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Item 1. Business

2021-03-01 compared with 2020-02-27 · 339 added, 201 removed, 386 unchanged (58% of the section changed)

Atara Biotherapeutics is a leading off-the-shelf, allogeneic T-cell immunotherapy company that is developing novel treatments for patients with cancer, autoimmune and viral diseases.

We have several T-cell immunotherapies in clinical development and are progressing a next-generation allogeneic chimeric antigen receptor T-cell, or CAR T program.

Atara Biotherapeutics is a pioneer in T-cell immunotherapy, leveraging its novel allogeneic Epstein-Barr virus (EBV) T-cell platform to develop transformative therapies for patients with serious diseases, including solid tumors, hematologic cancers and autoimmune disease.

With our lead program in Phase 3 clinical development, we are the most advanced allogeneic T-cell immunotherapy company and intend to rapidly deliver off-the-shelf treatments to patients with high unmet medical need.

Our platform leverages the unique biology of EBV T cells and has the capability to treat a wide range of EBV-driven diseases or other serious diseases through incorporation of engineered chimeric antigen receptors (CARs) or T-cell receptors (TCRs).

Atara is applying this one platform to create a robust pipeline.

Our strategic priorities are:

Atara’s most advanced T-cell immunotherapy, tab-cel ® (tabelecleucel), currently in Phase 3 development for patients with Epstein-Barr virus, or EBV, associated post-transplant lymphoproliferative disease, or EBV+ PTLD, who have failed rituximab or rituximab plus chemotherapy, as well as other EBV-associated hematologic malignancies and solid tumors;

Atara’s most advanced T-cell immunotherapy, tab-cel ® (tabelecleucel), currently in Phase 3 development for patients with EBV-driven post-transplant lymphoproliferative disease (EBV+ PTLD) who have failed rituximab or rituximab plus chemotherapy, as well as other EBV-driven diseases;

T-cell immunotherapy targeting EBV antigens believed to be important for the potential treatment of multiple sclerosis;

ATA2271/ATA3271 :

CAR T immunotherapy targeting mesothelin, with autologous (ATA2271) to allogeneic (ATA3271) development planned ;

Allogeneic CAR T targeting CD19 as proof-of-concept for our next generation technologies and EBV T-cell CAR T platform.

CAR T Programs :

Autologous CAR T immunotherapy targeting solid tumors expressing the tumor antigen mesothelin, which is partnered with Bayer AG (Bayer);

Allogeneic CAR T therapy targeting mesothelin, which is partnered with Bayer;

Allogeneic CAR T targeting CD19 and being developed as a potential best-in-class product, based on a next generation 1XX co-stimulatory domain and the innate advantages of EBV T cells as the foundation for an allogeneic CAR T platform.

Our T-cell immunotherapy platform includes the capability to progress both allogeneic and autologous programs and is potentially applicable to a broad array of targets and diseases.

Our off-the-shelf, allogeneic T-cell platform allows for rapid delivery of a T-cell immunotherapy product that has been manufactured in advance and stored in inventory, with each manufactured lot of cells providing therapy for numerous potential patients.

This differs from autologous treatments, in which each patient’s own cells must be extracted, modified outside the body and then delivered back to the patient.

For tab-cel ® , we utilize a proprietary cell selection algorithm to select the appropriate set of cells for use based on a patient’s unique immune profile.

This matching process is designed to allow our cells to be administered without the pre-treatment that is required for some therapies and to reduce monitoring following administration.

In addition, our manufacturing facility is capable of producing multiple types of therapies and Atara MatchMe™, our proprietary T-cell order management platform, is being developed to provide patient care teams with access to therapy.

We have entered into research collaborations with leading academic institutions such as Memorial Sloan Kettering Cancer Center, or MSK, the Council of the Queensland Institute of Medical Research, or QIMR Berghofer, and H.

Lee Moffitt Cancer Center and Research Institute, or Moffitt, to acquire rights to novel and proprietary technologies and programs.

We recognize that our clinical studies may not be available to all patients and we have established expanded access and compassionate use programs in instances where there is a significant patient need.

Our off-the-shelf, allogeneic T-cell platform allows for rapid delivery of a T-cell immunotherapy product manufactured in advance of patient need and stored in inventory, with each manufactured lot of cells providing therapy for numerous potential patients.

This differs from autologous treatments, in which each patient’s own cells must be extracted, genetically modified outside the body and then delivered back to the patient, requiring a complex logistics network.

For our allogeneic programs, we select the appropriate set of cells for use based on a patient’s unique immune profile.

In addition, our manufacturing facility has the flexibility to manufacture multiple T-cell and CAR T immunotherapies while integrating research and process science functions to enable increased collaboration for rapid product development .

We are currently in the process of completing our facility’s commercial production qualification activities for tab-cel ® while building inventory according to our commercial product supply strategy.

In December 2020, we entered into a Research, Development and License Agreement with Bayer (the Bayer License Agreement) pursuant to which we granted to Bayer an exclusive, field-limited license under the applicable patents and know-how owned or controlled by us and our affiliates covering or related to ATA2271 and ATA3271.

