed: A phase 2 study of combination therapy with an IL-15 superagonist (N‑803), off-the-shelf CD16‑targeted natural killer cells (haNK), and avelumab without cytotoxic chemotherapy in subjects with Merkel Cell Carcinoma (MCC) that has progressed on or after treatment with a checkpoint inhibitor .
−Removed: The ImmunityBio study drug included in the joint study is ImmunityBio’s proprietary IL-15 superagonist known as N‑803 and our study drug is our proprietary “off-the-shelf” CD16-targeted natural killer cell therapy known as haNK.
−Removed: We will act as the sponsor of this joint study for purposes of regulatory matters, including submissions, correspondence, and communications.
−Removed: Additionally, we are designated as the contracting party to execute agreements with third and related parties relating to the joint study under Work Order Number One.
−Removed: We and ImmunityBio will split certain joint study costs equally related to Work Order Number One, in accordance with the terms of the Agreement.
−Removed: Shared joint study costs include cost related to conducting the joint study development activities, such as personnel related costs, as well as all costs associated to regulatory matters.
+Added: Collaboration Agreement s
+Added: Joint COVID‑19 Collaboration Agreement.
+Added: As discussed above, on August 21, 2020, we entered into a definitive agreement, which we refer to as the Collaboration Agreement, with ImmunityBio to pursue collaborative joint development, manufacturing and marketing of certain COVID‑19 therapeutics and vaccines.
+Added: Cost Sharing Agreement.
+Added: In January 2020, but effective on October 1, 2019, we entered into a Cost Allocation Agreement with ImmunityBio and its subsidiaries to co-sponsor and conduct certain combination clinical trials (each a Joint Study) pursuant to clinical trial protocols wherein at least one investigational agent is a proprietary therapeutic drug candidate owned or controlled by NantKwest and at least one other investigational agent is a proprietary therapeutic drug candidate owned or controlled by ImmunityBio.
+Added: Prior to initiating any activities for a Joint Study the parties agreed to enter into written work orders describing, amongst other things, development and management responsibilities, allocation of Joint Study costs and expenses, regulatory responsibilities, and any other matters relating to the Joint Study.
+Added: Under the Cost Allocation Agreement, each of ImmunityBio and the company will receive exclusive rights to any new intellectual property developed that relates solely to its respective study drug, and the parties will have joint co-equal rights in any other intellectual property.
+Added: The Cost Allocation Agreement expires on June 22, 2022 with the option to renew for additional successive one-year terms, but work orders for any joint studies still in process at the time of termination will continue until the applicable study is completed.
+Added: We and ImmunityBio are splitting certain costs related to these joint studies equally in accordance with the terms of the Cost Allocation Agreement and related work orders.
+Added: Shared Joint Study costs include cost related to conducting the Joint Study development activities, such as personnel related costs, as well as all costs associated with regulatory matters.
Costs and expenses incurred in connection with the development, manufacturing, supply, delivery, and pre-patient administration dosing mechanism of each party’s study drug, are excluded from the shared Joint Study costs.
−Removed: As of December 31, 2019, there was minimal joint research activity under the Agreement.
−Removed: Under the agreement, each of ImmunityBio and the company will receive exclusive rights to any new intellectual property developed that relates solely to its respective study drug, and the parties will have joint co-equal rights in any other intellectual property.
−Removed: The Agreement expires upon the second anniversary of the effective date with the option to renew for additional successive one-year terms, but work orders for any joint studies still in process at the time of termination will continue until the applicable study is completed.
−Removed: Altor BioScience, LLC.
−Removed: In August 2016, we entered into an exclusive Co-Development Agreement, or the Co-Development Agreement, with Altor BioScience, LLC, or Altor.
−Removed: Altor is a related party, as it is a wholly owned subsidiary of ImmunityBio.
−Removed: ImmunityBio is an affiliate of NantWorks.
−Removed: Under the Co-Development Agreement, the parties agreed to exclusively collaborate on the development of certain therapeutic applications combining our proprietary NK cells with Altor's N‑801 and/or N‑803 products with respect to certain technologies and intellectual property rights as may be agreed between the parties for the purpose of jointly developing therapeutic applications of certain effector cell lines.
−Removed: We are the lead developer for each product developed by the parties pursuant to the Co-Development Agreement unless otherwise agreed to under a given project plan.
−Removed: Under the terms of the Co-Development Agreement, both parties granted a co-exclusive, royalty free, fully paid-up, worldwide license, with the right to sublicense (only to a third-party contractor assisting with research and development activities under this Co-Development Agreement and subject to prior consent, not to be unreasonably withheld), under the intellectual property, or IP, including the parties interest in the joint IP, solely to conduct any development activities agreed to by the steering committee as set forth in any development plan.
−Removed: Unless otherwise mutually agreed by the parties in the development plan for a project, we are responsible for all costs and expenses incurred by either party related to conducting clinical trials and other activities under each development program, including costs associated with patient enrollment, materials and supplies, third party staffing, and regulatory filings.
−Removed: Altor supplies free of charge, sufficient amounts of Altor products for all pre-clinical requirements and certain clinical requirements for up to 400 patients in phase I and/or phase II clinical trials, as required under the development plan for a project per the Co-Development Agreement.
−Removed: Each company owns an undivided interest in and to all rights, title and interest in and to the joint product rights.
−Removed: The Co-Development Agreement expires upon the fifth anniversary of the effective date.
−Removed: We have dosed patients with N‑803, an IL‑15 superagonist, in several phase Ib/II trials.
+Added: In January 2020, but effective on October 1, 2019, we executed Work Order Number One with ImmunityBio, pursuant to the Cost Allocation Agreement.
+Added: Under Work Order Number One, the parties are conducting a clinical trial pursuant to the protocol titled QUILT 3.063:
+Added: A phase 2 study of combination therapy with an IL‑15 superagonist (N‑803), off-the-shelf CD16‑targeted natural killer cells (haNK), and avelumab without cytotoxic chemotherapy in subjects with Merkel Cell Carcinoma (MCC) that has progressed on or after treatment with a checkpoint inhibitor .
+Added: The ImmunityBio study drug included in this Joint Study is ImmunityBio’s proprietary IL‑15 superagonist known as N‑803, and our study drug is our proprietary “off-the-shelf” CD16-targeted natural killer cell therapy known as haNK.
+Added: We are the sponsor of this Joint Study for purposes of regulatory matters, including submissions, correspondence, and communications.
+Added: Additionally, we are designated as the contracting party to execute agreements with third and related parties relating to the Joint Study.
+Added: In July 2020, but effective on June 22, 2020, we executed Work Order Number Two with ImmunityBio, pursuant to the Cost Allocation Agreement.
+Added: Under Work Order Number Two, the parties are conducting a clinical trial pursuant to the protocol titled QUILT 88:
+Added: Open-label, randomized, comparative phase 2 study of combination immunotherapy with standard-of-care chemotherapy versus standard-of-care chemotherapy for first and second line treatment of locally or advanced metastatic pancreatic cancer .
+Added: The ImmunityBio study drugs included in the joint study are ImmunityBio’s proprietary IL‑15 superagonist (N‑803) and Aldoxorubicin Hydrochloride (Aldoxorubicin), and our study drug is PD‑L1.t‑haNK.
+Added: ImmunityBio is the sponsor of this Joint Study for purposes of regulatory matters, including submissions, correspondence, and communications with the FDA.
+Added: Additionally, ImmunityBio is designated as the contracting party to execute agreements with third and related parties relating to this Joint Study.
Viracta Therapeutics, Inc.
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Fox Chase is obligated to assign the licensed patents to us if we commence a phase III clinical trial of a licensed product and, if this does not occur, our license expires when the last of the licensed patents expires.
+Added: In late May 2020, we received a letter from Fox Chase alleging breaches of our license.
+Added: If the letter is found to be a proper notice of termination and the alleged breaches are confirmed and found to be material, we will lose the licensed rights.
+Added: We do not consider these licensed rights to be material.
Rush University Medical Center.
−Removed: In March 2004, we entered into a license agreement with Rush University Medical Center, or Rush, pursuant to which Rush granted us an exclusive, worldwide, sublicensable license to certain intellectual property related to clinical use of NK‑92 to develop and commercialize products and processes for the treatment of melanoma and renal cancer, or for the diagnosis or treatment of non-melanoma and non-renal cancer.
−Removed: In consideration for the license, we were obligated to pay to Rush single-digit royalties on sales of licensed products with a minimum royalty payment of $25,000 per year.
+Added: In March 2004, we entered into a license agreement with Rush University Medical Center, pursuant to which Rush University Medical Center granted us an exclusive, worldwide, sublicensable license to certain intellectual property related to clinical use of NK‑92 to develop and commercialize products and processes for the treatment of melanoma and renal cancer, or for the diagnosis or treatment of non-melanoma and non-renal cancer.
+Added: In consideration for the license, we were obligated to pay to Rush University Medical Center single-digit royalties on sales of licensed products with a minimum royalty payment of $25,000 per year for 12 years.
The agreement also provided for payments upon completion of certain clinical, regulatory and commercialization milestones.
−Removed: We also agreed to pay to Rush a portion of certain payments that we receive under sublicensing arrangements.
+Added: We also agreed to pay to Rush University Medical Center a portion of certain payments that we receive under sublicensing arrangements.
The license had a term of 12 years from 2006, the year in which royalty payments were first made, and included customary termination rights for both parties.
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Joint Development and License Agreements
−Removed: Intrexon Corporation.
−Removed: In February 2010, we entered into a 17‑year agreement with Intrexon Corporation, or Intrexon, pursuant to which we granted to Intrexon a worldwide, sublicensable license which may be exclusive with respect to certain indications designated by Intrexon, under certain patents relating to NK‑92 cells to develop and commercialize modified NK‑92 cells that express Intrexon’s proprietary gene sequences for use as therapeutic and prophylactic agents in humans in specified therapeutic areas.
−Removed: Intrexon paid us a one-time license fee and is also obligated to pay non-material milestone payments with respect to specific indications, a royalty on net sales of the licensed products and a portion of the revenue Intrexon receives from third party sublicensees of its rights from us.
−Removed: Intrexon has the right to terminate the agreement upon 180 days’ notice and both parties have the right to terminate the agreement for the other’s uncured breach of the agreement.
+Added: Precigen Corporation, Inc.
+Added: (formerly known as Intrexon Corporation).
+Added: In February 2010, we entered into a 17‑year agreement with Precigen Corporation, Inc., or Precigen, pursuant to which we granted to Precigen a worldwide, sublicensable license which may be exclusive with respect to certain indications designated by Precigen, under certain patents relating to NK‑92 cells to develop and commercialize modified NK‑92 cells that express Precigen’s proprietary gene sequences for use as therapeutic and prophylactic agents in humans in specified therapeutic areas.
+Added: Precigen paid us a one-time license fee and is also obligated to pay non-material milestone payments with respect to specific indications, a royalty on net sales of the licensed products and a portion of the revenue Precigen receives from third party sublicensees of its rights from us.
+Added: Precigen has the right to terminate the agreement upon 180 days’ notice and both parties have the right to terminate the agreement for the other’s uncured breach of the agreement.
We have licensed or sub-licensed our cell lines and intellectual property to numerous other pharmaceutical and biotechnology companies for non-clinical uses such as laboratory testing.
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Supply Agreements
−Removed: In 2018, we entered into various supply agreements with third parties to provide investigational agents to be used in our clinical trials.
+Added: We have, and expect that we will continue, to enter into supply agreements with third parties and related parties to provide investigational agents to be used in our clinical trials.
Anticipated Agreements and Considerations
−Removed: In addition to the collaboration and license agreements discussed above, we may enter into a commercial agreement relating to an IL‑15 superagonist product developed by an affiliate, and we are also pursuing certain strategic research and/or license agreements with third parties to develop our candidate pipeline.
−Removed: These types of collaboration agreements do not typically specify how sales will be apportioned between the parties upon successful commercialization of the product.
+Added: In addition to the collaboration and license agreements discussed above, we may enter into a commercial agreement relating to an IL‑15 superagonist product developed by ImmunityBio, if the proposed merger with ImmunityBio is not consummated, and we are also pursuing certain strategic research and/or license agreements with third parties to develop our product candidate pipeline.
+Added: These types of agreements do not typically specify how sales will be apportioned between the parties upon successful commercialization of the product.
As a result, we cannot guarantee that we will receive a percentage of the revenue that is at least proportional to the costs that we will incur in commercializing the product candidate.
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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.
+Added: Further, as a result of the COVID‑19 pandemic, we may be required to develop and implement additional clinical trial policies and procedures designed to help protect subjects from the COVID‑19 virus.
+Added: For example, the FDA has issued guidance on conducting clinical trials during the pandemic, which describes a number of considerations for sponsors of clinical trials impacted by the pandemic, including certain reporting requirements, and additional guidance on GMP considerations for responding to COVID‑19 infection and other topics.
+Added: We may be required to make further adjustments to our clinical trials or business operations based on current or future guidance and regulatory requirements as a result of the COVID‑19 pandemic.
BLA Submission and Review by the FDA
126 unchanged sentences
In addition, there has been a recent trend of increased federal and state regulation of payments made to physicians and other healthcare providers.
−Removed: The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively, the Affordable Care Act, among other things, imposed new 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 physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.
+Added: The Physician Payment Sunshine Act, or the Sunshine Act, enacted as part of t he Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or collectively, the Affordable Care Act, among other things, imposed new 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 and other transfers of value made by them to physicians and teaching hospitals, as defined by law, as well as ownership and investment interests held by physicians and their immediate family members.
+Added: Effective January 1, 2022, these annual reporting obligations will extend to include payments and transfers of value made during the previous year to certain non-physician covered recipients, such as physician assistants, nurse practitioners, clinical nurse specialists, certified registered nurse anesthetists , anesthesiologist assistants, and certified nurse-midwives.
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.
−Removed: Failure to submit required information may result in civil monetary penalties of up to an aggregate of $150,000 per year (or up to an aggregate of $1 million per year for “knowing failures”), for all payments, transfers of value or ownership or investment interests that are not timely, accurately and completely reported in an annual submission.
+Added: Failure to submit required information may result in civil monetary penalties of up to an aggregate of $1 76 , 495 per year (or up to an aggregate of $ 1,176,638 per year for “knowing failures”) , subject to adjustment for inflation , 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.
+Added: Non-compliance under the Sunshine Act may increase government scrutiny and increase liability under other healthcare laws.
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.
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Foreign Corrupt Practices Act, or 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.
−Removed: We adopted an anti-corruption policy in connection with the initial public offering of our common stock in July 2015.
−Removed: The anti-corruption policy mandates compliance with the FCPA and similar anti-bribery laws applicable to our business throughout the world.
+Added: We also maintain an anti-corruption policy which 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.
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We may need to conduct expensive clinical studies to demonstrate the comparative cost-effectiveness of our products.
−Removed: The product candidates that we develop may not be considered cost-effective and thus may not be covered or sufficiently reimbursed.
+Added: The product candidates that we develop may not be considered cost-effective and thus may not be covered or
+Added: 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.
9 unchanged sentences
Among the provisions of the Affordable Care Act of importance to our potential drug candidates are:
−Removed: 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;
−Removed: 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;
−Removed: 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;
−Removed: a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% 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;
−Removed: extension of a manufacturer’s Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;
−Removed: 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;
+Added: an annual, nondeductible fee on any entity that manufactures or imports certain branded prescription drugs and biologic agents, apportioned among these entities according to their market share in certain government healthcare programs, not including orphan drug sales;
+Added: an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program to 23.1% and 13% of the average manufacturer price for most branded and generic drugs, respectively;
+Added: a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 70% point-of-sale discounts on negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D;
+Added: extension of manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;
+Added: 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 manufacturers’ Medicaid rebate liability;
expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program;
+Added: new requirements for 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 to report annually certain financial arrangements with physicians, as defined by such law, and teaching hospitals, as defined in ACA and its implementing regulations, including reporting any payment or “transfer of value” provided to physicians and teaching hospitals and any ownership and investment interests held by physicians and their immediate family members during the preceding calendar year;
+Added: expansion of healthcare fraud and abuse laws, including the U.S.
+Added: federal False Claims Act and the U.S.
+Added: federal Anti-Kickback Statute, new government investigative powers and enhanced penalties for noncompliance;
a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in and conduct comparative clinical effectiveness research, along with funding for such research;
+Added: 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.
In addition, other legislative changes have been proposed and adopted since the Affordable Care Act was enacted.
−Removed: 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 2024 unless additional Congressional action is taken.
−Removed: In January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, 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.
+Added: 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, will remain in effect through 2030, with the exception of a temporary suspension implemented under various COVID‑19 relief legislation from May 1, 2020 through March 31, 2021, unless additional Congressional action is taken.
+Added: The American Taxpayer Relief Act of 2012, 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.
1 unchanged sentence
Any reduction in reimbursement from Medicare or other government-funded programs may result in a similar reduction in payments from private payors.
−Removed: The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability or commercialize our drugs.
+Added: The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue , attain profitabili ty or commercialize our drugs.
Furthermore, the current presidential administration and Congress may continue to attempt broad sweeping changes to the current health care laws.
1 unchanged sentence
The impact of those changes on us and potential effect on the pharmaceutical and biotechnology industries as a whole is currently unknown.
−Removed: However, any changes to the Affordable Care Act are likely to have an impact on our results of operations and may have a material adverse effect on our results of operation.
−Removed: 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.
+Added: However , any changes to the Affordable Care Act are likely to have an impact on our results of operations and may have a material adverse effect on our results of operation s .
+Added: We cannot predict what other healthcare programs and regulations will ultimately be implemented at the federal or state level or the effect any future legislat ion or regulation in the U.S.
may have on our business.
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As of December 31, 2020, we had 171 employees.
+Added: Among our employees, 23% are focused on research and development, 8% on clinical development and regulatory, 51% on manufacturing and quality, and 18% on general and administrative functions.
Personnel of related companies who provide corporate, general and administrative, manufacturing strategy, research and development, regulatory and clinical trial strategy and other administrative support services under our shared services agreement with NantWorks are not included in this number.
For additional information, see Note 10, Related Party Agreements , of the “Notes to Consolidated Financial Statements” included in Part II, Item 8 of this Annual Report.
−Removed: Our ability to manage growth effectively will require us to continue to implement and improve our management systems, recruit and train new employees and select qualified independent contractors.
−Removed: None of our employees are represented by a labor union or covered by collective bargaining agreements, and we believe our relationship with our employees is good.
+Added: We believe our ability to successfully achieve our vision depends on how effectively we manage our growth.