See section ‘Terms of Certain License and Research and Development Collaboration Agreements’ below for additional details.

We have also entered into research collaborations with leading academic institutions such as Memorial Sloan Kettering Cancer Center (MSK), the Council of the Queensland Institute of Medical Research (QIMR Berghofer) and H.

Lee Moffitt Cancer Center and Research Institute (Moffitt) pursuant to which we acquired rights to novel and proprietary technologies and programs.

Our pipeline is summarized below:

These investigational agents have not been approved by any regulatory agency.

These investigational agents are not approved by any regulatory agencies.

Efficacy and safety have not been established.

EBV-Associated Post-Transplant Lymphoproliferative Disease;

EBV-driven Post-Transplant Lymphoproliferative Disease;

rituximab relapsed/refractory;

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Other programs:

ATA2321 (AML), ATA2431 (B-cell malignancies), ATA230 (CMV), ATA368 (HPV), ATA520 (WT1) and ATA621 (BK/JCV)

Phase 1b/2 study in combination with anti-PD-1 therapy, KEYTRUDA ® (pembrolizumab), in patients with platinum-resistant or recurrent EBV-associated NPC.

Phase 2 multi-cohort study planned with possible indications including EBV+ PTLD with CNS involvement, EBV+ PID/AID LPD, EBV+ LMS and other potential EBV-associated diseases

ATA2321 (AML), ATA2431 (B-cell malignancies), and ATA368 (HPV)

Phase 2 multi-cohort initiated in Q3 2020, with possible indications including EBV+ PTLD with CNS involvement, EBV+ PID/AID LPD, EBV+ LMS and other potential EBV-driven diseases

Phase 1b/2 study in combination with anti-PD-1 therapy, KEYTRUDA ® (pembrolizumab), in patients with platinum-resistant or recurrent EBV-driven NPC

Targeted antigen recognition technology;

Phase 2 Randomized Controlled Trial

Mesothelin is expressed at high levels on the surface of cells in aggressive solid tumors including mesothelioma, triple-negative breast cancer, esophageal cancer, pancreatic cancer and non-small cell lung cancer

MSK investigator-sponsored Phase 1 study (NCT02414269) of a mesothelin-targeted CAR T immunotherapy is ongoing;

Atara’s CAR T collaboration with MSK will focus on development of a next-generation, mesothelin-targeted CAR T using novel 1XX CAR signaling and PD-1 dominant negative receptor (DNR) checkpoint inhibition technologies

Worldwide license agreement and research, development and manufacturing collaboration with Bayer to develop Atara’s allogeneic off-the-shelf mesothelin CAR T program (ATA3271) and autologous program (ATA2271)

Since its discovery as the first human oncovirus, EBV has been implicated in the development of a wide range of diseases, including lymphomas and other cancers.

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In healthy individuals, a small percentage of T cells are devoted to keeping EBV in check.

In contrast, immunocompromised patients, such as those undergoing hematopoietic cell transplants, or HCT, or solid organ transplants, or SOT, have a reduced ability to control EBV.

In contrast, immunocompromised patients, such as those undergoing hematopoietic cell transplants (HCT) or solid organ transplants (SOT) have a reduced ability to control EBV.

Left without appropriate immune surveillance, EBV-transformed cells can, in some patients, proliferate and cause an aggressive, life-threatening cancer called EBV+ PTLD .

Nearly all cases of PTLD that occur following HCT are EBV positive while approximately 60% of PTLD cases that occur following SOT are EBV positive.

Approximately 10-15% of PTLD patients are children.

Historical studies suggest a high unmet medical need for improved therapies in patients with EBV+ PTLD who have failed rituximab or rituximab plus chemotherapy , with approximately 40 % to 60% of patients either not responding to or progressing following this first line of therapy.

Expected median overall survival in patients with EBV+ PTLD following HCT who have failed rituximab-based first line therapy is between 16 and 56 days, with a one-year survival rate of approximately 23% based on our evaluation of available historical outcomes data.

Estimated one- and two-year survival following incomplete response to rituximab in patients with high-risk EBV+ PTLD after SOT is 36% and 0%, respectively.

Expected median overall survival in patients with EBV+ PTLD following HCT who have failed rituximab-based first line therapy is approximately 1.7 months, and for patients with EBV+ PTLD following SOT who have failed rituximab-based first line therapy, the median overall survival is approximately 3.3 months.

The use of chemotherapy in patients with EBV+ PTLD who have failed rituximab is frequently associated with significant rates of treatment-related mortality due to the frailty of the patients and severe toxicities associated with chemotherapy.

Based on our market research, we estimate there were several hundred EBV+ PTLD patients who failed rituximab or rituximab plus chemotherapy in the U.S.

In June 2015, we licensed certain patent rights, know-how and a library of T cells and cell lines specific to EBV from MSK in an agreement we refer to as the 2015 MSK License Agreement.

In the 2015 MSK License Agreement, we agreed to use commercially reasonable efforts to commercialize the licensed products and to make milestone payments with respect to the licensed programs and to make royalty payments to MSK to the extent product candidates arising from the collaboration are commercialized.