+Added: Our leadership is focused on continuing to implement and improve our management systems, recruit and train new employees and cultivate and retain our existing team members.
+Added: Our employees are a highly unique group of individuals across our drug discovery, preclinical development, clinical operations, regulatory affairs, manufacturing and quality, and executive leadership teams with deep experience in biotech across a breadth of novel scientific areas.
+Added: We offer competitive compensation and benefits to all employees, as well as a host of other programs that enhance employee well-being in and outside of the workplace.
+Added: We believe we have a positive relationship with our employees, and none of our employees are represented by a labor union or covered by collective bargaining agreements.
Corporate Information
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We provide free of charge through a link on our website access to our Annual Reports on Form 10‑K, Quarterly Reports on Form 10‑Q and Current Reports on Form 8‑K, as well as amendments to those reports, as soon as reasonably practical after the reports are electronically filed with, or furnished to, the Securities and Exchange Commission.
−Removed: Ri sk Factors.
−Removed: Investing in our common stock involves a high degree of risk.
−Removed: You should carefully consider the risks described below, as well as other information included in this Annual Report on Form 10‑K, or Annual Report, including our financial statements and the related notes, and the section titled “Management’s Discussion and Analysis of Financial Condition and Results of Operations,” any of which may be relevant to decisions regarding an investment in or ownership of our stock.
−Removed: The occurrence of any of these risks could have a significant adverse effect on our reputation, business, financial condition, results of operations, growth and ability to accomplish our strategic objectives.
−Removed: We have organized the description of these risks into groupings in an effort to enhance readability, but many of the risks interrelate or could be grouped or ordered in other ways, so no special significance should be attributed to the groupings or order below.
−Removed: Risks Related to Our Financial Condition and Capital Requirements
−Removed: We are a clinical-stage biopharmaceutical company with a limited operating history and have incurred significant losses since our inception, and we anticipate that we will continue to incur losses for the foreseeable future, which makes it difficult to assess our future viability.
−Removed: We are a clinical-stage biopharmaceutical company with a limited operating history upon which our business can be evaluated.
−Removed: To date, we have generated minimal revenue related to the non-clinical use of our cell lines and intellectual property, and we have no products approved for commercial sale and have not generated any revenue from product sales.
−Removed: We have incurred operating losses on an annual basis since our formation and we may never become profitable.
−Removed: As of December 31, 2019, we had an accumulated deficit of approximately $662.2 million.
−Removed: We incurred net losses of $65.8 million, $96.2 million, and $96.4 million for the years ended December 31, 2019, 2018 and 2017, respectively.
−Removed: Our losses have resulted principally from costs incurred in ongoing preclinical studies, clinical trials and operations, research and development expenses, as well as general and administrative expenses.
−Removed: A critical aspect of our strategy is to invest significantly in expanding our haNK, taNK and t‑haNK platforms and the development of our product candidates.
−Removed: We expect to incur significant expenses as we continue to expand our business, including in connection with conducting research and development across multiple therapeutic areas, participating in clinical trial activities, continuing to acquire or in-license technologies, maintaining, protecting and expanding our intellectual property, seeking regulatory approvals and, upon successful receipt of U.S.
−Removed: Food and Drug Administration, or FDA, approval, commercializing our products.
−Removed: We will also incur costs as we hire additional personnel and increase our manufacturing capabilities, including the lease or purchase of a facility for the manufacturing of our product candidates for our ongoing and any future clinical trials and, upon potential receipt of FDA approval, for our initial commercialization activities.
−Removed: Moreover, we do not expect to have any significant product sales or revenue for a number of years.
−Removed: These losses have had and, as our operating losses continue to increase significantly in the future due to these expenditures, will continue to have an adverse effect on our stockholders’ equity and working capital.
−Removed: Because of the numerous risks and uncertainties associated with our product development efforts, we are unable to predict when we may become profitable, if at all.
−Removed: Additionally, our net losses may fluctuate significantly from quarter to quarter, and as a result, a period-to-period comparison of our results of operations may not be meaningful.
−Removed: Even if we do become profitable, we may not be able to sustain or increase our profitability on a quarterly or annual basis.
−Removed: We do not have any therapeutic products that are approved for commercial sale.
−Removed: Our ability to generate revenue from product sales and achieve and maintain profitability depends significantly on our success in a number of factors.
−Removed: We currently do not have any therapeutic products that are approved for commercial sale.
−Removed: We have not received, and do not expect to receive for at least the next several years, if at all, any revenues from the commercialization of our product candidates if approved.
−Removed: To obtain revenue from sales of our product candidates that are significant or large enough to achieve profitability, we must succeed, either alone or with third parties, in developing, obtaining regulatory approval for, manufacturing and marketing therapies with commercial potential.
−Removed: Our ability to generate revenue and achieve and maintain profitability depends significantly on our success in many areas, including:
−Removed: our research and development efforts, including preclinical studies and clinical trials of our haNK, taNK and t‑haNK platforms and our product candidates;
−Removed: continuing to develop sustainable, scalable, reliable and cost-effective manufacturing and distribution processes for our product candidates, including establishing and maintaining commercially viable supply relationships with third parties and establishing our own current Good Manufacturing Practices, or cGMP, manufacturing facilities and processes to support clinical development and meet the market demand for product candidates that we develop, if approved;
−Removed: addressing any competing technological and industry developments;
−Removed: identifying, assessing, acquiring and/or developing new technology platforms and product candidates across numerous therapeutic areas;
−Removed: establishing and maintaining relationships with contract research organizations, or CROs, and clinical sites for the clinical development, both in the U.S.
−Removed: and internationally, of our product candidates;
−Removed: successful and timely completion of preclinical and clinical development of our product candidates and any other future product candidates;
−Removed: obtaining regulatory approvals and marketing authorizations for product candidates, including a continued acceptable safety profile both prior to and following any marketing approval of our product candidates;
−Removed: making any required post-marketing approval commitments to applicable regulatory authorities;
−Removed: launching and commercializing any approved products, either directly or with a collaborator or distributor, including the development of a commercial infrastructure;
−Removed: obtaining market acceptance of and acceptable reimbursement for any approved products;
−Removed: identifying, assessing and developing new product candidates;
−Removed: completing collaborations, licenses and other strategic transactions on favorable terms, if at all;
−Removed: maintaining, protecting and expanding our portfolio of intellectual property rights, including patents, trade secrets and know-how;
−Removed: defending against third-party interference or infringement claims, if any;
−Removed: addressing any competing therapies and technological and market developments;
−Removed: attracting, hiring and retaining qualified personnel.
−Removed: Even if one or more of our product candidates is eventually approved for commercial sale, we anticipate incurring significant costs associated with commercializing any approved product candidate and we may not generate significant revenue from sales of such products, resulting in limited or no profitability in the future.
−Removed: Our prior losses and expected future losses have had and will continue to have an adverse effect on our stockholders’ equity and working capital for the foreseeable future.
−Removed: Any failure to become and remain profitable may adversely affect the market price of our common stock, our ability to raise additional capital and our future viability.
−Removed: We will need to obtain substantial additional financing to complete the development and any commercialization of our product candidates, and a failure to obtain this necessary capital when needed on acceptable terms, or at all, could force us to delay, limit, reduce or terminate our commercialization efforts, product development or other operations.
−Removed: Since our inception, we have used substantial amounts of cash to fund our operations and expect our expenses to increase substantially in the foreseeable future.
−Removed: Developing our product candidates and conducting clinical trials for the treatment of cancer, virally infectious diseases, and other diseases requires substantial amounts of capital.
−Removed: We will also require a significant additional amount of capital to commercialize any approved products.
−Removed: As of December 31, 2019, we had cash and cash equivalents of $15.5 million and marketable debt securities of $37.6 million.
−Removed: We are using and expect to continue to use our existing cash and cash equivalents and marketable debt securities to fund expenses in connection with our ongoing and any future clinical trials, our manufacturing facilities and processes and the hiring of additional personnel, and for other research and development activities, working capital and general corporate purposes, including our share repurchase program.
−Removed: We believe that our existing cash, cash equivalents, and investments in marketable debt securities, and our ability to borrow from affiliated entities, will be sufficient to fund our operations for at least the next 12 months following the issuance date of the financial statements based upon our Chairman and CEO’s intent and ability to support our operations with additional funds, including loans from affiliated entities, as required.
−Removed: Our estimate as to how long we expect our existing cash and cash equivalents to be available to fund our operations is based on assumptions that may be proved inaccurate, and we could deplete our available capital resources sooner than we currently expect.
−Removed: In addition, changing circumstances may cause us to consume capital significantly faster than we currently anticipate, and we may need to spend more money than currently expected because of circumstances beyond our control.
−Removed: We may require additional capital for the further development and any commercialization of our product candidates and may need to raise additional funds sooner than we anticipate if we choose to expand more rapidly than we presently anticipate.
−Removed: Our future capital requirements may depend on, and could increase significantly as a result of, many factors, including:
−Removed: the timing of, and the costs involved in, preclinical and clinical development and obtaining any regulatory approvals for our product candidates;
−Removed: the costs of manufacturing, distributing and processing our product candidates and any products for which we receive regulatory approval;
−Removed: the number and characteristics of any other product candidates we develop or acquire;
−Removed: our ability to establish and maintain strategic collaborations, licensing or other commercialization arrangements and the terms and timing of such arrangements, including our arrangements with ImmunityBio and its subsidiaries and Viracta;
−Removed: the degree and rate of market acceptance of any approved products;
−Removed: the emergence, approval, availability, perceived advantages, relative cost, relative safety and relative efficacy of other products or treatments;
−Removed: the expenses needed to attract and retain skilled personnel;
−Removed: the costs associated with being a public company;
−Removed: the costs involved in preparing, filing, prosecuting, maintaining, defending and enforcing intellectual property claims, including litigation costs and the outcome of such litigation;
−Removed: the costs related to commercializing product candidates independently;
−Removed: the timing, receipt and amount of sales of, or royalties on, any approved products;
−Removed: any product liability or other lawsuits related to our product candidates or the company.
−Removed: To the extent that we raise additional capital through the sale of equity or convertible debt securities, the ownership interest of our stockholders will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect our common stockholders’ rights.
−Removed: Debt financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends.
−Removed: If we raise additional funds through collaborations, strategic alliances or licensing arrangements with pharmaceutical partners, we may have to relinquish valuable rights to our technologies, future revenue streams, research programs or product candidates, or grant licenses on terms that may not be favorable to us.
−Removed: Additional capital may not be available when we need it, on terms that are acceptable to us or at all.
−Removed: If we are unable to raise additional funds through equity or debt financings when needed, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts or grant rights to develop and market any approved products that we would otherwise prefer to develop and market ourselves, or be unable to continue or expand our operations or otherwise capitalize on our business opportunities, as desired, which could materially affect our business, financial condition and results of operations and cause the price of our common stock to decline.
−Removed: We may use our financial and human resources to pursue a particular type of treatment, or treatment for a particular type of cancer, and fail to capitalize on programs or treatment of other types of cancer that may be more profitable or for which there is a greater likelihood of success.
−Removed: Because we have limited resources, we must choose to pursue and fund the development of specific types of treatment, or treatment for a specific type of cancer, and may forego or delay pursuit of opportunities with other programs, investigational medicines, or treatment for other types of cancer, which could later prove to have greater commercial potential.
−Removed: Moreover, given the rapidly evolving competitive landscape and the time it takes to advance a product through clinical development, an incorrect decision to pursue a particular type of treatment or cancer may have a material adverse effect on our results of operation and negatively impact our future clinical strategies.
−Removed: Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities.
−Removed: Our spending on current and future research and development programs for investigational medicines or clinical trials may not yield any commercially viable products.
−Removed: If we do not accurately evaluate and anticipate the commercial potential or target market for a particular type of treatment or cancer, we may choose to spend our limited resources on a particular treatment, or treatment for a particular type of cancer, and then later learn that another type of treatment or cancer that we previously decided not to pursue would have been more advantageous.
−Removed: We invest our cash on hand in various financial instruments which are subject to risks that could adversely affect our business, results of operations, liquidity and financial condition.
−Removed: We invest our cash in a variety of financial instruments, principally commercial paper, corporate debt securities and foreign government bonds.
−Removed: All of these investments are subject to credit, liquidity, market and interest rate risk.
−Removed: Such risks, including the failure or severe financial distress of the financial institutions that hold our cash, cash equivalents and investments, may result in a loss of liquidity, impairment to our investments, realization of substantial future losses, or a complete loss of the investments in the long-term, which may have a material adverse effect on our business, results of operations, liquidity and financial condition.
−Removed: In order to manage the risk to our investments, we maintain an investment policy that, among other things, limits the amount that we may invest in any one issue or any single issuer and requires us to only invest in high credit quality securities.
−Removed: Risks Relating to Our Business and Industry
−Removed: The foundation of our business is based upon the success of our aNK cells as a technology platform.
−Removed: Our aNK platform and product candidates derived thereof, including genetically modified haNK, taNK and t ‑ haNK product candidates, will require significant additional clinical testing before we can potentially seek regulatory approval and launch commercial sales.
−Removed: Our business and future success depend on our ability to utilize our aNK cells as a technology platform, and to obtain regulatory approval for one or more product candidates derived from it, and then successfully commercialize our product candidates addressing numerous therapeutic areas.
−Removed: Our aNK platform and our haNK, taNK and t‑haNK product candidates are in varying stages of development and may never become commercialized.
−Removed: All of our product candidates developed from our technology platform will require additional clinical and non-clinical development, regulatory review and approval in multiple jurisdictions, substantial investment, access to sufficient commercial manufacturing capacity and significant marketing efforts before they can be successfully commercialized.
−Removed: Because all of our product candidates are based on the same core aNK technology, if any of our product candidates encounter safety or efficacy problems, developmental delays or regulatory issues or other problems, these could impact the development plans for our other product candidates.
−Removed: Utilizing haNK, taNK and t ‑ haNK cells represents a novel approach to immunotherapy, including cancer treatment, and we must overcome significant challenges in order to successfully develop, commercialize and manufacture our product candidates.
−Removed: We have concentrated our research and development efforts on utilizing aNK cells as an immunotherapy platform and genetically modified aNK cells as product candidates based on this platform.
−Removed: We believe that our product candidates represent a novel approach to immunotherapy, including cancer treatment.
−Removed: Advancing this novel immunotherapy creates significant challenges for us, including:
−Removed: educating medical personnel regarding the potential side effect profile of our cells;
−Removed: training a sufficient number of medical personnel how to properly administer our cells;
−Removed: enrolling sufficient numbers of patients in clinical trials;
−Removed: developing a reliable, safe and effective means of genetically modifying our cells;
−Removed: manufacturing our cells on a large scale and in a cost-effective manner;
−Removed: submitting applications for and obtaining regulatory approval, as the FDA and other regulatory authorities have limited experience with commercial development of immunotherapies for cancer and viral associated infectious diseases;
−Removed: establishing sales and marketing capabilities, as well as developing a manufacturing process and distribution network to support the commercialization of any approved products.
−Removed: We must be able to overcome these challenges in order for us to successfully develop, commercialize and manufacture our product candidates utilizing haNK, taNK and t‑haNK cells.
−Removed: Even if we successfully develop and commercialize our haNK product candidate for Merkel cell carcinoma, we may not be successful in developing and commercializing our other product candidates, and our commercial opportunities may be limited.
−Removed: We believe that our ability to realize the full value of our aNK platform will depend on our ability to successfully develop and commercialize haNK and our other product candidates in a wider range of indications.
−Removed: We are simultaneously pursuing preclinical and clinical development of a number of product candidates spanning several types of cancers.
−Removed: For example, we are devoting substantial resources toward the development of haNK and t‑haNK product candidates as combination therapies with commercially approved monoclonal antibodies and late-stage product candidates for solid tumors such as breast, gastric, pancreatic, lung, head and neck and colorectal cancers, as well as hematologic malignancies such as indolent B‑cell lymphoma, acute lymphoblastic leukemia, or ALL, and diffuse large B‑cell lymphoma, or DLBCL.
−Removed: Even if we are successful in continuing to build our pipeline of product candidates based on our technology platform, obtaining regulatory approvals and commercializing any approved product candidates will require substantial additional funding beyond our existing cash and cash equivalents and marketable debt securities, and are prone to numerous risks of failure.
−Removed: Investment in biopharmaceutical product development involves significant risks that any product candidate will fail to demonstrate adequate efficacy or an acceptable safety profile to the satisfaction of regulatory authorities, gain regulatory approval or become commercially viable.
−Removed: We cannot assure you that we will be able to successfully advance any product candidates through the development process.
−Removed: Our research programs may initially show promise in identifying product candidates, but ultimately fail to yield product candidates for clinical development or commercialization for many reasons, including the following:
−Removed: our product candidates may not succeed in preclinical or clinical testing due to failing to generate enough data to support the initiation or continuation of clinical trials or due to lack of patient enrollment in clinical trials;
−Removed: a product candidate may be shown to have harmful side effects or other characteristics in larger scale clinical studies that indicate it is unlikely to meet applicable regulatory criteria;
−Removed: competitors may develop alternatives that render our product candidates obsolete or less attractive;
−Removed: we may not be able or willing to assemble sufficient resources to acquire or discover additional product candidates from our technology platform;
−Removed: product candidates we develop may nevertheless be covered by third parties’ patents or other exclusive rights;
−Removed: the market for a product candidate may change during our program so that the continued development of that product candidate is no longer reasonable;
−Removed: a product candidate may not be capable of being manufactured in commercial quantities at an acceptable cost, or at all;
−Removed: a product candidate may not be accepted as safe and effective by patients, the medical community or third-party payors.
−Removed: If any of these events occur, we may be forced to abandon our development efforts for a product candidate or the entire platform, or we may not be able to identify, discover, develop or commercialize additional product candidates, which would have a material adverse effect on our business and could potentially cause us to cease operations.
−Removed: We may not be able to file INDs to commence additional clinical trials on the timelines we expect, and even if we are able to, the FDA may not permit us to proceed in a timely manner, or at all.
−Removed: Prior to commencing clinical trials in the U.S.
−Removed: for any of our product candidates, we may be required to have an allowed IND for each product candidate.
−Removed: As of the date of this filing, we have numerous INDs for clinical trials that have been authorized in the U.S.
−Removed: We are required to file additional INDs prior to initiating our planned clinical trials.
−Removed: We believe that the data from previous preclinical studies will support the filing of additional INDs, to enable us to undertake additional clinical studies as we have planned.
−Removed: However, submission of an IND may not result in the FDA allowing further clinical trials to begin and, once begun, issues may arise that will require us to suspend or terminate such clinical trials.