Our most advanced product candidate, tab-cel ® , is part of this MSK collaboration and targets EBV.

Tab-cel ® is an allogeneic EBV-specific T-cell immunotherapy that is in development for the treatment of EBV-associated hematologic malignancies and solid tumors.

Tab-cel ® is currently in Phase 3 development for the treatment of patients with EBV+ PTLD who have failed rituximab or rituximab plus chemotherapy.

Based on our market research, we estimate there were several hundred EBV+ PTLD patients who failed rituximab or rituximab plus chemotherapy in the U.S.

Tab-cel ® received Breakthrough Therapy Designation, or BTD, from the U.S.

Food and Drug Administration, or FDA, for the treatment of patients with EBV+ PTLD after HCT who have failed rituximab, Priority Medicines, or PRIME, designation from the European Medicines Agency, or EMA, for the same indication, and orphan designation in the U.S.

and European Union for the treatment of patients with EBV+ PTLD following HCT or SOT.

Tab-cel ® is also under development for other EBV-associated hematologic malignancies and solid tumors through a multi-cohort study, and for nasopharyngeal carcinoma, or NPC, in a separate clinical study.

Tab-cel ® for EBV+ PTLD

In June 2015, we licensed certain patent rights, know-how and a library of T cells and cell lines specific to EBV from MSK under an exclusive license agreement.

In accordance with the license agreement, we agreed to use commercially reasonable efforts to commercialize the licensed products and to make milestone payments with respect to the licensed programs and to make royalty payments to MSK to the extent product candidates arising from the collaboration are commercialized.

Our most advanced product candidate, tab-cel ® , is part of this MSK collaboration and targets EBV.

Tab-cel ® is an allogeneic EBV-specific T-cell immunotherapy that is currently in Phase 3 development for the treatment of patients with EBV+ PTLD who have failed rituximab or rituximab plus chemotherapy.

Tab-cel ® is also under development for other EBV+ diseases with significant unmet medical need through a Phase 2 multi-cohort study that was initiated in the third quarter of 2020.

Tab-cel ® has received Breakthrough Therapy Designation (BTD) from the U.S.

Food and Drug Administration (FDA) for the treatment of patients with EBV+ PTLD after HCT who have failed rituximab, PRIority MEdicines (PRIME) designation from the European Medicines Agency (EMA) for the same indication, and orphan designation in the U.S.

and European Union (EU) for the treatment of patients with EBV+ PTLD following HCT or SOT.

In clinical studies conducted at MSK that have enrolled patients with EBV+ PTLD following HCT and SOT, efficacy following treatment with tab-cel ® monotherapy compared favorably with historical data in these patient populations.

Patients with EBV+ PTLD after HCT who have failed rituximab and were treated with tab-cel ® had one-year overall survival of approximately 70% in two separate clinical studies .

In the setting of EBV+ PTLD after SOT in patients who have failed rituximab , similar results were observed, with one-year overall survival of approximately 60% in tab-cel ® -treated patients.

Patients with EBV+ PTLD after HCT who have failed rituximab and were treated with tab-cel ® had two-year overall survival of approximately 83% in two separate clinical studies .

In the setting of EBV+ PTLD after SOT in patients who have failed rituximab , similar results were observed, with two-year overall survival of approximately 86% in tab-cel ® -treated patients.

A response rate of greater than or equal to 50% was observed in HCT and SOT patients in these studies.

In December 2017, we initiated two Phase 3 studies for tab-cel ® intended to support approval in two separate indications, the treatment of EBV+ PTLD following HCT (which was referred to as the MATCH study) and SOT in patients who have failed rituximab ( which was referred to as the ALLELE study).

The Phase 3 MATCH study was a multicenter, open label, single arm study designed to enroll approximately 35 patients with EBV+ PTLD following HCT who have failed rituximab .

The Phase 3 ALLELE study was initially a multicenter, open label study designed with two non-comparative cohorts of approximately 35 patients each.

The first cohort included patients who previously received rituximab monotherapy, and the second cohort included patients who previously received rituximab plus chemotherapy.

The primary endpoint of both the MATCH and ALLELE studies was confirmed best objective response rate, or ORR, defined as the percent of patients achieving either a complete or partial response to treatment with tab-cel ® confirmed after the initial tumor assessment showing a response.

In 2019 , after discussion and alignment with regulators, we combined MATCH and ALLELE into a single study (which we now refer to as the ALLELE study) that now consists of an HCT cohort for EBV+ PTLD patients who have failed rituximab and an SOT cohort for EBV+ PTLD patients who have failed rituximab with both chemotherapy and non-chemotherapy prior treatment experience.

The primary endpoint of ALLELE remains as confirmed best ORR, as determined by independent review, and is designed to rule out a 20% ORR as the null hypothesis.

This means that if the lower bound of the 95% confidence interval on ORR among patients receiving at least one dose of tab-cel ® exceeds 20% at the end of the study, then the study would be expected to meet the primary endpoint for the treatment of PTLD.

For example, assuming enrollment of 33 patients in a cohort of ALLELE, an observed

ORR above approximately 37% would be expected to meet the primary endpoint for that cohort .

Secondary endpoints include duration of response, overall survival, safety, quality of life metrics, and other measures to evaluate its health economic impact.

Additionally, we expect to expand the ALLELE study geographically to include clinical sites outside the U.S.

W e submitted clinical trial applications , or CTAs , to several European countries in 2019 to enable opening EU clinical sites in 2020 , and our CTAs in Austria, Spain and the United Kingdom have been approved .

We plan to initiate a biologics license application, or BLA, submission for patients with EBV+ PTLD to the FDA in the second half of 2020.

We plan to discuss the totality of tab-cel ® results with the FDA in a pre-BLA meeting prior to initiating the BLA submission.

We are also planning the submission of a marketing authorization of tab-cel ® in the European Union.

In February 2016, tab-cel ® was granted orphan drug designation by the European Commission for the treatment of patients with post-transplant lymphoproliferative disorder.

Tab-cel ® has also been granted access to the PRIME scheme.

PRIME is a program launched by the EMA to enhance support for the development of medicines that target an unmet medical need.

This voluntary program is based on enhanced interaction and early dialogue with developers of promising medicines, to optimize development plans and speed up evaluation so these medicines can reach patients earlier.

The program focuses on medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options.

These medicines are considered priority medicines by EMA.

To be accepted for PRIME, a medicine must show its potential to benefit patients with unmet medical needs based on early clinical data .

We remain in discussions with the European Medicines Agency, or EMA.

We have submitted a Pediatric Investigation Plan, or PIP, to EMA.

Following an agreement with EMA on the PIP, we plan to submit a tab-cel ® EU marketing authorization application for patients with EBV+ PTLD in 2021.

We are continuing our preparations to support the planned commercialization of tab-cel ® .

This includes the development of our proprietary T-cell order management platform, Atara MatchMe TM , that is being developed to provide patient care teams with access to therapy through a web-based interface.

We expect to pursue approvals in key geographies and may seek partners to aid in our commercialization efforts in select markets.

In 2019 , after discussion and alignment with regulators, we combined MATCH and ALLELE into a single study (which we now refer to as the ALLELE study) that now consists of an HCT cohort for EBV+ PTLD patients who have failed rituximab, and a single SOT cohort for EBV+ PTLD patients who have failed prior treatment with rituximab with or without chemotherapy.

Additionally, we expanded the ALLELE study geographically to include clinical sites in Europe and Canada .

We completed an interim analysis for the ALLELE study in the third quarter of 2020.

Data from the interim analysis showed a 50 percent objective response rate (ORR) to tab-cel ® with independent oncologic and radiographic assessment (IORA) in patients with relapsed-refractory EBV+ PTLD following HCT or SOT, that had reached at least six months follow-up after the ORR assessment.

This ORR is consistent with previously published investigator assessed data.

The tab-cel ® safety profile is also consistent with previously published data, with no new safety signals.

In January 2021, we presented transcriptional data for tab-cel ® at the 2021 Transplantation & Cellular Therapy Meeting demonstrating consistency of the product’s activation profile irrespective of donor and consistent enrichment of receptors targeting EBV-driven diseases.

Prior to initiating the BLA, we require a procedural decision from the FDA related to how the historical non-pivotal data should be presented in the BLA submission.

Following FDA agreement in October 2020 that the pivotal ALLELE data will be the primary basis for approval, and that historical non-pivotal clinical data will be supportive, the FDA needs to decide whether they view the drug product manufactured by our academic partner used in historical, non-pivotal studies as comparable to the drug product manufactured by Atara used in the pivotal ALLELE study.

This decision will then determine if we will submit in the clinical module the pivotal and non-pivotal data combined in pooled analyses or separately in parallel analyses.

The type of analysis does not change expectations regarding the proposed product indication for previously treated patients with EBV+ PTLD.

We continue to have ongoing active and productive dialogue with the FDA, which has already resulted in several key points of agreement, including:

(i) a rolling submission is acceptable for the BLA, (ii) we can complete the BLA submission with currently enrolled patients in the pivotal ALLELE study with at least six-months follow-up of duration of response, and (iii) the FDA will consider historical data from the Phase 2 trials conducted at MSK, our Phase 2 multicenter expanded access protocol (EAP) and the Single Patient Use (SPU) program as supportive data to the pivotal ALLELE study in the BLA clinical module.

We have completed the preclinical module 4 and are ready to initiate a rolling BLA with this module once the FDA decides on a procedural question related to how the historical non-pivotal data should be presented in the BLA submission.

We are also making progress through active and productive discussions with the FDA to align on the final content of the chemistry, manufacturing and control ( CMC ) module 3 of the BLA .

We remain on track to complete a rolling BLA submission for patients with EBV+ PTLD with the clinical module in the third quarter of 2021.

We expect to present data from the pivotal ALLELE study at an appropriate congress in the fourth quarter of 2021.

We anticipate potential approval of the BLA in the first half of 2022.

We are also planning to submit a tab-cel ® marketing authorization application (MAA) for patients with EBV+ PTLD in the EU in the fourth quarter of 2021.