−Removed: Additionally, even if relevant regulatory authorities agree with the design and implementation of the clinical trials set forth in an IND or clinical trial application, these regulatory authorities may change their requirements in the future.
−Removed: The fact that we are pursuing novel technologies may also exacerbate these risks with respect to our product candidates, and as a result, we may not meet our anticipated clinical development timelines.
−Removed: We face significant competition in the biopharmaceutical industry, and many of our competitors have substantially greater experience and resources than we have.
−Removed: Even if our aNK platform products prove successful, we might not be able to remain competitive because of the rapid pace of technological development in the biopharmaceutical field.
−Removed: Our haNK, taNK and t‑haNK product candidates will compete with other cell and molecule-based immunotherapy approaches using and/or targeting natural killer cells, T‑cells and dendritic cells.
−Removed: Competitors focused on CAR‑T related treatment approaches include AbbVie Inc., Atara Biotherapeutics, Inc., Intrexon Corporation, Allogene Therapeutics, Inc., Bristol‑Myers Squibb Company, JW Therapeutics Co., Ltd., Amgen, Inc., Leucid Bio Ltd., Bellicum Pharmaceuticals, Inc., Medisix Therapeutics Pte Ltd., Bluebird Bio, Inc., Mesoblast Ltd., Calibr/Scripps Research, Mustang Bio, Inc., CARsgen Therapeutics, Nanjing Legend Biotechnology Co., Ltd, Cartherics Pty Ltd, Novartis AG, Pfizer, Inc., Cellectis SA, Poseida Therapeutics, Inc., Celularity, Inc., Servier Laboratories, Celyad SA, Takeda/Shire, Fortress Biotech, Inc., TC BioPharm Ltd., Gilead Sciences, Inc., Transposagen Biopharmaceuticals, Inc., Humanigen, Inc., Unum Therapeutics, Inc., Immune Therapeutics, Inc., and Xyphos, Inc.
−Removed: Competitor companies focused on other T‑cell based approaches include Adaptimmune Ltd., Adicet Bio, Inc., Autolus Therapeutics, plc, Cell Medica Limited, GlaxoSmithKline plc., Green Cross LabCell Corp., Immunocore Limited, Iovance Biotherapeutics, Inc., Kiadis Pharma Netherlands B.V., Lion TCR Pte Ltd., MolMed, S.p.A., Precision Biosciences, Inc., Janssen Pharmaceuticals, Inc., Noile‑Immune Biotech, Inc., Anixa Biosciences, Inc., Beam Therapeutics Inc., BioNTech SE, Cartesian Therapeutics, Inc., and Takara Bio, Inc.
−Removed: Competitor companies focused on dendritic cell based approaches include Argos Therapeutics, Inc., Biovest International, Inc., ImmunoCellular Therapeutics, Ltd., Merck & Co, Inc./Immune Design, Inc., Inovio Pharmaceuticals, Inc., Intrexon Corporation, Medigene AG, and Northwest Biotherapeutics, Inc.
−Removed: Competitor companies focused on natural killer cell based approaches include Kiadis Pharma Netherlands B.V./CytoSen Therapeutics, Inc., Dragonfly Therapeutics, Inc., Fate Therapeutics, Inc., Gamida Cell, Ltd., Nkarta Therapeutics, Inc., Onkimmune Ltd., NKMax America, Artiva Biotherapeutics, HebeCell Corp., Vycellix, Inc., oNKo‑innate Pty Ltd., and Ziopharm Oncology, Inc.
−Removed: Competitor companies focused on large molecule immunotherapy approaches include Cytomx Therapeutics, Inc., Innate Pharma SA, and Sorrento Therapeutics, Inc.
−Removed: Other potential immunotherapy competitors include Affimed GmbH, Agios Pharmaceuticals, Inc., Codiak Biosciences, Glycostem Therapeutics BV, Triumvira Immunologics, Century Therapeutics, Incysus Therapeutics, Inc., GammaDelta Therapeutics Ltd., Lyell Immunopharma, Inc., and GT Biopharma, Inc.
−Removed: There are currently two approved T‑cell based treatments which are marketed by Novartis AG and Gilead Sciences/Kite Pharma.
−Removed: There is currently one approved dendritic cell-based cancer vaccine which is marketed by Dendron Pharmaceuticals, LLC for the treatment of metastatic castration resistant prostate cancer.
−Removed: Many of our current or potential competitors have greater financial and other resources, larger research and development staffs, and more experienced capabilities in researching, developing and testing products than we do.
−Removed: Many of these companies also have more experience in conducting clinical trials, obtaining FDA and other regulatory approvals, and manufacturing, marketing and distributing therapeutic products.
−Removed: Smaller or clinical-stage companies like us may successfully compete by establishing collaborative relationships with larger pharmaceutical companies or academic institutions.
−Removed: Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors.
−Removed: These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.
−Removed: Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient, or are less expensive than any products that we may develop.
−Removed: Furthermore, currently approved products could be discovered to have application for treatment of cancer and other diseases, which could give such products significant regulatory and market timing advantages over any of our product candidates.
−Removed: In addition, large pharmaceutical companies or other companies with greater resources or experience than us may choose to forgo therapy opportunities that would have otherwise been complementary to our product development and collaboration plans.
−Removed: Our competitors may succeed in developing, obtaining patent protection for, or commercializing their products more rapidly than us, which could result in our competitors establishing a strong market position before we are able to enter the market.
−Removed: A competing company developing or acquiring rights to a more effective therapeutic product for the same diseases targeted by us, or one that offers significantly lower costs of treatment could render our products noncompetitive or obsolete.
−Removed: We may not be successful in marketing any product candidates we may develop against competitors.
−Removed: Our business plan involves the creation of a complex integrated ecosystem capable of addressing a wide range of indications.
−Removed: As a result, our future success depends on our ability to prioritize among many different opportunities.
−Removed: We do not have sufficient resources to pursue development of all or even a substantial portion of the potential opportunities that we believe will be afforded to us by our planned integrated ecosystem.
−Removed: Because we have limited resources and access to capital to fund our operations, our management must make significant prioritization decisions as to which product candidates to pursue and how much of our resources to allocate to each.
−Removed: Our management has broad discretion to suspend, scale down, or discontinue any or all of these development efforts, or to initiate new programs to treat other diseases.
−Removed: If we select and commit resources to opportunities that we are unable to successfully develop, or we forego more promising opportunities, our business, financial condition and results of operations will be adversely affected.
−Removed: Our planned integrated ecosystem is to be comprised of multiple novel technologies that have never been tested in combination with our product candidates, and we do not know whether our attempts to use them in combination will be effective.
−Removed: Our business strategy includes using our integrated discovery engine to introduce new product candidates in combination with technologies that were developed by other companies with whom we have entered into strategic collaborations.
−Removed: Each technology and collaboration is unique and has its own risks, and the failure of any individual technology or the combination could materially impair our ability to successfully pursue our own aNK platform and related product candidates.
−Removed: While we are free to pursue all antibodies, we are reliant on third parties and affiliates for such antibodies on which to base our taNK, haNK and t‑haNK product candidates.
−Removed: We do not know if we can obtain such antibodies from third parties on commercially reasonable terms and such reliance on third parties may delay our development and increase the associated development costs.
−Removed: We have also entered into collaborations with affiliates of NantWorks, LLC, or NantWorks, to provide us with access to their database of genomic, transcriptomic and proteomic information collected from a broad array of tumor cell and peripheral blood samples.
−Removed: Our rights to use the database are non-exclusive and are governed by agreements cancelable with 90 days’ notice, and we therefore cannot guarantee that we would ultimately have any competitive advantage based on our use of this technology.
−Removed: The database also may not be able to identify novel tumor-associated antigens that are targetable with our technology and the genetic and proteomic analysis capability may not be effective as a companion diagnostic to guide therapeutic treatments.
−Removed: Although we have agreements with these parties, we cannot control their actions and they may make mistakes, work with our competitors, or not devote sufficient time and attention to us.
−Removed: The arrangements may become cost-prohibitive for us, and their technologies may become obsolete or better options may be available that we are unable to utilize.
−Removed: We cannot assure you that using our technology in combination with theirs will be successful in producing product candidates in connection with these arrangements.
−Removed: Clinical drug development involves a lengthy and expensive process with an uncertain outcome, results of earlier studies and clinical trials may not be predictive of future clinical trial results, we may not be able to rely on the aNK and haNK phase I and II clinical trials data for our other product candidates, and our clinical trials may fail to adequately demonstrate substantial evidence of safety and efficacy of our product candidates.
−Removed: The results of our clinical trials may not satisfy the requirements of the FDA or other comparable foreign regulatory authorities, and we may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of such product candidate.
−Removed: Clinical testing is expensive and can take many years to complete, and its outcome is inherently uncertain.
−Removed: A failure of one or more of our clinical trials can occur at any time during the clinical trial process.
−Removed: The results of preclinical studies and early clinical trials of our product candidates may not be predictive of the results of later-stage clinical trials.
−Removed: There is a high failure rate for product candidates proceeding through clinical trials, and product candidates in later stages of clinical trials may fail to show the required safety and efficacy despite having progressed through preclinical studies and initial clinical trials.
−Removed: A number of companies in the pharmaceutical industry have suffered significant setbacks in advanced clinical trials due to lack of efficacy or adverse safety profiles, notwithstanding promising results in earlier clinical trials, and we cannot be certain that we will not face similar setbacks.
−Removed: Even if our clinical trials are completed, the results may not be sufficient to support obtaining regulatory approval for our product candidates.
−Removed: In addition, our strategy and anticipated timelines are predicated upon our ability to utilize the phase I and II clinical trial data for aNK, haNK, and t‑haNK observed to date to support our planned clinical trials for all of our product candidates, including our haNK, taNK and t‑haNK product candidates.
−Removed: To date, we have several INDs for our haNK product candidates, and we cannot offer assurances that the FDA will allow us to utilize the phase I and II aNK and haNK data to support other planned clinical trials or allow our anticipated INDs for (i) planned phase I or phase Ib/IIa clinical trials for our other product candidates, (ii) planned phase IIb/III clinical trials for our haNK and t‑haNK product candidates as potential combination therapies, or (iii) any other planned clinical trials, including registration studies.
−Removed: We have in the past experienced delays in our ongoing clinical trials and we may experience additional delays in the future.
−Removed: We do not know whether future clinical trials, if any, will begin on time, need to be redesigned, enroll an adequate number of patients on time or be completed on schedule, if at all.
−Removed: Clinical trials can be delayed, suspended or terminated by us, regulatory authorities, clinical trial investigators, and ethics committees for a variety of reasons, including failure to:
−Removed: generate sufficient preclinical, toxicology, or other in vivo or in vitro data to support the initiation or continuation of clinical trials;
−Removed: obtain regulatory authorization, or feedback on clinical trial design, to commence a clinical trial;
−Removed: identify, recruit and train suitable clinical investigators;
−Removed: reach agreement on acceptable terms with prospective Contract Research Organizations, or CROs, and clinical trial sites;
−Removed: obtain and maintain institutional review board, or IRB, approval at each clinical trial site;
−Removed: identify, recruit and enroll suitable patients to participate in a clinical trial;
−Removed: have a sufficient number of patients complete a clinical trial or return for post-treatment follow-up;
−Removed: ensure that our third-party contractors and clinical investigators comply with clinical trial protocols, comply with regulatory requirements, or meet their obligations to us in a timely manner;
−Removed: address any patient safety concerns that arise during the course of a clinical trial;
−Removed: address any conflicts with new or existing laws or regulations;
−Removed: add a sufficient number of clinical trial sites;
−Removed: timely manufacture sufficient quantities of product candidate for use in clinical trials;
−Removed: raise sufficient capital to fund a clinical trial.
−Removed: Patient enrollment is a significant factor in the timing of clinical trials and is affected by many factors, including the size and nature of the patient population, the proximity of patients to clinical sites, the eligibility criteria for the clinical trial, the design of the clinical trial, competing clinical trials and clinicians’ and patients’ or caregivers’ perceptions as to the potential advantages of the drug candidate being studied in relation to other available therapies, including any new drugs or treatments that may be approved for the indications we are investigating.
−Removed: We could also encounter delays if a clinical trial is suspended or terminated by us, by the data safety monitoring board for such clinical trial or by the FDA or any other regulatory authority, or if the IRBs of the institutions in which such clinical trials are being conducted suspend or terminate the participation of their clinical investigators and sites subject to their review.
−Removed: Such authorities may suspend or terminate a clinical trial due to a number of factors, including failure to conduct the clinical trial in accordance with regulatory requirements, including Good Clinical Practices, or GCPs, or our clinical protocols, inspection of the clinical trial operations or clinical trial site by the FDA or other regulatory authorities resulting in the imposition of a clinical hold, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from using a product candidate, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial.
−Removed: In addition, even if such clinical trials are successfully completed, we cannot guarantee that the FDA or foreign regulatory authorities will interpret the results as we do, and more trials could be required before we submit our product candidates for approval.
−Removed: To the extent that the results of the trials are not satisfactory to the FDA or foreign regulatory authorities for support of a marketing application, we may be required to expend significant resources, which may not be available to us, to conduct additional trials in support of potential approval of our product candidates.
−Removed: Even if regulatory approval is secured for any of our product candidates, the terms of such approval may limit the scope and use of our product candidate, which may also limit its commercial potential.
−Removed: If we experience delays in the completion of, or termination of, any clinical trial of our product candidates for any reason, the commercial prospects of our product candidates may be harmed, and our ability to generate product revenues from any of these product candidates will be delayed.
−Removed: In addition, any delays in completing our clinical trials will increase our costs, slow down our product candidate development and approval process and jeopardize our ability to commence product sales and generate revenues.
−Removed: Any of these occurrences may significantly harm our business, financial condition and prospects.
−Removed: In addition, many of the factors that cause, or lead to, a delay in the commencement or completion of clinical trials may also ultimately lead to the denial of regulatory approval of our product candidates.
−Removed: We may be unable to obtain regulatory approval for our product candidates.
−Removed: The denial or delay of any such approval would delay commercialization and have a material adverse effect on our potential to generate revenue, our business and our results of operations.
−Removed: The research, development, testing, manufacturing, labeling, packaging, approval, promotion, advertising, storage, recordkeeping, marketing, distribution, post-approval monitoring and reporting, and export and import of biopharmaceutical products are subject to extensive regulation by the FDA, and by foreign regulatory authorities in other countries.
−Removed: These regulations differ from country to country.
−Removed: To gain approval to market our product candidates, we must provide regulatory authorities with substantial evidence of safety, purity and potency of the product for each indication we seek to commercialize.
−Removed: We have not yet obtained regulatory approval to market any of our product candidates in the U.S.
−Removed: or any other country.
−Removed: Our business depends upon obtaining these regulatory approvals.
−Removed: The FDA can delay, limit or deny approval of our product candidates for many reasons, including:
−Removed: our inability to satisfactorily demonstrate with substantial clinical evidence that the product candidates are safe, pure and potent for the requested indication;
−Removed: the FDA’s disagreement with our clinical trial protocol or the interpretation of data from preclinical studies or clinical trials;
−Removed: the population studied in the clinical trial not being sufficiently broad or representative to assess safety in the full population for which we seek approval;
−Removed: our inability to demonstrate that clinical or other benefits of our product candidates outweigh any safety or other perceived risks;
−Removed: the FDA’s determination that additional preclinical or clinical trials are required;
−Removed: the FDA’s non-approval of the labeling or the specifications of our product candidates;
−Removed: the FDA’s failure to accept the manufacturing processes or facilities of third-party manufacturers with which we may contract;
−Removed: for clinical trials conducted by the Immuno-Oncology Clinic, Inc., or the Clinic, a related party, the FDA or other regulatory authorities could view our study results as potentially biased even if we achieve such clinical trial endpoints;
−Removed: the potential for approval policies or regulations of the FDA to significantly change in a manner rendering our clinical data insufficient for approval.
−Removed: Even if we eventually successfully complete clinical testing and receive approval of any regulatory filing for our product candidates, the FDA may only grant approval contingent on the performance of costly additional post-approval clinical trials.
−Removed: The FDA may also approve our product candidates for a more limited indication or a narrower patient population than we originally requested, and the FDA may not approve the labeling that we believe is necessary or desirable for the successful commercialization of our product candidates.
−Removed: To the extent we seek regulatory approval in foreign countries, we may face challenges similar to those described above with regulatory authorities in applicable jurisdictions.
−Removed: Any delay in obtaining, or our inability to obtain, applicable regulatory approval for any of our product candidates would delay or prevent commercialization of our product candidates and would materially adversely impact our business, results of operations, financial condition and prospects.
−Removed: Use of our product candidates could be associated with side effects or adverse events.
−Removed: As with most biopharmaceutical products, use of our product candidates could be associated with side effects or adverse events, which can vary in severity and frequency.
−Removed: Side effects or adverse events associated with the use of our product candidates may be observed at any time, including in clinical trials or once a product is commercialized, and any such side effects or adverse events may negatively affect our ability to obtain regulatory approval or market our product candidates.
−Removed: Side effects such as toxicity or other safety issues associated with the use of our product candidates could require us to perform additional studies or halt development or sale of these product candidates or expose us to product liability lawsuits, which will harm our business.
−Removed: We may be required by regulatory agencies to conduct additional preclinical or clinical trials regarding the safety and efficacy of our product candidates, which we have not planned or anticipated.
−Removed: We cannot provide any assurance that we will resolve any issues related to any product-related adverse events to the satisfaction of the FDA or any regulatory agency in a timely manner or ever, which could harm our business, prospects and financial condition.
−Removed: Adverse events observed in our phase I clinical trials of aNK conducted at third party centers included several grade 1 and 2 transient fevers and chills and individual occurrences of back pain, a transient grade 4 hypoglycemia and transient hypotension, all responsive to supportive care.
−Removed: If we are successful in commercializing our product candidates, the FDA and other foreign regulatory agency regulations will require that we report certain information about adverse medical events if those products may have caused or contributed to those adverse events.
−Removed: The timing of our obligation to report would be triggered by the date we become aware of the adverse event , as well as the nature of the event.
−Removed: We may inadvertently fail to report adverse events we become aware of within the prescribed timeframe.
−Removed: We may also fail to appreciate that we have become aware of a reportable adverse event, especially if it is not reported to us as an adverse event or if it is an adverse event that is unexpected or removed in time from the use of our products.
−Removed: If we fail to comply with our reporting obligations, the FDA or other foreign regulatory agencies could take action including criminal prosecution, the imposition of civil monetary penalties, seizure of our products, or delay in approval or clearance of future products.
−Removed: The clinical and commercial utility of our aNK platform is uncertain and may never be realized.
−Removed: Our aNK platform is in the early stages of development.
−Removed: To date, aNK cells have only been evaluated in early clinical trials including four published phase I clinical safety trials in approximately 46 patients.
−Removed: These clinical trials were designed to evaluate safety and tolerability, and not designed to produce statistically significant results as to efficacy.
−Removed: Most of the data to date regarding aNK cells were derived from clinical trials not conducted by us, including physician-sponsored clinical trials, and utilizing product not manufactured by us but which we believe is comparable to aNK.
−Removed: The company currently has multiple ongoing clinical trials to evaluate cryopreserved haNK cells in company sponsored clinical trials.
−Removed: Success in early clinical trials does not ensure that large-scale clinical trials will be successful nor does it predict final results.
−Removed: In addition, we will not be able to treat patients if we cannot manufacture a sufficient quantity of NK cells that meet our minimum specifications.
−Removed: In addition, our haNK product candidate has only been tested in a small number of patients.
−Removed: Results from these clinical trials may not necessarily be indicative of the safety and tolerability or efficacy of our products as we expand into larger clinical trials.
−Removed: We may not ultimately be able to provide the FDA with substantial clinical evidence to support a claim of safety, purity and potency sufficient to enable the FDA to approve aNK platform product candidates for any indication.
−Removed: This may be because later clinical trials fail to reproduce favorable data obtained in earlier clinical trials, because the FDA disagrees with how we interpret the data from these clinical trials, or because the FDA does not accept these therapeutic effects as valid endpoints in pivotal clinical trials necessary for market approval.
−Removed: We will also need to demonstrate that aNK platform product candidates are safe.
−Removed: We do not have data on possible harmful long-term effects of aNK platform product candidates and do not expect to have this data in the near future.
−Removed: As a result, our ability to generate clinical safety and effectiveness data sufficient to support submission of a marketing application or commercialization of our aNK platform therapy is uncertain and is subject to significant risk.
−Removed: We have limited experience as a company conducting clinical trials and have relied and will rely on third parties and related parties to conduct many of our preclinical studies and clinical trials.
−Removed: Any failure by a third party, related party, or by us to conduct the clinical trials according to Good Clinical Practices and in a timely manner may delay or prevent our ability to seek or obtain regulatory approval for or commercialize our product candidates.
−Removed: Three of our four completed phase I clinical trials with aNK have been investigator-initiated studies sponsored by the investigator’s institution.
−Removed: To date, the only company sponsored studies to engage in patient enrollment have been for the following indications:
−Removed: Merkel cell, pancreatic, squamous head and neck, non-small cell lung, triple negative breast, AML, colorectal and advanced solid tumor.
−Removed: This relative lack of experience may contribute to our planned clinical trials not beginning or completing on time, if at all.
−Removed: In addition, we have entered into an agreement with the Clinic, a related party, to continue to conduct and oversee certain of our clinical trials.
−Removed: Large-scale clinical trials will require significant additional resources and reliance on Contract Research Organizations, or CROs, clinical investigators, or consultants.
−Removed: Consequently, our reliance on outside parties may introduce delays beyond our control.
−Removed: Our CROs, the Clinic, and other third parties must communicate and coordinate with one another in order for our trials to be successful.
−Removed: Additionally, our CROs, the Clinic, and other third parties may also have relationships with other commercial entities, some of which may compete with us.
−Removed: If our CROs, the Clinic, or other third parties conducting our clinical trials do not perform their contractual duties or regulatory obligations, experience work stoppages, do not meet expected deadlines, terminate their agreements with us or need to be replaced, or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical trial protocols, GCPs, or other regulatory requirements or for any other reason, we may need to conduct additional clinical trials or enter into new arrangements with alternative CROs, clinical investigators or other third parties.
−Removed: We may be unable to enter into arrangements with alternative CROs on commercially reasonable terms, or at all.
−Removed: We, the Clinic, and the third parties upon which we rely are required to comply with GCPs.
−Removed: GCPs are regulations and guidelines enforced by regulatory authorities around the world, through periodic inspections, for products in clinical development.
−Removed: If we or these third parties fail to comply with applicable GCP regulations, the clinical data generated in our clinical trials may be deemed unreliable and have to be repeated, and our submission of marketing applications may be delayed or the regulatory authorities may require us to perform additional clinical trials before approving our marketing applications.
−Removed: We are subject to the risk that, upon inspection, a regulatory authority will determine that any of our clinical trials fail to comply or failed to comply with applicable GCP regulations.
−Removed: In addition, our clinical trials must be conducted with material produced under GMP and Good Tissue Practice, or GTP, regulations, which are enforced by regulatory authorities.
−Removed: In addition, our clinical trials must be conducted with material produced under GMP regulations, which are enforced by regulatory authorities.
−Removed: Our failure to comply with these regulations may require us to repeat clinical trials, which would delay the regulatory approval process.
−Removed: Moreover, our business may be significantly impacted if our CROs, the Clinic, clinical investigators or other third parties violate federal or state healthcare fraud and abuse or false claims laws and regulations or healthcare privacy and security laws.
−Removed: We also anticipate that part of our strategy for pursuing the wide range of indications potentially addressed by our aNK, haNK, taNK and t‑haNK platforms will involve further investigator-initiated clinical trials.
−Removed: While these trials generally provide us with valuable clinical data that can inform our future development strategy in a cost-efficient manner, we generally have less control over not only the conduct but also the design of these clinical trials.
−Removed: Third-party investigators may design clinical trials involving our product candidates with clinical endpoints that are more difficult to achieve or in other ways that increase the risk of negative clinical trial results compared to clinical trials we may design on our own.
−Removed: Negative results in investigator-initiated clinical trials, regardless of how the clinical trial was designed or conducted, could have a material adverse effect on our prospects and the perception of our product candidates.
−Removed: Moreover, principal investigators for our clinical trials may serve as scientific advisors or consultants to us from time to time and receive compensation in connection with such services.
−Removed: In addition, some of our trials are being run by the Clinic, which is controlled by one of our employees.
−Removed: Under certain circumstances, the company may be required to report some of these relationships to the FDA.
−Removed: The FDA may conclude that a financial relationship between the company, the Clinic and/or a principal investigator has created a conflict of interest or otherwise affected interpretation of the study.
−Removed: The FDA may therefore question the integrity of the data generated at the applicable clinical trial site and the utility of the clinical trial itself may be jeopardized.
−Removed: This could result in a delay in approval, or rejection, of our marketing applications by the FDA and may ultimately lead to the denial of regulatory approval of one or more of our product candidates.
−Removed: We are heavily dependent on our senior management, particularly Drs.
−Removed: Patrick Soon-Shiong and Barry Simon, and a loss of a member of our senior management team in the future, even if only temporary, could harm our business.
−Removed: If we lose members of our senior management for a short or an extended time, we may not be able to find appropriate replacements on a timely basis, and our business could be adversely affected.
−Removed: Our existing operations and continued future development depend to a significant extent upon the performance and active participation of certain key individuals, including Drs.
−Removed: Patrick Soon-Shiong, our Chairman and CEO and our principal stockholder, and Barry Simon, our President and Chief Administrative Officer.
−Removed: Soon-Shiong focuses heavily on NantKwest matters and is highly active in our management, he does devote a certain amount of his time to a number of different endeavors and companies, including ImmunityBio and NantWorks, which is a collection of multiple companies in the healthcare and technology space.
−Removed: The risks related to our dependence upon Dr.
−Removed: Soon-Shiong are particularly acute given his ownership percentage, the commercial and other relationships that we have with entities affiliated with him, role in our company and reputation.
−Removed: If we were to lose Drs.
−Removed: Soon-Shiong or Simon for a short or an extended time, for any reason, including the contraction of COVID‑19, we may not be able to find appropriate replacements on a timely basis and our financial condition and results of operations could be materially adversely affected.
−Removed: Competition for qualified personnel in the biotechnology and pharmaceuticals industry is intense due to the limited number of individuals who possess the skills and experience required.
−Removed: To induce valuable employees to remain at our company, in addition to salary and cash incentives, we have provided stock options, warrants, and restricted stock units that vest over time.
−Removed: Additionally, we provided warrants that vested upon the achievement of certain performance milestones to Dr.
−Removed: These performance warrants provided to Dr.
−Removed: Soon-Shiong were exercised in full in March 2019.
−Removed: The value to employees of stock options, warrants, and restricted stock units that vest over time may be significantly affected by movements in our stock price that are beyond our control, and may at any time be insufficient to counteract more lucrative offers from other companies.
−Removed: Despite our efforts to retain valuable employees, members of our management, scientific and development teams may terminate their employment with us on short notice.
−Removed: We face significant competition for employees, particularly scientific personnel, from other biopharmaceutical companies, which include both publicly traded and privately held companies, and we may not be able to hire new employees quickly enough to meet our needs.
−Removed: Although we have employment agreements with our key employees, these employment agreements provide for at-will employment, which means that any of our employees could leave our employment at any time, with or without notice.
−Removed: Except with respect to Dr.
−Removed: Simon, we do not maintain “key man” insurance policies on the lives of these individuals or the lives of any of our other employees.
−Removed: We may not be able to attract and retain quality personnel on acceptable terms, or at all, which may cause our business and operating results to suffer.
−Removed: Soon-Shiong, our Chairman and CEO and our principal stockholder, has significant interests in other companies which may conflict with our interests.
−Removed: Our Chairman and CEO, Dr.
−Removed: Soon-Shiong, is the founder of NantWorks.
−Removed: The various NantWorks companies are currently exploring opportunities in the immunotherapy, infectious disease and inflammatory disease fields.
−Removed: In particular, we have agreements with a number of related parties that provide services, technology and equipment for use in our efforts to develop our product pipeline.
−Removed: Soon-Shiong holds a controlling interest, either directly or indirectly, in these entities.
−Removed: Consequently, Dr.
−Removed: Soon-Shiong’s interests may not be aligned with our other stockholders and he may from time to time be incentivized to take certain actions that benefit his other interests and that our other stockholders do not view as being in their interest as investors in our company.
−Removed: In addition, other companies affiliated with Dr.
−Removed: Soon-Shiong may compete with us for business opportunities or, in the future, develop products that are competitive with ours (including products in other therapeutic fields which we may target in the future).
−Removed: Moreover, even if they do not directly relate to us, actions taken by Dr.
−Removed: Soon-Shiong and the companies with which he is involved could impact us.
−Removed: We are also pursuing supply arrangements for various investigational agents controlled by affiliates to be used in our clinical trials.
−Removed: Soon-Shiong was to cease his affiliation with us, ImmunityBio, or with NantWorks, these entities may be unwilling to continue these relationships with us on commercially reasonable terms, or at all, and as a result may impede our ability to control the supply chain for our combination therapies.
−Removed: These collaboration agreements do not typically specify how sales will be apportioned between the parties upon successful commercialization of the product.
−Removed: As a result, we cannot guarantee that we will receive a percentage of the revenue that is at least proportional to the costs that we will incur in commercializing the product candidate.
−Removed: Furthermore, in November 2015, we entered into a Shared Services Agreement with NantWorks, pursuant to which NantWorks and/or any of its affiliates provides corporate, general and administrative, manufacturing strategy, research and development, regulatory and clinical trial strategy, and other support services to us and our subsidiaries.
−Removed: Soon-Shiong was to cease his affiliation with us or with NantWorks, we may be unable to establish or maintain this relationship with NantWorks on a commercially reasonable basis, if at all.
−Removed: As a result, we could experience a lack of business continuity due to loss of historical and institutional knowledge and a lack of familiarity of new employees and/or new service providers with business processes, operating requirements, policies and procedures, and we may incur additional costs as new employees and/or service providers gain necessary experience, particularly in connection with issues or concerns we may have as a public company.
−Removed: In addition, the loss of the services of NantWorks might significantly delay or prevent the development of our products or achievement of other business objectives by diverting management’s attention to transition matters and identification of suitable replacements, if any, and could have a material adverse effect on our business and results of operations.
−Removed: We will need to grow the size and capabilities of our organization, and we may experience difficulties in managing this growth.
−Removed: To effect our business plan, we will need to add other management, accounting, regulatory, manufacturing and scientific staff.
−Removed: As of December 31, 2019, we had 148 employees.
−Removed: We will need to attract, retain and motivate a significant number of new additional managerial, operational, sales, marketing, financial, and other personnel, as well as highly skilled scientific and medical personnel, and to expand our capabilities to successfully pursue our research, development, manufacturing and commercialization efforts and secure collaborations to market and distribute our products.
−Removed: This growth may strain our existing managerial, operational, financial and other resources.
−Removed: We also intend to add personnel in our research and development and manufacturing departments as we expand our clinical trial and research capabilities.
−Removed: Moreover, we may need to hire additional accounting and other personnel and augment our infrastructure as a result of operating as a public company.
−Removed: Any inability to attract and retain qualified employees to enable our planned growth and establish additional capabilities or our failure to manage our growth effectively could delay or curtail our product development and commercialization efforts and harm our business.
−Removed: We have limited manufacturing experience and may not be able to manufacture haNK, taNK or t ‑ haNK cells on a large scale or in a cost-effective manner.
−Removed: haNK, taNK and t‑haNK cells have been grown in various quantities in closed cell culture systems and intermediate to larger-scale bioreactors.
−Removed: With all manufacturing efforts being conducted in-house, we will need to develop the ability to grow haNK, taNK and t‑haNK cells on a large-scale basis in a cost efficient manner.
−Removed: While we have made great strides with our haNK production, including a validated cryopreserved form of the product, we have not demonstrated the ability to manufacture these cells beyond quantities sufficient for our clinical programs.
−Removed: We have not demonstrated the ability to manufacture our taNK and t‑haNK cells beyond quantities sufficient for research and development and limited clinical activities.
−Removed: We have also experienced increases in manufacturing costs and sporadic decreases in manufacturing yield of both haNK, taNK and t‑haNK cells.
−Removed: In addition, we have no experience manufacturing our NK cells specifically at the capacity that will be necessary to support commercial sales.
−Removed: The novel nature of our technology also increases the complexity and risk in the manufacturing process.
−Removed: In 2017, we opened our Culver City, California, site for the manufacture of cryopreserved haNK cells for our planned clinical trials and finished the build-out of our larger El Segundo, California, site in 2018 for the manufacture of our haNK, taNK and t‑haNK cells for our clinical trials and, if we receive
−Removed: FDA approval, initial commercialization.
−Removed: However, we may encounter difficulties in obtaining the approvals for, and designing, constructing, validating and operating, any new manufacturing facility.
−Removed: We may also be unable to hire the qualified personnel that we will require to accommodate the expansion of our operations and manufacturing capabilities.
−Removed: If we relocate our manufacturing activities to a new facility during or after a pivotal clinical trial, we may be unable to obtain regulatory approval unless and until we demonstrate to the FDA’s satisfaction the similarity of our haNK, taNK and t ‑haNK cells manufactured in the new facility to our cells manufactured in prior facilities.
−Removed: If we cannot adequately demonstrate similarity to the FDA, we could be required to repeat clinical trials, which would be expensive, and would substantially delay regulatory approval.
−Removed: Because our product candidates are cell-based, their manufacture is complicated.
−Removed: In addition, we rely on certain third party suppliers for manufacturing supplies such as X‑VIVO 10 media to grow and produce our cells.
−Removed: Reliance on such third-party suppliers exposes us to supply interruptions and shortages that could have an adverse effect on our ability to produce product.
−Removed: Moreover, our present production process may not meet our initial expectations as to reproducibility, yield, purity or other measurements of performance.
−Removed: Any supply interruption from third parties and entities that are affiliated with Patrick Soon-Shiong and/or NantWorks could materially harm our ability to manufacture our product candidates until a new source of supply, if any, could be identified and qualified.
−Removed: We may be unable to find a sufficient alternative supply channel in a reasonable time or on commercially reasonable terms.
−Removed: In addition, we may have to customize a bioreactor system to our manufacturing process.
−Removed: Because our manufacturing process is unproven, we may never successfully commercialize our products.
−Removed: In addition, because the clinical trials were conducted using a system that will not be sufficient for commercial quantities, we may have to show comparability of the different versions of systems we have used.
−Removed: For these and other reasons, we may not be able to manufacture haNK, taNK and t‑haNK cells on a large scale or in a cost-effective manner.
−Removed: aNK platform cells have been produced at academic institutions associated with our other clinical trial sites.
−Removed: In the past, the lack of production of aNK platform cells has caused delays in the commencement of our clinical trials.
−Removed: We have been establishing NK cell production capacity to meet anticipated demand for our planned clinical trials but may not be able to successfully build out our capacity to meet our current and anticipated future needs.
−Removed: Any damage to or destruction of our facility and equipment, prolonged power outage, contamination or shut down by the FDA or other regulatory authority could significantly impair or curtail our ability to produce haNK, taNK and t‑haNK cells.
−Removed: We are dependent on third parties to store our aNK, haNK, taNK and t ‑ haNK cells, and any damage or loss to our master cell bank would cause delays in replacement, and our business could suffer.
−Removed: The aNK cells of our master and working cell banks are stored in freezers at a third party biorepository and also stored in our freezers at our production facility.
−Removed: If these cells are damaged at both facilities, including by the loss or malfunction of these freezers or our back-up power systems, as well as by damage from fire, power loss or other natural disasters, we would need to establish replacement master and working cell banks, which would impact clinical supply and delay our patients’ treatments.
−Removed: If we are unable to establish replacement cell banks, we could incur significant additional expenses and liability to patients whose treatment is delayed, and our business could suffer.
−Removed: If we or any of our third party manufacturers that we may use do not maintain high standards of manufacturing, our ability to develop and commercialize haNK, taNK or t‑haNK cells could be delayed or curtailed.
−Removed: We and any third parties that we may use in the future to manufacture our products must continuously adhere to cGMP regulations rigorously enforced by the FDA through its facilities inspection program.
−Removed: If our facilities or the facilities of third parties who we may use in the future to produce our products do not pass a pre-approval inspection, the FDA will not grant market approval for haNK, taNK or t‑haNK cells.
−Removed: In complying with cGMP, we and any third-party manufacturers must expend significant time, money and effort in production, record keeping and quality control to assure that each component of our haNK, taNK or t‑haNK cell therapies meets applicable specifications and other requirements.
−Removed: We or any of these third-party manufacturers may also be subject to comparable or more stringent regulations of foreign regulatory authorities.
−Removed: If we or any of our third-party manufacturers fail to comply with these requirements, we may be subject to regulatory action, which could delay or curtail our ability to develop, obtain regulatory approval of, and commercialize haNK, taNK or t‑haNK cells.