We received a positive opinion from the Pediatric Committee (PDCO) of the EMA regarding a Pediatric Investigation Plan (PIP) in November 2020, and the EMA ratified our PIP in December 2020.

We anticipate potential approval of the MAA in the second half of 2022.

While clinical study operations and the opening of additional ALLELE sites in the United States, Canada and Europe have been impacted by the spread of COVID-19, most sites are currently open for patient enrollment.

We are continuing our preparations and investing further in commercial readiness activities in anticipation of planned commercialization of tab-cel ® in the U.S.

We expect to pursue approvals in key geographies and are seeking a partner for the commercialization of tab-cel ® outside the U.S.

Tab-cel ® Multi-Cohort Study

We expect to pursue development of tab-cel ® in earlier lines of therapy, including in our planned Phase 2 multi-cohort study.

We expect to initiate enrollment in this study including up to six additional EBV+ ultra-rare diseases for patients, in the second half of 2020 based on previous clinical experience treating these patients.

We continue to pursue development of tab-cel ® in earlier lines of therapy with the goal of expanding the potential label in PTLD and closely related diseases.

We intend to focus on extending further into immunodeficiency-associated lymphoproliferative diseases (IA-LPDs) as the next step in the tab-cel ® potential label expansion given the commonality of their EBV-driven mechanism of disease in immunocompromised patients, high unmet medical need and positive clinical data to date with tab-cel ® .

We initiated a Phase 2 multi-cohort study in the third quarter of 2020 concurrently in the U.S.

The multi-cohort study will evaluate both treatment-naïve and previously treated patients in six patient populations, including four within IA-LPDs and two in other EBV-driven diseases.

Data from this Phase 2 study is expected in 2023.

Data was featured in an e-poster at the European Society for Medical Oncology (ESMO) 2020 Virtual Congress in September 2020 and demonstrated that tab-cel ® was well-tolerated and showed encouraging clinical activity in patients with EBV+ AID-LPD and EBV+ PID-LPD (Acquired and Primary Immunodeficiency Lymphoproliferative Diseases).

In patients where previous treatments have failed, the objective response rates, including complete response, were 33.3% (three out of nine patients) in AID-LPD and 37.5% (three out of eight patients) in PID-LPD groups.

Tab-cel ® was generally well-tolerated with a favorable safety profile consistent with previously published clinical studies.

Data on tab-cel ® in patients with life-threatening complications stemming from persistent EBV viremia were presented at the 62 nd American Society of Hematology (ASH) Annual Meeting and Exposition in December 2020.

These clinical data demonstrated that tab-cel ® was well-tolerated and showed encouraging clinical activity in this patient population, with objective response rates ranging from 50% (two out of four patients) to 80% (four out of five patients).

The overall survival (OS) rate at one year in patients with EBV viremia treated in the EAP-201 study was 100 percent for a median follow-up of 14.6 months (min 12.2, max 17.8).

Tab-cel ® for NPC

NPC is a type of head and neck cancer that is primarily associated with EBV.

Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer that is primarily associated with EBV.

Standard treatment for NPC typically includes radiation therapy, platinum-based chemotherapy or a combination of both.

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In April 2017, we entered into an agreement with Merck Sharp & Dohme (known as MSD outside of the U.S.

and Canada) to provide drug supply for a study to be sponsored and conducted by us to evaluate tab-cel ® in combination with Merck’s anti-PD-1 (programmed death receptor-1) therapy, KEYTRUDA ® (pembrolizumab), in patients with platinum-resistant or recurrent EBV-associated NPC.

This Phase 1b/2 study, which was initiated in the fourth quarter of 2018, will evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the combination.

We enrolled the final planned patient in the Phase 1b part of the study in February 2020.

Based on our market research, we estimate the incidence during 2018 of NPC in the U.S., United Kingdom, France, Italy and Spain was collectively approximately 3,800 patients and approximately 71,000 patients in East Asia.

Our study is designed to address a sub-population of the total incidence of this disease.

EAP and SPU Programs

Atara continues to see strong tab-cel ® investigator, physician and patient interest and, for cases in which we are not able to enroll patients in its EBV+ PTLD Phase 3 clinical study, we are providing tab-cel ® to patients in need under our expanded access protocol, or EAP, and single patient use, or SPU, programs.

The primary objective of these programs is to provide tab-cel ® monotherapy to patients with EBV-associated diseases or certain EBV + malignancies for whom there are no other therapeutic options.

Our Phase 1b study, which was initiated in 2018, achieved its safety endpoints and stable disease in some patients.

Based on a strategic prioritization to expand tab-cel ® business potential through the significant opportunity in IA-LPDs, we will focus our tab-cel ® efforts on the execution of the Phase 2 multi-cohort study and the planned BLA initiation in EBV+ PTLD.

At this time, we will not initiate the Phase 2 portion of the NPC study in combination with pembrolizumab .

W e intend to generate additional translational data in NPC in 2021 to further inform our strategy on this p atient population .

We plan to share data from the NPC study at an appropriate forum in the future.