−Removed: If our component part manufacturers and suppliers fail to provide components of sufficient quality, that meet our required specifications, our clinical trials or commercialization of haNK, taNK or t‑haNK cells could be delayed or halted, and we could face product liability claims.
−Removed: If we or any of our third-party manufacturers that we may engage use hazardous and biological materials in a manner that causes injury or violates applicable law, we may be liable for damages.
−Removed: Our research and development activities involve the controlled use of potentially hazardous substances, including chemical and biological materials, by us and any third-party manufacturers that we may use in the future.
−Removed: We and any of our third party manufacturers that we may engage are subject to federal, state and local laws and regulations in the U.S.
−Removed: governing the use, manufacture, storage, handling and disposal of medical and hazardous materials.
−Removed: Although we believe that our procedures for using, storing and disposing of these materials comply with legally prescribed standards, we cannot completely eliminate the risk of contamination or injury resulting from medical or hazardous materials.
−Removed: As a result of any such contamination or injury, we may incur liability or local, city, state or federal authorities may curtail the use of these materials and interrupt our business operations.
−Removed: In the event of an accident, we could be held liable for damages or penalized with fines, and the liability could exceed our resources.
−Removed: We do not have any insurance for liabilities arising from medical or hazardous materials.
−Removed: Compliance with applicable environmental laws and regulations is expensive, and current or future environmental regulations may impair our research, development and production efforts, which could harm our business, prospects, financial condition or results of operations.
−Removed: We have not yet developed a validated methodology for freezing and thawing large quantities of taNK and t ‑ haNK cells, which we believe will be required for the storage and distribution of our taNK and t ‑ haNK product candidates.
−Removed: We have not demonstrated that taNK and t‑haNK cells can be frozen and thawed in large quantities without damage, in a cost-efficient manner and without degradation over time.
−Removed: We may encounter difficulties not only in developing freezing and thawing methodologies, but also in obtaining the necessary regulatory approvals for using such methodologies in treatment.
−Removed: If we cannot adequately demonstrate similarity of our frozen product to the unfrozen form to the satisfaction of the FDA, we could face substantial delays in our regulatory approvals.
−Removed: If we are unable to freeze taNK and t‑haNK cells for shipping purposes, our ability to promote adoption and standardization of our products, as well as achieve economies of scale by centralizing our production facility, will be limited.
−Removed: Even if we are able to successfully freeze and thaw taNK and t‑haNK cells in large quantities, we will still need to develop a cost-effective and reliable distribution and logistics network, which we may be unable to accomplish.
−Removed: For these and other reasons, we may not be able to commercialize haNK, taNK or t‑haNK cells on a large scale or in a cost-effective manner.
−Removed: We rely on third party healthcare professionals to administer haNK, taNK or t ‑ haNK cells to patients, and our business could be harmed if these third parties administer these cells incorrectly.
−Removed: We rely on the expertise of physicians, nurses and other associated medical personnel to administer haNK, taNK or t‑haNK cells to clinical trial patients.
−Removed: If these medical personnel are not properly trained to administer, or do not properly administer, haNK, taNK or t‑haNK cells, the therapeutic effect of haNK, taNK or t‑haNK cells may be diminished or the patient may suffer injury.
−Removed: In addition, if we achieve the ability to freeze and thaw our taNK and t‑haNK cells, third party medical personnel will have to be trained on proper methodology for thawing haNK, taNK or t‑haNK cells received from us.
−Removed: If this thawing is not performed correctly, the cells may become damaged and/or the patient may suffer injury.
−Removed: While we intend to provide training materials and other resources to these third-party medical personnel, the thawing of haNK, taNK or t‑haNK cells will occur outside our supervision and may not be administered properly.
−Removed: If, due to a third-party error, people believe that haNK, taNK or t‑haNK cells are ineffective or harmful, the desire to use haNK, taNK or t‑haNK cells may decline, which would negatively impact our business, reputation and prospects.
−Removed: We may also face significant liability even though we may not be responsible for the actions of these third parties.
−Removed: Even if any of our product candidates receive regulatory approvals, they may fail to achieve the broad degree of market acceptance and use necessary for commercial success.
−Removed: Any potential future commercial success of any of our product candidates will depend, among other things, on its acceptance by physicians, patients, healthcare payors, and other members of the medical community as a therapeutic and cost-effective alternative to commercially available products.
−Removed: Because only a few cell-based therapy products have been commercialized, we do not know to what extent cell-based immunotherapy products will be accepted as therapeutic alternatives.
−Removed: If we fail to gain market acceptance, we may not be able to earn sufficient revenues to continue our business.
−Removed: Market acceptance of, and demand for, any product that we may develop, if approved for commercial sale, will depend on many factors, including:
−Removed: our ability to provide substantial evidence of safety and efficacy;
−Removed: convenience and ease of administration;
−Removed: prevalence and severity of adverse side effects;
−Removed: availability of alternative and competing treatments;
−Removed: cost effectiveness;
−Removed: the ability to offer appropriate patient access programs, such as co-pay assistance;
−Removed: the extent to which physicians recommend our products to their patients;
−Removed: effectiveness of our marketing and distribution strategy and pricing of any product that we may develop;
−Removed: publicity concerning our products or competitive products;
−Removed: our ability to obtain sufficient third-party coverage and adequate reimbursement.
−Removed: If haNK, taNK and t‑haNK cells are approved for use, but fail to achieve the broad degree of market acceptance necessary for commercial success, our operating results and financial condition will be adversely affected.
−Removed: In addition, even if haNK, taNK and t‑haNK cells gain acceptance, the markets for treatment of patients with our target indications may not be as significant as we estimate.
−Removed: Even if we are able to commercialize any product candidates, such products may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, which would harm our business.
−Removed: The regulations that govern marketing approvals, pricing and reimbursement for new drugs vary widely from country to country.
−Removed: Some countries require approval of the sale price of a drug before it can be marketed.
−Removed: In many countries, the pricing review period begins after marketing or product licensing approval is granted.
−Removed: In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted.
−Removed: As a result, we might obtain marketing approval for a product in a particular country, but then be subject to price regulations that delay the commercial launch of the product and negatively impact the revenue we are able to generate from the sale of the product in that country.
−Removed: Adverse pricing limitations may hinder our ability to recoup our investment in one or more product candidates, even if any product candidates we may develop obtain marketing approval.
−Removed: Our ability to successfully commercialize any products that we may develop also will depend in part on the extent to which reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations.
−Removed: Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels.
−Removed: A primary trend in the U.S.
−Removed: healthcare industry and elsewhere is cost containment.
−Removed: Government authorities and third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications.
−Removed: Reimbursement may impact the demand for, or the price of, any product candidate for which we obtain marketing approval.
−Removed: Government authorities also impose mandatory discounts for certain patient groups and may seek to increase such discounts at any time.
−Removed: Future regulation may negatively impact the price of our products, if approved.
−Removed: It may be difficult to promptly obtain coverage and profitable payment rates from both the government-funded and private payors for any of our approved product candidates, and this may have a material adverse effect on our operating results, our ability to raise capital and our overall financial condition.
−Removed: There are risks inherent in our business that may subject us to potential product liability suits and other claims, which may require us to engage in expensive and time-consuming litigation or pay substantial damages and may harm our reputation and reduce the demand for our product.
−Removed: Our business exposes us to product liability risks, which are inherent in the testing, manufacturing, marketing and sale of biopharmaceutical products.
−Removed: We will face an even greater risk of product liability if we commercialize haNK, taNK and t‑haNK cells.
−Removed: For example, we may be sued if any product we develop allegedly causes or is perceived to cause injury or is found to be otherwise unsuitable during product testing, manufacturing, marketing or sale.
−Removed: Any such product liability claims may include allegations of defects in manufacturing, defects in design, a failure to warn of dangers inherent in the product, negligence, strict liability and a breach of warranties.
−Removed: Claims could also be asserted under state consumer protection acts.
−Removed: If we cannot successfully defend ourselves against product liability claims, we may incur substantial liabilities or be required to limit commercialization of our products.
−Removed: Even a successful defense would require significant financial and management resources.
−Removed: Certain aspects of how haNK, taNK and t‑haNK cells are processed and administered may increase our exposure to liability.
−Removed: Medical personnel administer haNK, taNK and t‑haNK cells to patients intravenously in an outpatient procedure.
−Removed: This procedure poses risks to the patient similar to those occurring with infusions of other cell products, such as T‑cells and stem cells, including blood clots, infection and mild to severe allergic reactions.
−Removed: Additionally, haNK, taNK and t‑haNK cells or components of our haNK, taNK and t‑haNK cell therapy may cause unforeseen harmful side effects.
−Removed: For example, a patient receiving haNK, taNK and/or t‑haNK cells could have a severe allergic reaction or could develop an autoimmune condition to materials infused with the haNK, taNK and/or t‑haNK cells.
−Removed: In addition, we have not conducted studies on the long-term effects associated with the media that we use to grow our haNK, taNK and t ‑haNK cells.
−Removed: Similarly, we expect to use media in freezing our haNK, taNK and t ‑haNK cells for shipment.
−Removed: These media could contain substances that have proved harmful if used in certain quantities.
−Removed: As we continue to develop our haNK, taNK and t ‑haNK cell therapy, we may encounter harmful side effects that we did not previously observe in our prior studies and clinical trials.
−Removed: Additionally, the discovery of unforeseen side effects of haNK, taNK and t ‑haNK cells could also lead to lawsuits against us.
−Removed: Regardless of merit or eventual outcome, product liability or other claims may, among other things, result in:
−Removed: decreased demand for any approved products;
−Removed: injury to our reputation and significant negative media attention;
−Removed: withdrawal of clinical trial participants or cancellation of clinical trials;
−Removed: costs to defend the related litigation;
−Removed: a diversion of management’s time and our resources;
−Removed: substantial monetary awards to clinical trial participants or patients;
−Removed: regulatory investigations, product recalls, withdrawals or labeling, marketing or promotional restrictions;
−Removed: exhaustion of any available insurance and our capital resources;
−Removed: loss of revenue;
−Removed: a potential decrease in our share price;
−Removed: the inability to commercialize any products we develop.
−Removed: Our inability to obtain and maintain sufficient product liability insurance at an acceptable cost and scope of coverage to protect against potential product liability claims could prevent or inhibit the commercialization of our products.
−Removed: We obtained product liability insurance covering our clinical trials with policy limits that we believe are customary for similarly situated companies and adequate to provide us with coverage for foreseeable risks.
−Removed: Although we maintain such insurance, any claim that may be brought against us could result in a court judgment or settlement in an amount that is not covered, in whole or in part, by our insurance or that is in excess of the limits of our insurance coverage.
−Removed: If we determine that it is prudent to increase our product liability coverage due to the commercial launch of any approved product, we may be unable to obtain such increased coverage on acceptable terms, or at all.
−Removed: Our insurance policies also have various exclusions and deductibles, and we may be subject to a product liability claim for which we have no coverage.
−Removed: We will have to pay any amounts awarded by a court or negotiated in a settlement that exceed our coverage limitations or that are not covered by our insurance, and we may not have, or be able to obtain, sufficient capital to pay such amounts.
−Removed: Moreover, in the future, we may not be able to maintain insurance coverage at a reasonable cost or in sufficient amounts to protect us against losses.
−Removed: If and when we obtain approval for marketing our product candidates, we intend to expand our insurance coverage to include the sale of the applicable products;
−Removed: however, we may be unable to obtain this liability insurance on commercially reasonable terms.
−Removed: If a successful product liability or other claim or series of claims is brought against us for uninsured liabilities or in excess of insured liabilities, our assets may not be sufficient to cover these claims and our business operations could suffer.
−Removed: We currently have no marketing and sales organization and have no experience in marketing products.
−Removed: If we are unable to establish marketing and sales capabilities or enter into agreements with third parties to market and sell our product candidates, we may not be able to generate product revenue.
−Removed: We currently have no sales, marketing or distribution capabilities and have no experience as a company in marketing products.
−Removed: If we develop internal sales, marketing and distribution organization, this would require significant capital expenditures, management resources and time, and we would have to compete with other pharmaceutical and biotechnology companies to recruit, hire, train and retain marketing and sales personnel.
−Removed: If we are unable or decide not to establish internal sales, marketing and distribution capabilities, we expect to pursue collaborative arrangements regarding the sales, marketing and distribution of our products.
−Removed: However, we may not be able to establish or maintain such collaborative arrangements, or if we are able to do so, their sales forces may not be successful in marketing our products.
−Removed: Any revenue we receive would depend upon the efforts of such third parties, which may not be successful.
−Removed: We may have little or no control over the sales, marketing and distribution efforts of such third parties and our revenue from product sales may be lower than if we had commercialized our product candidates ourselves.
−Removed: We also face competition in our search for third parties to assist us with the sales, marketing and distribution efforts of our product candidates.
−Removed: There can be no assurance that we will be able to develop internal sales, marketing and distribution capabilities or establish or maintain relationships with third-party collaborators to commercialize any product in the U.S.
−Removed: A variety of risks associated with marketing our product candidates internationally could materially adversely affect our business.
−Removed: We plan to seek regulatory approval of our product candidates outside of the U.S.
−Removed: and, accordingly, we expect that we will be subject to additional risks related to operating in foreign countries if we obtain the necessary approvals, including:
−Removed: differing regulatory requirements in foreign countries;
−Removed: unexpected changes in tariffs, trade barriers, price and exchange controls and other regulatory requirements;
−Removed: economic weakness, including inflation, or political instability in particular foreign economies and markets;
−Removed: compliance with tax, employment, immigration and labor laws for employees living or traveling abroad;
−Removed: foreign taxes, including withholding of payroll taxes;
−Removed: foreign currency fluctuations, which could result in increased operating expenses and reduced revenue, and other obligations incident to doing business in another country;
−Removed: difficulties staffing and managing foreign operations;
−Removed: workforce uncertainty in countries where labor unrest is more common than in the U.S.;
−Removed: differing payor reimbursement regimes, governmental payors or patient self-pay systems, and price controls;
−Removed: potential liability under the Foreign Corrupt Practices Act of 1977 or comparable foreign regulations;
−Removed: challenges enforcing our contractual and intellectual property rights, especially in those foreign countries that do not respect and protect intellectual property rights to the same extent as the U.S.;
−Removed: production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad;
−Removed: the impact of public health epidemics on the global economy, such as the coronavirus currently impacting China and elsewhere;
−Removed: business interruptions resulting from geo-political actions, including war and terrorism.
−Removed: These and other risks associated with international operations may materially adversely affect our ability to attain or maintain profitable operations.
−Removed: We have formed, and may in the future form or seek, strategic alliances or enter into additional licensing arrangements in the future, and we may not realize the benefits of such alliances or licensing arrangements.
−Removed: We have formed, and may in the future form or seek, strategic alliances, create joint ventures or collaborations or enter into additional licensing arrangements with third parties that we believe will complement or augment our development and commercialization efforts with respect to our product candidates and any future product candidates that we may develop.
−Removed: For example, we entered into an agreement whereby Viracta granted to us exclusive world-wide rights to Viracta’s phase II drug candidate, VRx‑3996, for use in combination with our platform of NK cell therapies.
−Removed: However, if Viracta fails to raise sufficient capital to complete their pivotal phase II trial, if their trial is unsuccessful, or if our future clinical trial of NK cell therapy in combination with VRx‑3996 fails, the value of the Viracta license would be materially adversely affected.
−Removed: Any of these relationships may require us to incur non-recurring and other charges, increase our near and long-term expenditures, issue securities that dilute our existing stockholders or disrupt our management and business.
−Removed: In addition, we face significant competition in seeking appropriate strategic partners and the negotiation process is time-consuming and complex.
−Removed: Moreover, we may not be successful in our efforts to establish a strategic partnership or other alternative arrangements for our product candidates because they may be deemed to be at too early of a stage of development for collaborative effort and third parties may not view our product candidates as having the requisite potential to demonstrate safety and efficacy.
−Removed: If we license products or businesses, we may not be able to realize the benefit of such transactions if we are unable to successfully integrate them with our existing operations and company culture.
−Removed: We cannot be certain that, following a strategic transaction or license, we will achieve the revenue or specific net income that justifies such transaction.
−Removed: Any delays in entering into new strategic partnership agreements related to our product candidates could delay the development and commercialization of our product candidates in certain geographies for certain indications, which would harm our business prospects, financial condition and results of operations.
−Removed: Our internal computer systems, or those used by our contractors or consultants, may fail or suffer security breaches.
−Removed: Our business model involves the storage and transmission of clinical trial and other data on our systems and on the systems of our consultants and contractors, and security breaches expose us to a risk of loss of this information, governmental fines and penalties, litigation and/or potential liability, in addition to negative publicity.
−Removed: Despite the implementation of security measures, our internal computer systems and those of our contractors and consultants are vulnerable to damage from computer viruses and unauthorized access.
−Removed: Our security measures and those of our contractors and consultants may also be breached due to employee error, malfeasance or otherwise.
−Removed: If such an event were to occur and cause interruptions in our operations, it could result in a material disruption of our development programs and our business operations.
−Removed: For example, the loss of clinical trial data from completed, ongoing or future clinical trials could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data.
−Removed: Likewise, we rely on affiliated entities and third parties for research and development of our product candidates and to conduct clinical trials and may rely on third parties for the manufacture of our product candidates and similar events relating to their computer systems could have a material adverse effect on our business.
−Removed: We expect that these risks and exposures related to our internal computer systems will remain high for the foreseeable future due to the rapidly evolving nature and sophistication of cyber threats to our internal computer systems.
−Removed: There can be no assurance that our efforts to implement adequate security measures will remain sufficient to protect the company against future cyber-attacks.
−Removed: To the extent that any disruption or security breach were to result in a loss of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability, suffer damage to our reputation, the further development and commercialization of our product candidates could be delayed and our stock price could decline.
−Removed: Future acquisitions and investments could disrupt our business and harm our financial condition and operating results.
−Removed: Our success may depend, in part, on our ability to expand our products and services.
−Removed: In some circumstances, we may determine to do so through the acquisition of complementary businesses and technologies rather than through, or in conjunction with, internal development.
−Removed: The identification of suitable acquisition candidates can be difficult, time-consuming and costly, and we may not be able to successfully complete identified acquisitions.
−Removed: The risks we face in connection with acquisitions include:
−Removed: diversion of management time and focus from operating our business to addressing acquisition integration challenges;
−Removed: retention of key employees from the acquired company;
−Removed: coordination of research and development functions;
−Removed: integration of the acquired company’s accounting, management information, human resources and other administrative systems;
−Removed: liability for activities of the acquired company before the acquisition, including intellectual property infringement claims, employee disputes, and alleged violations of laws;
−Removed: unanticipated write-offs or charges.