Multiple Sclerosis

Atara is also developing ATA188, a T-cell immunotherapy targeting EBV antigens believed to be important for the potential treatment of multiple sclerosis, or MS.

MS is a chronic autoimmune disorder of the central nervous system, or CNS, that disrupts the myelination and normal functioning of the brain, optic nerves and spinal cord through inflammation and tissue loss.

We are also developing ATA188, an allogeneic T-cell immunotherapy targeting EBV antigens believed to be important for the potential treatment of multiple sclerosis (MS).

MS is a chronic autoimmune disorder of the central nervous system (CNS) that disrupts the myelination and normal functioning of the brain, optic nerves and spinal cord through inflammation and tissue loss.

The evolution of MS results in an increasing loss of both physical and cognitive (e.g., memory) function.

This has a substantial negative impact on the more-than two million people worldwide affected by MS, with approximately 800,000 diagnosed prevalent cases of MS in the U.S.

and EU in 2019 .

This has a substantial negative impact on the approximately 2.3 million patients worldwide diagnosed and living with MS, with approximately one million of those patients having a progressive form of MS.

There are two categories of MS:

progressive MS, or PMS, and relapsing-remitting MS, or RRMS.

progressive MS (PMS) and relapsing-remitting MS (RRMS).

RRMS is a form of MS that is characterized by episodes of new or worsening signs or symptoms (relapses) followed by periods of recovery and quiescence during which the disease does not progress.

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There are two types of PMS:

primary progressive MS, or PPMS, and secondary progressive MS, or SPMS.

Published reports indicate that together, PPMS and SPMS make up approximately 43% of MS patients.

primary progressive MS (PPMS) and secondary progressive MS (SPMS).

PPMS occurs when the patient has a disease course characterized by steady and progressive worsening after disease onset.

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The role of B cells in MS is supported by the approval by the FDA of ocrelizumab for PPMS, which broadly targets B cells (and not plasma cells) outside of the CNS through their expression of a cell surface marker known as CD20.

Based on our analysis of industry data and assumed increases in treatment rates and market share for a best-in-class treatment, we estimate that the potential annual U.S.

market opportunity in PMS could be at least $3.5 billion by 2025.

ATA188 for MS

We licensed rights to certain know-how and technology from QIMR Berghofer that uses targeted antigen recognition to create off-the-shelf T-cell immunotherapy product candidates applicable to a variety of diseases, including autoimmune conditions such as MS.

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The primary objective of this Phase 1 study is to assess the safety of ATA188 in patients followed for at least one year after the first dose.

Key secondary endpoints in the study include measures of clinical improvement, using recognized scales for MS symptoms, function and disability including Expanded Disability Status Scale, or EDSS, Fatigue Severity Score, MS Impact Scale-29 (physical), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test, 12-Item MS Walking Scale (MSWS-12) and Visual Acuity.

Enrollment for the fourth and final Phase 1 dose escalation cohort was completed in the third quarter of 2019 and we presented initial efficacy and updated safety results from this study in September 2019 at the 35 th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

These results were based on data as of July 29, 2019, and showed that across four planned dose cohorts, ATA188 was well tolerated in PMS patients, with no evidence of cytokine release syndrome, graft versus host disease or dose-limiting toxicities.

Following a six-month assessment of patients in cohort 3 of this study, we selected this cohort 3 dose to initiate the randomized, double-blind, placebo-controlled Phase 1b part of this study , for which we plan to initiate enrollment for patients with PMS in the second or third quarter of 2020 .

We expect to present six- and twelve-month ATA188 Phase 1a clinical results for cohorts 3 and 4 in the first and second halves of 2020, respectively .

In addition to ATA188, QIMR Berghofer had previously completed a Phase 1 study of ATA190, an autologous EBV-specific T-cell preparation that utilizes the same approach to targeted antigen recognition as ATA188, for the treatment of patients with PMS.

Based on continued encouraging ATA188 results, acceleration of the ATA188 randomized Phase 1b study and the Company’s strategic focus on off-the-shelf, allogeneic T-cell immunotherapies, Atara does not plan to initiate a randomized study of ATA190 in PMS at this time and will evaluate strategic options for this program.

Key secondary endpoints in the study include measures of clinical improvement , using recognized scales for MS symptoms, function and disability including Expanded Disability Status Scale ( EDSS ) , Fatigue Severity Score, MS Impact Scale-29 (physical), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test, 12-Item MS Walking Scale (MSWS-12) and Visual Acuity .

Enrollment for the fourth and final dose escalation cohort in the Phase 1a portion of the study was completed in the third quarter of 2019 and we presented updated efficacy and safety results from this study at the MSVirtual2020:

8 th Joint ACTRIMS-ECTRIMS Meeting in September 2020.

The data demonstrated that ATA188 was well-tolerated across all four dose cohorts, with no dose-limiting toxicities and no fatal adverse events.

Additionally, patients who demonstrated sustained disability improvement (SDI) at any timepoint maintained improvement at all future timepoints, and higher proportion of patients showed SDI with increasing dose (42% in cohorts 3 and 4 (higher doses) versus 17% in cohorts 1 and 2 (lower doses)).