−Removed: Our failure to address these risks or other problems encountered in connection with our past or future acquisitions and investments could cause us to fail to realize the anticipated benefits of these acquisitions or investments, cause us to incur unanticipated liabilities, and harm our business generally.
−Removed: Future acquisitions could also result in dilutive issuances of our equity securities, the incurrence of debt, contingent liabilities, amortization expenses, incremental operating expenses or the write-off of goodwill, any of which could harm our financial condition or operating results.
−Removed: Business disruptions could seriously harm our future revenue and financial condition and increase our costs and expenses.
−Removed: Our operations, and those of our contractors and consultants, could be subject to earthquakes, power shortages, telecommunications failures, water shortages, floods, hurricanes, typhoons, fires, extreme weather conditions, medical epidemics, acts of terrorism, acts of war and other natural or man-made disasters or business interruptions, for which we are predominantly self-insured.
−Removed: The occurrence of any of these business disruptions could seriously harm our operations and financial condition and increase our costs and expenses.
−Removed: We may rely on third-party manufacturers to produce and process our product candidates.
−Removed: Our ability to obtain clinical supplies of our product candidates could be disrupted if the operations of these suppliers are affected by a man-made or natural disaster, pandemics, epidemics, or other business interruption, including the recent novel strain of coronavirus (SARS‑CoV‑2) that originally surfaced in Wuhan, China in December 2019.
−Removed: The extent to which COVID‑19 impacts our business will depend on future developments, which are highly uncertain and cannot be predicted, including new information which may emerge concerning the severity of COVID‑19 and the actions to contain SARS‑CoV‑2 or treat its impact, among others.
−Removed: If any disaster were to occur, our ability to operate our clinical trials could be seriously, or potentially completely, impaired.
−Removed: Our corporate headquarters are in California near major earthquake faults and fire zones.
−Removed: Our operations and financial condition could suffer in the event of a major earthquake, fire or other natural disaster.
−Removed: A coronavirus pandemic is ongoing in many parts of the world and may result in significant disruptions to our clinical trials and/or supply chain which could have a material adverse effect on our business.
−Removed: A coronavirus pandemic exists as of the filing of this report.
−Removed: As the pandemic is still evolving as of this time, much of its impact remains unknown, and it is impossible to predict the impact it may have on the development of our business.
−Removed: The coronavirus pandemic may result in significant delays or disruptions in our clinical trials, which could affect or delay the regulatory approval process of our product candidates.
−Removed: If the patients involved with these clinical trials become infected with the coronavirus disease, we may have more adverse events and deaths in our clinical trials as a result.
−Removed: We may also face difficulties enrolling patients in our clinical trials if the patient populations that are eligible for our clinical trials are impacted by the coronavirus pandemic.
−Removed: Additionally, if our clinical trial patients are unable to travel to our clinical trial sites as a result of quarantines or other restrictions resulting from the coronavirus pandemic, we may experience higher drop-out rates or delays in our clinical trials.
−Removed: The severity of the coronavirus pandemic could also make access to our existing supply chain difficult or impossible by delaying the delivery of key raw materials used in our product candidates and therefore delay the delivery of such products for use in our clinical trials.
−Removed: Any of these results could materially impact our business and have an adverse effect on our business.
−Removed: Our employees, affiliates, independent contractors, clinical investigators, CROs, data safety and monitoring boards, consultants, commercial partners and vendors may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements, and insider trading.
−Removed: We are exposed to the risk of employee fraud, misconduct or other illegal activity by our employees, affiliates, independent contractors, clinical investigators, CROs, data safety and monitoring boards, consultants, commercial partners and vendors.
−Removed: Misconduct by these parties could include intentional, reckless and/or negligent conduct that fails to:
−Removed: comply with the laws of the FDA and other similar foreign regulatory bodies;
−Removed: provide true, complete and accurate information to the FDA and other similar foreign regulatory bodies;
−Removed: comply with manufacturing standards we have established;
−Removed: comply with healthcare fraud and abuse, privacy and security and other laws in the U.S.
−Removed: and similar foreign fraudulent misconduct laws;
−Removed: comply with federal securities laws regulating insider trading;
−Removed: report financial information or data accurately or to disclose unauthorized activities to us.
−Removed: If we obtain FDA approval of any of our product candidates and begin commercializing those products in the U.S., our potential exposure under such laws will increase significantly, and our costs associated with compliance with such laws are also likely to increase.
−Removed: These laws may impact, among other things, our current activities with principal investigators and research patients, as well as proposed and future sales, marketing and education programs.
−Removed: In particular, the promotion, sales and marketing of healthcare items and services, as well as certain business arrangements in the healthcare industry, are subject to extensive laws designed to prevent fraud, kickbacks, self-dealing and other abusive practices.
−Removed: These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, structuring and commission(s), certain customer incentive programs and other business arrangements generally.
−Removed: Activities subject to these laws also include the collection and/or use of information obtained in the course of patient recruitment for clinical trials.
−Removed: The healthcare laws that may affect our ability to operate include, but are not limited to:
−Removed: the federal Anti-Kickback Statute, which prohibits, among other things, knowingly and willfully soliciting, receiving, offering or providing any remuneration (including any kickback, bribe, or rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual, or the purchase, lease, order or recommendation of any good, facility, item or service for which payment may be made, in whole or in part, under a federal healthcare program, such as the Medicare and Medicaid programs;
−Removed: federal civil and criminal false claims laws and civil monetary penalty laws, including the civil False Claims Act, which impose criminal and civil penalties against individuals or entities for, among other things, knowingly presenting, or causing to be presented, claims for payment or approval from the federal government including Medicare and Medicaid, that are false or fraudulent or knowingly making a false statement to improperly avoid, decrease or conceal an obligation to pay money to the federal government;
−Removed: federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created additional U.S.
−Removed: federal criminal statutes that prohibit, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private), and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters;
−Removed: HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, which impose requirements, including mandatory contractual terms, on certain covered healthcare providers, health plans, and healthcare clearinghouses, as well as their respective business associates that perform services for them that involve the use, or disclosure of, individually identifiable health information, relating to the privacy, security and transmission of individually identifiable health information;
−Removed: federal Physician Payments Sunshine Act, created under the Patient Protection and Affordable Care Act, as amended by the Health Care Education Reconciliation Act, which we refer to collectively as ACA, and its implementing regulations, which require certain manufacturers of drugs, devices, biologicals and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually to the U.S.
−Removed: Department of Health and Human Services, or HHS, information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members by the 90th day of each subsequent calendar year, and disclosure of such information will be made by HHS on a publicly available website;
−Removed: federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers.
−Removed: Additionally, we are subject to state and foreign laws and regulations that are analogous to the healthcare laws and regulations described above, among others, some of which may be broader in scope and may apply regardless of the payor.
−Removed: Some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and relevant compliance guidance promulgated by the federal government;
−Removed: some state laws require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures;
−Removed: and some state and foreign laws govern the privacy and security of health information in ways that differ, and in certain cases are more stringent than, HIPAA, thus complicating compliance efforts.
−Removed: We have adopted a code of business conduct and ethics, but it is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent inappropriate conduct may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations.
−Removed: Efforts to ensure that our business arrangements will comply with applicable healthcare laws may involve substantial costs.
−Removed: It is possible that governmental and enforcement authorities will conclude that our business practices do not comply with current or future statutes, regulations or case law interpreting applicable fraud and abuse or other healthcare laws and regulations.
−Removed: If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of civil, criminal and/or administrative penalties, damages, disgorgement, monetary fines, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings, and curtailment of our operations, any of which could adversely affect our ability to operate our business and our results of operations.
−Removed: Defending against any such actions can be costly, time-consuming, and may require significant financial and personnel resources.
−Removed: Therefore, even if we are successful in defending against any such actions that may be brought against us, our business may be impaired.
−Removed: Competing generic medicinal products or biosimilars may be approved.
−Removed: In the European Union, or E.U., there exists a process for approval of generic biological medicinal products once patent protection and other forms of data and market exclusivity have expired.
−Removed: Arrangements for approval of biosimilar products exist in the U.S., as well.
−Removed: Other jurisdictions are considering adopting legislation that would allow the approval of generic biological medicinal products.
−Removed: If generic medicinal products are approved, competition from such products may substantially reduce sales of our products.
−Removed: Public opinion and scrutiny of cell-based immunotherapy approaches may impact public perception of our company and product candidates, or may adversely affect our ability to conduct our business and our business plans.
−Removed: Our platform utilizes a relatively novel technology involving the genetic modification of human cells and utilization of those modified cells in other individuals, and no natural killer cell-based immunotherapy has been approved to date.
−Removed: Public perception may be influenced by claims, such as claims that cell-based immunotherapy is unsafe, unethical, or immoral and, consequently, our approach may not gain the acceptance of the public or the medical community.
−Removed: Negative public reaction to cell-based immunotherapy in general could result in greater government regulation and stricter labeling requirements of cell-based immunotherapy products, including any of our product candidates, and could cause a decrease in the demand for any products we may develop.
−Removed: Adverse public attitudes may adversely impact our ability to enroll clinical trials.
−Removed: Moreover, our success will depend upon physicians specializing in the treatment of those diseases that our product candidates target prescribing, and their patients being willing to receive, treatments that involve the use of our product candidates in lieu of, or in addition to, existing treatments they are already familiar with and for which greater clinical data may be available.
−Removed: More restrictive government regulations or negative public opinion could have an adverse effect on our business or financial condition and may delay or impair the development and commercialization of our product candidates or demand for any products we may develop.
−Removed: Adverse events in our clinical trials, even if not ultimately attributable to our product candidates, and the resulting publicity could result in increased governmental regulation, unfavorable public perception, potential regulatory delays in the testing or approval of our potential product candidates, stricter labeling requirements for those product candidates that are approved and a decrease in demand for any such product candidates.
−Removed: Our business may be materially affected by changes to fiscal and tax policies.
−Removed: Negative or unexpected tax consequences could adversely affect our results of operations.
−Removed: The Tax Cuts and Jobs Act of 2017 was approved by Congress on December 20, 2017.
−Removed: This legislation significantly changed the U.S.
−Removed: Internal Revenue Code.
−Removed: Such changes include a reduction in the corporate tax rate and limitations on certain corporate deductions and credits, among other changes.
−Removed: Certain of these changes could have a negative impact on our business.
−Removed: In addition, adverse changes in financial outlook of our operations or changes in tax law could lead to changes in our valuation allowances against deferred tax assets on our consolidated balance sheets, which could materially affect our results of operations.
−Removed: Risks Relating to Government Regulation
−Removed: We may fail to obtain or may experience delays in obtaining regulatory approval to market our aNK platform product candidates, which will significantly harm our business.
−Removed: We do not have the necessary approval to market or sell aNK platform products in the U.S.
−Removed: or any foreign market.
−Removed: Before marketing aNK platform product candidates, we must successfully complete extensive preclinical studies and clinical trials and rigorous regulatory approval procedures.
−Removed: We cannot offer assurances that we will apply for or obtain the necessary regulatory approval to commercialize aNK platform product candidates in a timely manner, or at all.
−Removed: Conducting clinical trials is uncertain and expensive and often takes many years to complete.
−Removed: The results from preclinical testing and early clinical trials are often not predictive of results obtained in later clinical trials.
−Removed: In conducting clinical trials, we may fail to establish the effectiveness of haNK, taNK and t‑haNK cells for the targeted indication or we may discover unforeseen side effects.
−Removed: Moreover, clinical trials may require the enrollment of large numbers of patients, and suitable patients may be difficult to identify and recruit.
−Removed: Clinical trials are also often subject to unanticipated delays.
−Removed: In addition, haNK, taNK and t‑haNK cells are produced in small-scale cell culture systems and we may be unable to adapt the production method to large-scale production systems.
−Removed: In addition, patients participating in the trials may die before completion of the clinical trial or suffer adverse medical effects unrelated to treatment with haNK, taNK and t‑haNK cells.
−Removed: This could delay or lead to termination of our clinical trials.
−Removed: A number of companies in the biotechnology industry have suffered significant setbacks in every stage of clinical trials, even in advanced clinical trials after positive results in earlier clinical trials.
−Removed: To date, the FDA has approved only a few cell-based therapies for commercialization.
−Removed: The processes and requirements imposed by the FDA may cause delays and additional costs in obtaining regulatory approvals for our product candidates.
−Removed: Because our aNK platform product is novel, and cell-based therapies are relatively new, regulatory agencies may lack experience in evaluating product candidates like our aNK platform products.
−Removed: This inexperience may lengthen the regulatory review process, increase our development costs and delay or prevent commercialization of our aNK platform products.
−Removed: In addition, the following factors may impede or delay our ability to obtain timely regulatory approvals, if at all:
−Removed: potential delays in or failure to reach agreement on acceptable terms with prospective CROs and clinical sites, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and trial sites;
−Removed: our failure to obtain sufficient enrollment in our clinical trials or participants may fail to complete our clinical trials;
−Removed: clinical trials of our product candidates may produce negative or inconclusive results, and we may decide, or regulators may require us, to conduct additional clinical trials or abandon product development programs;
−Removed: regulators may require us to perform additional or unanticipated clinical trials to obtain approval or we may be subject to additional post-marketing testing requirements to maintain regulatory approval;
−Removed: regulators may revise the requirements for approving our product candidates, or such requirements may not be as we anticipate;
−Removed: the cost of clinical trials of our product candidates may be greater than we anticipate, and we may need to delay or suspend one or more trials until we complete additional financing transactions or otherwise receive adequate funding;
−Removed: the supply or quality of our product candidates or other materials necessary to conduct clinical trials of our product candidates may be insufficient or inadequate or may be delayed;
−Removed: our product candidates may have undesirable side effects or other unexpected characteristics, causing us or our investigators, regulators or institutional review boards to suspend or terminate trials;
−Removed: regulatory authorities may suspend or withdraw their approval of a product or impose restrictions on its distribution;
−Removed: our limited experience in filing and pursuing Biologics License Applications, or BLAs, necessary to gain regulatory approvals related to genetically modified cancer cell line therapies;
−Removed: any failure to develop substantial evidence of clinical efficacy and safety, and to develop quality standards and manufacturing processes to demonstrate consistent safety, purity, identity, and potency standards;
−Removed: a decision by us, institutional review boards, or regulators to suspend or terminate our clinical trials for various reasons, including noncompliance with regulatory requirements or a finding that the participants are being exposed to unacceptable health risks;
−Removed: regulatory inspections of our clinical trials, clinical trial sites or manufacturing facilities, which may, among other things, require us to undertake corrective action or suspend or terminate our clinical trials if regulators find us not to be in compliance with applicable regulatory requirements;
−Removed: our ability to produce sufficient quantities of haNK, taNK or t‑haNK cells to complete our clinical trials;
−Removed: varying interpretations of the data generated from our clinical trials;
−Removed: changes in governmental regulations or administrative action.
−Removed: Any delays in, or termination of, our clinical trials could materially and adversely affect our development and collaboration timelines, which may cause our stock price to decline.
−Removed: If we do not complete clinical trials for haNK, taNK and t‑haNK cells and seek and obtain regulatory approvals, we may not be able to recover any of the substantial costs we have invested in the development of haNK, taNK and t‑haNK cells.
−Removed: Even if we obtain regulatory approvals for aNK related platform products, those approvals and ongoing regulation of our products may limit how we manufacture and market our products, which could prevent us from realizing the full benefit of our efforts.
−Removed: If we obtain regulatory approvals, our aNK platform products, and our manufacturing facilities will be subject to continual regulatory review, including periodic unannounced inspections, by the FDA and other U.S.
−Removed: and foreign regulatory authorities.
−Removed: In addition, regulatory authorities may impose significant restrictions on the indicated uses or impose ongoing requirements for potentially costly post-approval studies.
−Removed: aNK platform product candidates would also be subject to ongoing FDA requirements governing the labeling, packaging, storage, advertising, promotion, recordkeeping and submission of safety and other post-market information.
−Removed: These and other factors may significantly restrict our ability to successfully commercialize haNK, taNK and t‑haNK cell therapies.
−Removed: Manufacturers of biopharmaceutical products and their facilities, vendors and suppliers are subject to continual review and periodic unannounced inspections by the FDA and other regulatory authorities for compliance with cGMP regulations, which include requirements relating to quality control and quality assurance, as well as to the corresponding maintenance of records and documentation.
−Removed: Furthermore, our manufacturing facilities must be approved by regulatory agencies before these facilities can be used to manufacture aNK platform products, and they will also be subject to additional regulatory inspections.
−Removed: Any material changes we may make to our manufacturing process or to the components used in our products may require additional prior approval by the FDA and state or foreign regulatory authorities.
−Removed: Failure to comply with FDA or other applicable regulatory requirements may result in criminal prosecution, civil penalties, recall or seizure of products, partial or total suspension of production or withdrawal of a product from the market.
−Removed: We must also report adverse events that occur when our products are used.
−Removed: The discovery of previously unknown problems with aNK, haNK, taNK and t ‑haNK cells and therapies or our manufacturing facilities may result in restrictions or sanctions on our products or manufacturing facilities, including withdrawal of our products from the market or suspension of manufacturing.
−Removed: Regulatory agencies may also require us to reformulate our products, conduct additional clinical trials, make changes in the labeling of our product or obtain further approvals.
−Removed: This may harm our business and results of operations or cause our reputation in the market place to suffer or subject us to lawsuits, including class action suits.
−Removed: Additionally, if one or more of our product candidates receives marketing approval, and we or others later identify undesirable side effects or adverse events caused by such products, a number of potentially significant negative consequences could result, including but not limited to:
−Removed: regulatory authorities may withdraw approvals of such product or require additional warnings on the label;
−Removed: we may be required to change the way the product is administered or conduct additional clinical trials or post-approval studies;
−Removed: we may be required to create a Risk Evaluation and Mitigation Strategy (REMS) plan, which could include a medication guide outlining the risks of such side effects for distribution to patients, a communication plan for healthcare providers, or other elements to assure safe use;
−Removed: we could be sued and held liable for harm caused to patients;
−Removed: our reputation may suffer.
−Removed: Any of these events could prevent us from achieving or maintaining market acceptance of the particular product candidate, if approved, and could significantly harm our business, results of operations, and prospects.
−Removed: In addition, if we, our product candidates or the manufacturing facilities for our product candidates fail to comply with applicable regulatory requirements, a regulatory agency may:
−Removed: issue warning letters that can produce adverse publicity;
−Removed: impose civil or criminal penalties;
−Removed: suspend regulatory approval;
−Removed: suspend any ongoing clinical trials;
−Removed: refuse to approve pending applications or supplements to applications filed by us;
−Removed: impose restrictions on operations, including costly new manufacturing requirements;
−Removed: seize or detain products or request us to initiate a product recall;
−Removed: pursue and obtain an injunction.
−Removed: Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining regulatory approval of our product candidates in other jurisdictions.
−Removed: Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not guarantee that we will be able to obtain or maintain regulatory approval in any other jurisdiction, while a failure or delay in obtaining regulatory approval in one jurisdiction may have a negative effect on the regulatory approval process in others.
−Removed: For example, even if the FDA grants marketing approval of a product candidate, comparable regulatory authorities in foreign jurisdictions must also approve the product, manufacturing, and in many cases reimbursement of the product candidate in those countries.
−Removed: Approval procedures vary among jurisdictions and can involve requirements and administrative review periods different from, and greater than, those in the U.S., including additional preclinical studies or clinical trials as clinical studies conducted in one jurisdiction may not be accepted by regulatory authorities in other jurisdictions.
−Removed: In some cases, the price that we intend to charge for our products is also subject to approval by regulatory authorities.
−Removed: We may also submit marketing applications in other countries.
−Removed: Regulatory authorities in jurisdictions outside of the U.S.
−Removed: have requirements for approval of product candidates with which we must comply prior to marketing in those jurisdictions.
−Removed: Obtaining foreign regulatory approvals and compliance with foreign regulatory requirements could result in significant delays, difficulties and costs for us and could delay or prevent the introduction of our products in certain countries.
−Removed: If we fail to comply with the regulatory requirements in international markets and/or receive applicable marketing approvals, our target market will be reduced and our ability to realize the full market potential of our product candidates will be harmed.
−Removed: We may seek orphan drug status or breakthrough therapy designation for one or more of our product candidates, but even if either is granted, we may be unable to maintain any benefits associated with breakthrough therapy designation or orphan drug status, including market exclusivity.
−Removed: Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biologic intended to treat a rare disease or condition or for which there is no reasonable expectation that the cost of developing and making available in the U.S.
−Removed: a drug or biologic for a disease or condition will be recovered from sales in the U.S.
−Removed: for that drug or biologic.
−Removed: If a product that has orphan drug designation subsequently receives the first FDA approval 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 to market the same drug or biologic 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.
−Removed: In 2012, the FDA established a Breakthrough Therapy Designation, which is intended to expedite the development and review of products that treat serious or life-threatening conditions.
−Removed: We may seek orphan drug status for one or more of our product candidates, but exclusive marketing rights in the U.S.
−Removed: may be lost if we seek approval for an indication broader than the orphan designated indication and may be lost if the FDA later determines that the request for designation was materially defective or if we are unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.
−Removed: In addition, we may seek breakthrough therapy designation for one or more of our product candidates, but there can be no assurance that we will receive such designation.
−Removed: We will need to obtain FDA approval of any proposed product brand names, and any failure or delay associated with such approval may adversely impact our business.
−Removed: A biopharmaceutical product cannot be marketed in the U.S.
−Removed: or other countries until we have completed rigorous and extensive regulatory review processes, including review and approval of a brand name.
−Removed: Any brand names we intend to use for our product candidates will require approval from the FDA regardless of whether we have secured a formal trademark registration from the U.S.
−Removed: Patent and Trademark Office, or the USPTO.
−Removed: The FDA may object to a product brand name if they believe the name creates potential for confusion or inappropriately implies medical claims.
−Removed: If the FDA objects to any of our proposed product brand names, we may be required to adopt an alternative brand name for our product candidates.
−Removed: If we adopt an alternative brand name, we would lose the benefit of our existing trademark applications for such product candidate and may be required to expend significant additional resources in an effort to identify a suitable product brand name that would qualify under applicable trademark laws, not infringe the existing rights of third parties and be acceptable to the FDA.
−Removed: We may be unable to build a successful brand identity for a new trademark in a timely manner or at all, which would limit our ability to commercialize our product candidates.
−Removed: Coverage and reimbursement decisions by third-party payors may have an adverse effect on pricing and market acceptance.
−Removed: There is significant uncertainty related to the third-party coverage and reimbursement of newly approved drugs.
−Removed: Patients who are provided medical treatment for their conditions generally rely on third-party payors to reimburse all or part of the costs associated with their treatment.
−Removed: Therefore, market acceptance and sales of our products, if approved, in both domestic and international markets will depend significantly on the availability of adequate coverage and reimbursement from third party and/or government payors for any of our products and may be affected by existing and future healthcare reform measures.
−Removed: Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which drugs they will cover and establish approved lists, known as formularies, and establish payment levels for such drugs.
−Removed: Formularies may not include all FDA-approved drugs for a particular indication.
−Removed: Private payors often follow Medicare coverage policy and payment limitations in setting their own payment rates.
−Removed: Any reduction in payment under Medicare Part D may result in a similar reduction in payments from non-governmental payors.
−Removed: We cannot be certain that coverage and adequate reimbursement will be available for any of our products, if approved, or that such coverage and reimbursement will be authorized in a timely fashion.
−Removed: In addition, we cannot be certain that reimbursement policies will not reduce the demand for, or the price paid for, any of our products, if approved.
−Removed: If reimbursement is not available or is available on a limited basis for any of our products, if approved, we may not be able to successfully commercialize any such products.
−Removed: Reimbursement by a third party or government payor may depend upon a number of factors, including, without limitation, the third-party or government payor’s determination that use of a product is:
−Removed: a covered benefit under its health plan;
−Removed: safe, effective and medically necessary;
−Removed: appropriate for the specific patient;
−Removed: cost-effective;
−Removed: neither experimental nor investigational.
−Removed: Obtaining coverage and reimbursement approval for a product from a government or other third-party payor is a time consuming and costly process that could require us to provide supporting scientific, clinical and cost-effectiveness data for the use of our products to the payor.
−Removed: We may not be able to provide data sufficient to gain acceptance with respect to coverage and reimbursement or to have pricing set at a satisfactory level.
−Removed: If reimbursement of our products, if any, is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels such as may result where alternative or generic treatments are available, we may be unable to achieve or sustain profitability.
−Removed: Assuming we obtain coverage for a given product, the resulting reimbursement payment rates might not be adequate or may require co-payments that patients find unacceptably high.
−Removed: Patients are unlikely to use our products unless coverage is provided and reimbursement is adequate to cover a significant portion of the cost of our products.
−Removed: In the U.S., third-party payors include federal and state healthcare programs, government authorities, private managed care providers, private health insurers, and other organizations.
−Removed: No uniform policy of coverage and reimbursement for products exists among third-party payors, and third-party payors are increasingly challenging the price, examining the medical necessity, and reviewing the cost-effectiveness of medical drug products and medical services, in addition to questioning their safety and efficacy.
−Removed: Therefore, coverage and reimbursement for products can differ significantly from payor to payor.
−Removed: As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained.
−Removed: We or our collaborators may need to conduct expensive pharmaco-economic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain the FDA approvals.
−Removed: In some foreign countries, particularly in Europe, the pricing of prescription pharmaceuticals is subject to governmental control.
−Removed: In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product.
−Removed: To obtain reimbursement or pricing approval in some countries, we may be required to conduct additional clinical trials that compare the cost-effectiveness of our products to other available therapies.
−Removed: If reimbursement of any of our products, if approved, is unavailable or limited in scope or amount in a particular country, or if pricing is set at unsatisfactory levels, we may be unable to achieve or sustain profitability of our products in such country.
−Removed: Recent legislative and regulatory activity may exert downward pressure on potential pricing and reimbursement for our products, if approved, that could materially affect the opportunity to commercialize.
−Removed: and several other jurisdictions are considering, or have already enacted, a number of legislative and regulatory proposals to change the healthcare system in ways that could affect our ability to sell any of our products profitably, if approved.
−Removed: Among policy-makers and payors in the U.S.
−Removed: 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 to healthcare.
−Removed: In the U.S., the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives.
−Removed: There have been, and likely will continue to be, legislative and regulatory proposals at the federal and state levels directed at broadening the availability of healthcare and containing or lowering the cost of healthcare.
−Removed: We cannot predict the initiatives that may be adopted in the future.
−Removed: The continuing efforts of the government, insurance companies, managed care organizations and other payors of healthcare services to contain or reduce costs of healthcare may adversely affect:
−Removed: the demand for any of our products, if approved;
−Removed: our ability to set a price that we believe is fair for any of our products, if approved;
−Removed: our ability to generate revenues and achieve or maintain profitability;
−Removed: the level of taxes that we are required to pay;
−Removed: the availability of capital.
−Removed: In March 2010, ACA became law in the U.S.
−Removed: The goal of ACA is to reduce the cost of healthcare, broaden access to health insurance, constrain healthcare spending, enhance remedies against fraud and abuse, add transparency requirements for the healthcare and health insurance industries, impose taxes and fees on the health industry, impose additional health policy reforms, and substantially change the way healthcare is financed by both governmental and private insurers.
−Removed: While we cannot predict what impact on federal reimbursement policies this legislation will have in general or on our business specifically, ACA may result in downward pressure on pharmaceutical reimbursement, which could negatively affect market acceptance of any of our products, if they are approved.
−Removed: Provisions of ACA relevant to the pharmaceutical industry include the following:
−Removed: an annual, nondeductible fee on any entity that manufactures or imports certain branded prescription drugs and biologic agents, apportioned among these entities according to their market share in certain government healthcare programs, not including orphan drug sales;
−Removed: an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program to 23.1% and 13% of the average manufacturer price for most branded and generic drugs, respectively;
−Removed: a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% point-of-sale discounts on negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D;
−Removed: extension of manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;
−Removed: 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 manufacturers’ Medicaid rebate liability;
−Removed: expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program;
−Removed: new requirements for 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 to report annually certain financial arrangements with physicians and teaching hospitals, as defined in ACA and its implementing regulations, including reporting any payment or “transfer of value” provided to physicians and teaching hospitals and any ownership and investment interests held by physicians and their immediate family members during the preceding calendar year;
−Removed: expansion of healthcare fraud and abuse laws, including the U.S.
−Removed: federal False Claims Act and the U.S.
−Removed: federal Anti-Kickback Statute, new government investigative powers and enhanced penalties for noncompliance;
−Removed: a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in and conduct comparative clinical effectiveness research, along with funding for such research;
−Removed: 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.
−Removed: The ACA has been modified and amended recently, including the elimination of the individual mandate that individuals purchase healthcare insurance.
−Removed: Furthermore, the current presidential administration and Congress may continue to attempt broad sweeping changes to the current health care laws.
−Removed: We face uncertainties that might result from modification or repeal of any of the provisions of the ACA, including as a result of current and future executive orders and legislative actions.
−Removed: The impact of those changes on us and potential effect on the pharmaceutical and biotechnology industry as a whole is currently unknown.
−Removed: 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.
−Removed: We cannot predict what other healthcare programs and regulations will ultimately be implemented at the federal or state level or the effect of any future legislation or regulation in the U.S.
−Removed: may have on our business.
−Removed: We are subject to governmental export and import controls that could impair our ability to compete in international markets due to licensing requirements and subject us to liability if we are not in compliance with applicable laws.
−Removed: Compliance with these legal requirements could limit our ability to compete in foreign markets and subject us to liability if we violate them.
−Removed: Our products and solutions are subject to export control and import laws and regulations, including the U.S.
−Removed: Export Administration Regulations, U.S.
−Removed: Customs regulations, and various economic and trade sanctions regulations administered by the U.S.
−Removed: Treasury Department’s Office of Foreign Assets Controls.
−Removed: Exports of our products and solutions outside of the U.S.
−Removed: must be made in compliance with these laws and regulations.
−Removed: If we fail to comply with these laws and regulations, we and certain of our employees could be subject to substantial civil or criminal penalties, including the possible loss of export or import privileges;
−Removed: fines, which may be imposed on us and responsible employees or managers;
−Removed: and, in extreme cases, the incarceration of responsible employees or managers.
−Removed: In addition, changes in our products or solutions or changes in applicable export or import laws and regulations may create delays in the introduction, provision, or sale of our products and solutions in international markets, prevent customers from using our products and solutions or, in some cases, prevent the export or import of our products and solutions to certain countries, governments or persons altogether.
−Removed: Any limitation on our ability to export, provide, or sell our products and solutions could adversely affect our business, financial condition and results of operations.
−Removed: We are subject to U.S.
−Removed: and foreign anti-corruption and anti-money laundering laws with respect to our operations and non-compliance with such laws can subject us to criminal and/or civil liability and harm our business.
−Removed: We are subject to the U.S.
−Removed: Foreign Corrupt Practices Act of 1977, as amended, or the FCPA, the U.S.
−Removed: domestic bribery statute contained in 18 U.S.C.
−Removed: §201, the U.S.
−Removed: Travel Act, the USA PATRIOT Act, and possibly other state and national anti-bribery and anti-money laundering laws in countries in which we conduct activities.
−Removed: Anti-corruption laws are interpreted broadly and prohibit companies and their employees, agents, third-party intermediaries, joint venture partners and collaborators from authorizing, promising, offering, or providing, directly or indirectly, improper payments or benefits to recipients in the public or private sector.
−Removed: We have used contract research organizations abroad for clinical trials.
−Removed: In addition, we may engage third party intermediaries to sell our products and solutions abroad once we enter a commercialization phase for our product candidates and/or to obtain necessary permits, licenses, and other regulatory approvals.
−Removed: We or our third-party intermediaries may have direct or indirect interactions with officials and employees of government agencies or state-owned or affiliated entities.
−Removed: We can be held liable for the corrupt or other illegal activities of these third-party intermediaries, our employees, representatives, contractors, partners, and agents, even if we do not explicitly authorize or have actual knowledge of such activities.
−Removed: We adopted an anti-corruption policy in connection with the consummation of the IPO of our common stock in July 2015.
−Removed: The anti-corruption policy mandates compliance with the FCPA and other anti-corruption laws applicable to our business throughout the world.
−Removed: However, there can be no assurance that our employees and third party intermediaries will comply with this policy or such anti-corruption laws.
−Removed: Noncompliance with anti-corruption and anti-money laundering laws could subject us to whistleblower complaints, investigations, sanctions, settlements, prosecution, other investigations, or other enforcement actions.
−Removed: If such actions are launched, or governmental or other sanctions are imposed, or if we do not prevail in any possible civil or criminal litigation, our business, results of operations and financial condition could be materially harmed.
−Removed: In addition, responding to any action will likely result in a materially significant diversion of management’s attention and resources and significant defense and compliance costs and other professional fees.
−Removed: In certain cases, enforcement authorities may even cause us to appoint an independent compliance monitor, which can result in added costs and administrative burdens.
−Removed: Changes in funding for the FDA, the SEC and other government agencies could hinder their ability to hire and retain key leadership and other personnel, prevent new products and services from being developed or commercialized in a timely manner or otherwise prevent those agencies from performing normal functions on which the operation of our business may rely, which could negatively impact our business.
−Removed: The ability of the FDA to review and approve new products can be affected by a variety of factors, including government budget and funding levels, ability to hire and retain key personnel and accept payment of user fees, and statutory, regulatory, and policy changes.
−Removed: Average review times at the agency have fluctuated in recent years as a result.
−Removed: In addition, government funding of the FDA, SEC and other government agencies on which our operations may rely is inherently fluid and unpredictable.
−Removed: Disruptions at the FDA and other agencies may also slow the time necessary for new drugs to be reviewed and/or approved by necessary government agencies, which would adversely affect our business.
−Removed: For example, over the last several years, including beginning on December 22, 2018, the U.S.
−Removed: government has shut down several times and certain regulatory agencies, such as the FDA and the SEC, have had to furlough critical FDA, SEC and other government employees and stop critical activities.
−Removed: If a prolonged government shutdown occurs, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business.
−Removed: Further, future government shutdowns could potentially impact our ability to access the public markets and obtain necessary capital in order to properly capitalize and continue our operations.
−Removed: We may be, or may become, subject to data protection laws and regulations, and our failure to comply with such laws and regulations could lead to government enforcement actions and significant penalties against us, and adversely impact our operating results.
−Removed: has adopted data protection laws and regulations which may apply to us in certain circumstances, or in the future.
−Removed: These laws, which impose significant compliance obligations, are commonly known as the General Data Protection Regulation, or GDPR.
−Removed: The GDPR, which is wide-ranging in scope and applicability, imposes several requirements relating to the consent of the individuals to whom the personal data relates, the information provided to the individuals, the security and confidentiality of the personal data, data breach notification and the use of third party processors in connection with the processing of personal data, including clinical trials.
−Removed: The GDPR also imposes strict rules on the transfer of personal data out of the E.U.
−Removed: to the U.S., provides an enforcement authority, and imposes large penalties for noncompliance, including the potential for fines of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater.
−Removed: Implementation of the GDPR, as applicable to us, will increase our responsibility and liability in relation to personal data that we process, including in clinical trials, and we may in the future be required to put in place additional mechanisms to ensure compliance with the GDPR, which could divert management’s attention and increase our cost of doing business.
−Removed: In addition, other new regulation or legislative actions regarding data privacy and security (together with applicable industry standards) may increase our costs of doing business.
−Removed: In this regard, we expect that there will continue to be new proposed laws, regulations and industry standards relating to privacy and data protection in the U.S., the E.U.
−Removed: and other jurisdictions, and we cannot determine the impact such future laws, regulations and standards may have on our business.
−Removed: Risks Relating to Our Intellectual Property
−Removed: If our efforts to protect the intellectual property related to our product candidates are not adequate, we may not be able to compete effectively in our market.
−Removed: We rely upon a combination of patents, trade secret protection and contractual agreements, including confidentiality agreements to protect the intellectual property related to our product candidates and technology.
−Removed: Any disclosure to or misappropriation by third parties of our confidential proprietary information could enable competitors to quickly duplicate or surpass our technological achievements, eroding our competitive position in the market.
−Removed: We believe that we have worldwide commercial rights to the NK‑92 cell line and we believe that we control commercial use of our haNK, taNK and t‑haNK cells in key territories.
−Removed: We have developed and in-licensed numerous patents and patent applications and we possess substantial know-how and trade secrets relating to the development and commercialization of natural killer cell-based immunotherapy product candidates, including related manufacturing processes and technology.
−Removed: Our owned and licensed patent portfolio consists of patents and pending patent applications in the U.S.
−Removed: disclosing subject matter directed to certain of our proprietary technology, inventions, and improvements and our most advanced product candidates, as well as licensed and owned patents and pending applications in jurisdictions outside of the U.S., that, in many cases, are counterparts to the foregoing U.S.