SDI is defined as clinically significant improvement in EDSS or T25FW observed at two consecutive time points.

ATA188 treatment showed no clinically meaningful effect on cytokine levels and no dose-related safety trends were identified.

Rhinorrhea (runny nose) was the only treatment-related event that occurred in more than one subject.

No dose-limiting toxicities and no fatal adverse events have been reported.

The safety profile has remained consistent with previously reported data.

We also presented preclinical translation data at ACTRIMS-ECTRIMS that further support the proposed mechanism of action of ATA188 targeting EBV-infected B cells.

These combined analyses of T cells comprising ATA188 are consistent with its proposed mechanism of targeting EBV-infected B cells by recognizing MS-relevant EBV antigens on these cells via defined TCRs.

While these data will need to be confirmed in a double-blind, placebo-controlled, randomized study, they indicate the potential for the first treatment option in PMS to halt or reverse the progression of disease.

We believe these results align with the body of evidence supporting the important role of EBV-infected B cells in the chronic autoimmune pathology of MS.

We are also re-treating patients with Cohort 3 dose in an open-label extension (OLE) of the Phase 1a study and we presented the first available data from the OLE at the ACTRIMS-ECTRIMS Meeting in September 2020 .

We presented updated data from the OLE in an e-poster at the European Charcot Foundation 28 th Annual Meeting in November 2020, including data on 24 patients from the 12-month dose escalation portion of the trial, 16 of whom entered the OLE and had ≥ 15-month data available as of October 2020.

Throughout the entire Phase 1a and OLE study, nine of the 16 patients who entered the OLE demonstrated SDI with ATA188 treatment (seven achieved SDI in the first 12 months and two during the OLE).

In seven out of the nine patients, SDI was driven by sustained improvement in EDSS.

A dose-related increase in the number of patients meeting SDI criteria was observed.

Similar safety profile with no dose-limiting toxicities was shown in the highest dose cohorts (Cohorts 3 and 4).

In the two highest dose cohorts, five out of 12 total patients (42%) and six out of 12 total patients (50%) demonstrated SDI at 12 and 15 months, respectively.

SDI was driven by EDSS in all but one of the patients in Cohorts 3 and 4;

all SDI observed in Cohort 4 was based on EDSS improvement.

The Cohort 3 and 4 doses demonstrated similar efficacy profile based on SDI, with the Cohort 4 dose trending toward greater effect on EDSS.

We plan to re-treat patients in the OLE with Cohort 4 dose in subsequent years.

We plan to present translational data in the first half of 2021 at an appropriate forum and long-term two-year clinical data from the OLE in the second half of 2021.

In January 2021, we presented a poster at the 2021 Transplantation & Cellular Therapy Meeting an innovative testing solution that enables detection and quantification of non-engineered allogeneic T-cell therapies for use in ATA188 clinical development.

We initiated a randomized, double-blind, placebo-controlled trial (RCT) to evaluate the efficacy and safety of ATA188 in patients with PMS using the cohort 3 dose and enrolled the first patient in June 2020.

This study was previously designated as Phase 1b and, based on recent program changes, it is now designated as a Phase 2.

We discussed updates to the design of the RCT study with the FDA in January 2021 and gained alignment on several points for the RCT, as well as potential registrational studies:

(i) a disability improvement endpoint is appropriate, with the FDA articulating a preference for EDSS improvement;

(ii) the criteria used to enroll the study population of SPMS and PPMS are appropriate;

and (iii) the Phase 2 RCT should run for at least 12 months, and a properly conducted interim analysis is appropriate.

We also submitted a protocol amendment to the FDA, increasing the number of patients to 80, changing the primary end point of the study to EDSS disability improvement and maintaining the biological and functional endpoints.

We plan to continue discussions with the FDA about potential opportunities for accelerated development of ATA188.

We plan to conduct an interim analysis to assess efficacy and safety in the first half of 2022 and following the interim analysis, we expect to complete planned enrollment of the Phase 2 RCT in the first half of 2022.

Based on the most recent data from the Phase 1a portion of the study, which shows a higher proportion of patients showing sustained EDSS improvements and a consistent safety profile over 15 months, we have selected the cohort 4 dose for enrollment in the Phase 2 RCT.

In addition to measuring change in disability measures compared to baseline, especially SDI over time, the study also includes multiple measures of patients’ function as well as various biomarkers.

CAR T Programs

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Dominant Negative Receptor

Mesothelin is expressed at high levels on the surface of cells in aggressive solid tumors including mesothelioma, triple-negative breast cancer, pancreatic cancer and non-small cell lung cancer.

ATA2271/ATA3271

Atara’s pipeline includes next-generation CAR T immunotherapies for patients with hematologic malignancies and solid tumors, and viral diseases, including ATA2271 and ATA3271 targeting mesothelin, which are partnered with MSK .

Our next-generation CAR T immunotherapy programs include autologous ATA2271 and allogeneic ATA3271 targeting mesothelin, which is a tumor antigen expressed on a number of solid tumors including mesothelioma, ovarian cancer, pancreatic cancer, non-small cell lung cancer and other tumors over-expressing mesothelin .