−Removed: patents and patent applications.
−Removed: We believe we have intellectual property rights that are necessary to commercialize haNK, taNK and t‑haNK cells.
−Removed: However, our patent applications may not result in issued patents, and, even if issued, the patents may be challenged and invalidated.
−Removed: Moreover, our patents and patent applications may not be sufficiently broad to prevent others from practicing our technologies or developing competing products.
−Removed: We also face the risk that others may independently develop similar or alternative technologies or may design around our proprietary property.
−Removed: The patent application process, also known as patent prosecution, is expensive and time-consuming, and we and our current or future licensors and licensees may not be able to prepare, file and prosecute all necessary or desirable patent applications at a reasonable cost or in a timely manner.
−Removed: It is also possible that we or our current licensors, or any future licensors or licensees, will fail to identify patentable aspects of inventions made in the course of development and commercialization activities before it is too late to obtain patent protection on them.
−Removed: Therefore, these and any of our patents and applications may not be prosecuted and enforced in a manner consistent with the best interests of our business.
−Removed: Defects of form in the preparation or filing of our patents or patent applications may exist, or may arise in the future, for example with respect to proper priority claims, inventorship, etc.
−Removed: If we or our current licensors, or any future licensors or licensees, fail to establish, maintain or protect such patents and other intellectual property rights, such rights may be reduced or eliminated.
−Removed: If our current licensors, or any future licensors or licensees, are not fully cooperative or disagree with us as to the prosecution, maintenance or enforcement of any patent rights, such patent rights could be compromised.
−Removed: If there are material defects in the form or preparation of our patents or patent applications, such patents or applications may be invalid and unenforceable.
−Removed: Any of these outcomes could impair our ability to prevent competition from third parties, which may have an adverse impact on our business.
−Removed: The strength of patents in the biopharmaceutical field involves complex legal and scientific questions and can be uncertain.
−Removed: This uncertainty includes changes to the patent laws through either legislative action to change statutory patent law or court action that may reinterpret existing law or rules in ways affecting the scope or validity of issued patents.
−Removed: The patent applications that we own or in-license may fail to result in issued patents in the U.S.
−Removed: or foreign countries with claims that cover our product candidates.
−Removed: Even if patents do successfully issue from the patent applications that we own or in-license, third parties may challenge the validity, enforceability or scope of such patents, which may result in such patents being narrowed, invalidated or held unenforceable.
−Removed: Any successful challenge to our patents could deprive us of exclusive rights necessary for the successful commercialization of our product candidates.
−Removed: Furthermore, even if they are unchallenged, our patents may not adequately protect our product candidates, provide exclusivity for our product candidates, or prevent others from designing around our claims.
−Removed: If the breadth or strength of protection provided by the patents we hold or pursue with respect to our product candidates is challenged, it could dissuade companies from collaborating with us to develop, or threaten our ability to commercialize our product candidates.
−Removed: Patents have a limited lifespan.
−Removed: In the U.S., the natural expiration of a patent is generally 20 years after its earliest effective non-provisional filing date.
−Removed: Various extensions may be available;
−Removed: however, the life of a patent, and the protection it affords, is limited.
−Removed: Without patent protection for our product candidates, we may be open to competition from generic versions of our product candidates.
−Removed: Further, if we encounter delays in our development efforts, including our clinical trials, the period of time during which we could market our product candidates under patent protection would be reduced.
−Removed: In addition to the protection afforded by patents, we also rely on trade secret protection to protect proprietary know-how that may not be patentable or that we elect not to patent, processes for which patents may be difficult to obtain or enforce, and any other elements of our product candidates, and our product development processes (such as a manufacturing and formulation technologies) that involve proprietary know-how, information or technology that is not covered by patents.
−Removed: However, trade secrets can be difficult to protect.
−Removed: If the steps taken to maintain our trade secrets are deemed inadequate, we may have insufficient recourse against third parties for misappropriating any trade secrets.
−Removed: Misappropriation or unauthorized disclosure of our trade secrets could significantly affect our competitive position and may have a material adverse effect on our business.
−Removed: Furthermore, trade secret protection does not prevent competitors from independently developing substantially equivalent information and techniques and we cannot guarantee that our competitors will not independently develop substantially equivalent information and techniques.
−Removed: The FDA, as part of its Transparency Initiative, is currently considering whether to make additional information publicly available on a routine basis, including information that we may consider to be trade secrets or other proprietary information, and it is not clear at the present time how the FDA’s disclosure policies may change in the future, if at all.
−Removed: In an effort to protect our trade secrets and other confidential information, we require our employees, consultants, advisors, and any other third parties that have access to our proprietary know-how, information or technology, for example, third parties involved in the formulation and manufacture of our product candidates, and third parties involved in our clinical trials to execute confidentiality agreements upon the commencement of their relationships with us.
−Removed: These agreements require that all confidential information developed by the individual or made known to the individual by us during the course of the individual’s relationship with us be kept confidential and not disclosed to third parties.
−Removed: However, we cannot be certain that our trade secrets and other confidential proprietary information will not be disclosed despite having such confidentiality agreements.
−Removed: Adequate remedies may not exist in the event of unauthorized use or disclosure of our trade secrets.
−Removed: In addition, in some situations, these confidentiality agreements may conflict with, or be subject to, the rights of third parties with whom our employees, consultants, or advisors have previous employment or consulting relationships.
−Removed: To the extent that our employees, consultants or contractors use any intellectual property owned by third parties in their work for us, disputes may arise as to the rights in any related or resulting know-how and inventions.
−Removed: If we are unable to prevent unauthorized material disclosure of our trade secrets to third parties, we may not be able to establish or maintain a competitive advantage in our market, which could materially adversely affect our business, operating results and financial condition.
−Removed: Changes in U.S.
−Removed: patent law could diminish the value of patents in general, thereby impairing our ability to protect our products.
−Removed: As is the case with other biopharmaceutical companies, our success is heavily dependent on intellectual property, particularly on obtaining and enforcing patents.
−Removed: Obtaining and enforcing patents in the pharmaceutical industry involves both technological and legal complexity, and therefore, is costly, time-consuming and inherently uncertain.
−Removed: In addition, the U.S.
−Removed: had previously enacted and implemented wide-ranging patent reform legislation (e.g., the Leahy-Smith America Invents Act in September 2011) and are currently considering additional legislation that may materially impact our ability to obtain or enforce our patents.
−Removed: Further, recent U.S.
−Removed: Supreme Court rulings and recent decisions from the United States Court of Appeals for the Federal Circuit have either narrowed the scope of patent protection available in certain circumstances or weakened the rights of patent owners in certain situations.
−Removed: In addition to increasing uncertainty with regard to our ability to obtain patents in the future, this combination of events has created uncertainty with respect to the value of patents, once obtained.
−Removed: In addition, changes to U.S.
−Removed: patent laws provide additional procedures for third parties to challenge the validity of issued patents based on patent applications filed after March 15, 2013.
−Removed: If the breadth or strength of protection provided by the patents and patent applications we hold or pursue with respect to our current or future product candidates is challenged, then it could threaten our ability to commercialize our current or future product candidates and could threaten our ability to prevent competitive products from being marketed.
−Removed: Further, if we encounter delays in our clinical trials, the period of time during which we could market our current or future product candidates under patent protection would be reduced.
−Removed: patent applications are confidential for a period of time after filing, we cannot be certain that we were the first to either (i) file any patent application related to our product candidates, or (ii) invent any of the inventions claimed in our patents or patent applications.
−Removed: Furthermore, for applications filed before March 16, 2013, or patents issuing from such applications, an interference proceeding can be provoked by a third party or instituted by the U.S.
−Removed: Patent and Trademark Office, or USPTO, to determine who was the first to invent any of the subject matter covered by the patent claims of our applications and patents.
−Removed: As of March 16, 2013, the U.S.
−Removed: transitioned to a “first-to-file” system for deciding which party should be granted a patent when two or more patent applications are filed by different parties claiming the same invention.
−Removed: A third party that files a patent application with the USPTO before us could, therefore, be awarded a patent covering an invention of ours even if we had made the invention before it was made by the third party.
−Removed: The change to “first-to-file” from “first-to-invent” is one of the changes to the U.S.
−Removed: patent laws resulting from the Leahy-Smith America Invents Act, or the Leahy-Smith Act, signed into law on September 16, 2011.
−Removed: Among some of the other significant changes to the patent laws are changes that limit where a patentee may file a patent infringement suit and provide opportunities for third parties to challenge any issued patent in the USPTO.
−Removed: This applies to all of our U.S.
−Removed: patents, even those issued before March 16, 2013.
−Removed: Because of a lower evidentiary standard in USPTO proceedings compared to the evidentiary standard in U.S.
−Removed: federal court necessary to invalidate a patent claim, a third party could potentially provide evidence in a USPTO proceeding sufficient for the USPTO to hold a claim invalid even though the same evidence would be insufficient to invalidate the claim if first presented in a district court action.
−Removed: Accordingly, a third party may attempt to use the USPTO procedures to invalidate our patent claims that would not have been invalidated if first challenged by the third party as a defendant in a district court action.
−Removed: It is not yet clear what, if any, impact the Leahy-Smith Act will have on the operation of our business.
−Removed: However, the Leahy-Smith Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have a material adverse effect on our b usiness and financial condition.
−Removed: We may not be able to protect our intellectual property rights throughout the world.
−Removed: We strive to control cell line distribution, as well as limit commercial use through licenses and material transfer agreements with third parties in addition to its patents and patent applications.
−Removed: However, a company may illicitly obtain our cells or create their own modified variants and attempt to commercialize them in foreign countries where we do not have any patents or patent applications where legal recourse may be limited.
−Removed: For example, we believe that certain companies, including at least one in China, may be using our NK‑92 cell line without our permission.
−Removed: This may have a significant commercial impact on our foreign business operations.
−Removed: Filing, prosecuting and defending patents on our product candidates in all countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries outside the U.S.
−Removed: can be less extensive than those in the U.S.
−Removed: The requirements for patentability may differ in certain countries, particularly developing countries.
−Removed: In addition, the laws of some foreign countries do not protect intellectual property rights to the same extent as federal and state laws in the U.S.
−Removed: and in some cases, may even force us to grant a compulsory license to competitors or other third parties.
−Removed: Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the U.S., or from selling or important products made using our inventions in and into the U.S.
−Removed: or other jurisdictions.
−Removed: Competitors may use our technologies in jurisdictions where we have not obtained patent protection to develop their own products and further, may export otherwise infringing products to territories where we have patent protection, but enforcement on infringing activities is inadequate or not as strong as that in the U.S.
−Removed: These products may compete with our products, and our patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.
−Removed: Patents granted by the European Patent Office may be opposed by any person within nine months from the publication of their grant and, in addition, may be challenged before national courts at any time.
−Removed: Furthermore, even if they are unchallenged, our patents and patent applications may not adequately protect our intellectual property or prevent others from designing around our claims.
−Removed: If the breadth or strength of protection provided by the patents and patent applications we hold, license or pursue with respect to our product candidates is threatened, it could threaten our ability to commercialize our product candidates.
−Removed: Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions.
−Removed: The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents and other intellectual property protection, particularly those relating to pharmaceuticals or biopharmaceuticals, which could make it difficult for us to stop the infringement of our patents or marketing of competing products in violation of our proprietary rights generally.
−Removed: Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing, and could provoke third parties to assert claims against us.
−Removed: We may not prevail in any lawsuits that we initiate and the damages or other remedies awarded, if any, may not be commercially meaningful.
−Removed: In addition, certain countries in Europe and certain developing countries, including India and China, have compulsory licensing laws under which a patent owner may be compelled to grant licenses to third parties.
−Removed: In those countries, we may have limited remedies if our patents are infringed or if we are compelled to grant a license to our patents to a third party, which could materially diminish the value of those patents.
−Removed: This could limit our potential revenue opportunities.
−Removed: Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we own or license.
−Removed: Finally, our ability to protect and enforce our intellectual property rights may be adversely affected by unforeseen changes in foreign intellectual property laws.
−Removed: Obtaining and maintaining our patent protection depends on compliance with various procedural, documentary, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.
−Removed: The USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent prosecution process.
−Removed: Periodic maintenance fees and various other governmental fees on any issued patent and/or pending patent applications are due to be paid to the USPTO and foreign patent agencies in several stages over the lifetime of a patent or patent application.
−Removed: We have systems in place to remind us to pay these fees, and we employ an outside firm and rely on our outside counsel to pay these fees.
−Removed: While an inadvertent lapse may sometimes be cured by payment of a late fee or by other means in accordance with the applicable rules, there are many situations in which noncompliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction.
−Removed: If we fail to maintain the patents and patent applications directed to our product candidates, our competitors might be able to enter the market earlier than should otherwise have been the case, which would have a material adverse effect on our business.
−Removed: Third-party claims alleging intellectual property infringement may adversely affect our business.
−Removed: Our commercial success depends in part on our avoiding infringement of the patents and proprietary rights of third parties, for example, the intellectual property rights of competitors.
−Removed: Our research, development and commercialization activities may be subject to claims that we infringe or otherwise violate patents owned or controlled by third parties.
−Removed: Numerous U.S.
−Removed: and foreign issued patents and pending patent applications, which are owned by third parties, exist in the fields in which we are developing our product candidates.
−Removed: As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that our activities related to our product candidates may give rise to claims of infringement of the patent rights of others.
−Removed: We cannot assure you that our product candidates will not infringe existing or future patents.
−Removed: We may not be aware of patents that have already issued that a third party, for example a competitor in our market, might assert are infringed by our product candidates.
−Removed: It is also possible that patents of which we are aware, but which we do not believe are relevant to our product candidates, could nevertheless be found to be infringed by our product candidates.
−Removed: Nevertheless, we are not aware of any issued patents that we believe would prevent us from marketing our product candidates, if approved.
−Removed: There may also be patent applications that have been filed but not published that, when issued as patents, could be asserted against us.
−Removed: Third parties making claims against us for infringement or misappropriation of their intellectual property rights may seek and obtain injunctive or other equitable relief, which could effectively block our ability to further develop and commercialize our product candidates.
−Removed: Further, if a patent infringement suit were brought against us, we could be forced to stop or delay research, development, manufacturing or sales of the product or product candidate that is the subject of the suit.
−Removed: Defense of these claims, regardless of their merit, would cause us to incur substantial expenses, and would be a substantial diversion of employee resources from our business.
−Removed: In the event of a successful claim of infringement against us by a third party, we may have to (1) pay substantial damages, including treble damages and attorneys’ fees if we are found to have willfully infringed the third party’s patents;
−Removed: (2) obtain one or more licenses from the third party;
−Removed: (3) pay royalties to the third party;
−Removed: and/or (4) redesign any infringing products.
−Removed: Redesigning any infringing products may be impossible or require substantial time and monetary expenditure.
−Removed: Further, we cannot predict whether any required license would be available at all or whether it would be available on commercially reasonable terms.
−Removed: In the event that we could not obtain a license, we may be unable to further develop and commercialize our product candidates, which could harm our business significantly.
−Removed: Even if we are able to obtain a license, the license would likely obligate us to pay license fees or royalties or both, and the rights granted to us might be nonexclusive, which could result in our competitors gaining access to the same intellectual property.
−Removed: Ultimately, we could be prevented from commercializing a product, or be forced to cease some aspect of our business operations, if, as a result of actual or threatened patent infringement claims, we are unable to enter into licenses on acceptable terms.
−Removed: Defending ourselves or our licensors in litigation is very expensive, particularly for a company of our size, and time-consuming.
−Removed: Some of our competitors may be able to sustain the costs of litigation or administrative proceedings more effectively than we can because of greater financial resources.
−Removed: Patent litigation and other proceedings may also absorb significant management time.
−Removed: Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could impair our ability to compete in the marketplace.
−Removed: The occurrence of any of the foregoing could have a material adverse effect on our business, financial condition or results of operations.
−Removed: We may become involved in lawsuits to protect or enforce our patents or other intellectual property or the patents of our licensors, which could be expensive and time consuming.
−Removed: Third parties may infringe or misappropriate our intellectual property, including our existing patents, patents that may issue to us in the future, or the patents of our licensors to which we have a license.
−Removed: As a result, we may be required to file infringement claims to stop third-party infringement or unauthorized use.
−Removed: Further, we may not be able to prevent, alone or with our licensors, misappropriation of our intellectual property rights, particularly in countries where the laws may not protect those rights as fully as in the U.S.
−Removed: Generic drug manufacturers may develop, seek approval for, and launch generic versions of our products.
−Removed: If we file an infringement action against such a generic drug manufacturer, that company may challenge the scope, validity or enforceability of our or our licensors’ patents, requiring us and/or our licensors to engage in complex, lengthy and costly litigation or other proceedings.
−Removed: For example, if we or one of our licensors initiated legal proceedings against a third party to enforce a patent covering our product candidates, the defendant could counterclaim that the patent covering our product candidates is invalid and/or unenforceable.
−Removed: In patent litigation in the U.S., defendant counterclaims alleging invalidity and/or unenforceability are commonplace, and there are numerous grounds upon which a third party can assert invalidity or unenforceability of a patent.
−Removed: In addition, within and outside of the U.S., there has been a substantial amount of litigation and administrative proceedings, including interference and reexamination proceedings before the USPTO or oppositions and other comparable proceedings in various foreign jurisdictions, regarding patent and other intellectual property rights in the biopharmaceutical industry.
−Removed: The Leahy-Smith Act introduced procedures including inter partes review and post grant review.
−Removed: The implementation of these procedures brings uncertainty to the possibility of challenges to our patents in the future, including those that patents perceived by our competitors as blocking entry into the market for their products, and the outcome of such challenges.
−Removed: Such litigation and administrative proceedings could result in revocation of our patents or amendment of our patents such that they do not cover our product candidates.
−Removed: They may also put our pending patent applications at risk of not issuing, or issuing with limited and potentially inadequate scope to cover our product candidates.
−Removed: The outcome following legal assertions of invalidity and unenforceability is unpredictable.
−Removed: With respect to the validity question, for example, we cannot be certain that there is no invalidating prior art, of which we and the patent examiner were unaware during prosecution.
−Removed: Additionally, it is also possible that prior art of which we are aware, but which we do not believe affects the validity or enforceability of a claim, may, nonetheless, ultimately be found by a court of law or an administrative panel to affect the validity or enforceability of a claim, for example if a priority claim is found to be improper.
−Removed: If a defendant were to prevail on a legal assertion of invalidity and/or unenforceability, we would lose at least part, and perhaps all, of the patent protection on our
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.