ATA2271 is designed to improve efficacy persistence, and durability of response versus CD28/CD3z-based CARs by using a novel 1XX CAR co-stimulatory signaling domain and cell intrinsic checkpoint inhibition technology with a PD-1 dominant negative receptor (DNR).

In 2018, we entered into several agreements to expand our collaboration with MSK to the development of CAR T immunotherapies, with a license in May 2018 related to multiple collaboration targets and a license in December 2018 related to our next-generation CAR T program targeting mesothelin.

Under these CAR T agreements, we agreed to use commercially reasonable efforts to develop, obtain regulatory approval and, if approved, commercialize certain collaboration targets and to make certain milestone and royalty payments.

We have prioritized our mesothelin-targeted next-generation CAR T program, which consists of ATA2271 and ATA3271.

Results presented by our collaborators at MSK have demonstrated that their regionally-delivered mesothelin-targeted, 1 st generation autologous CAR T cells were well tolerated and showed encouraging anti-tumor activity in combination with pembrolizumab, a PD-1 checkpoint inhibitor.

These collaborator results support our planned development of ATA2271, a next-generation, mesothelin-targeted autologous CAR T immunotherapy using MSK’s novel 1XX CAR signaling domain and PD-1 dominant negative receptor, or DNR, checkpoint inhibition technologies for patients with mesothelin-associated solid tumors.

We expect our collaborators at MSK to submit an investigational new drug, or IND, application to the FDA for ATA2271 for patients with advanced mesothelioma in the second or third quarter of 2020.

In parallel, we are conducting preclinical work on an allogeneic version of this mesothelin CAR T program, ATA3271.

We are also developing ATA3219, an off-the-shelf allogeneic CAR T immunotherapy targeting CD19 for patients with B-cell lymphomas , to serve as a potential proof-of-concept for our next generation technologies and allogeneic EBV CAR T platform.

In February 2020, an academic off-the-shelf, allogeneic CD19 CAR T clinical study using an EBV T-cell construct for patients with relapsed/refractory B-cell malignancies was presented at the 2020 Transplantation and Cellular Therapy (TCT) Meetings.

Findings from this study provide initial clinical proof-of-principle that an EBV T-cell platform has the potential to generate off-the-shelf, allogeneic CAR T immunotherapies with high and durable responses, low risk of toxicity and that can be rapidly delivered to patients.

Data from investigational new drug (IND) enabling studies for ATA2271 were presented at the American Association for Cancer Research (AACR) Virtual Meeting II in June 2020.

These data support the first application of the combination of 1XX co-stimulatory domain and cell intrinsic checkpoint inhibition technology with a PD-1 DNR that are associated with less cell exhaustion, improvements in functional persistence, serial cell killing and in vivo efficacy, which was maintained through multiple tumor re-challenges when compared with first-generation CD28/CD3z-based mesothelin CAR.

The FDA accepted the IND application submitted by our collaborators at MSK in August 2020, and in September 2020, MSK initiated an open-label, single-arm Phase 1 clinical study of ATA2271 for patients with advanced mesothelioma.

MSK has enrolled several patients into this study and we expect first Phase 1 data from this study to be presented in the fourth quarter of 2021.

We are also developing and have initiated IND-enabling studies for ATA3271, an off-the-shelf, allogeneic CAR T therapy targeting mesothelin using a PD-1 DNR and 1XX CAR co-stimulatory signaling domain through our EBV T-cell platform, and we expect to file the IND in the second half of 2022.

Preclinical data for ATA3271 demonstrates potent anti-tumor activity, functional persistence and significant survival benefit with no evidence of allocytotoxicity in vivo, suggesting that allogeneic MSLN-CAR-engineered EBV T cells are a promising approach for the treatment of MSLN-positive cancers.

These data were presented at the Society for Immunotherapy of Cancer (SITC) 35 th Anniversary Annual Meeting in November 2020.

In December 2020, we entered into the Bayer License Agreement pursuant to which we granted to Bayer an exclusive, field-limited license under the applicable patents and know-how owned or controlled by us and our affiliates covering or related to ATA2271 and ATA3271.

See section ‘Terms of Certain License and Research and Development Collaboration Agreements’ below for additional details.

We are also developing ATA3219, an off-the-shelf, allogeneic CD19 CAR T immunotherapy targeting B-cell malignancies as a potential best-in-class therapy without the need for TCR gene editing, using our next-generation 1XX CAR co-stimulatory domain and EBV T-cell platform.

In February 2020, an academic off-the-shelf, allogeneic CD19 CAR T clinical study using an allogeneic EBV T-cell construct and CD28/CD3z co-stimulatory domain for patients with relapsed/refractory B-cell malignancies was presented at the 2020 Transplantation and Cellular Therapy (TCT) Meetings.

Findings from this study provided initial clinical proof-of-principle that an EBV T-cell platform has the potential to generate off-the-shelf, allogeneic CAR T immunotherapies with high response rates, durable responses and low risk of toxicity that can be rapidly delivered to patients.

Preclinical data for ATA3219 demonstrate functional persistence, polyfunctional phenotype and efficient targeting of CD19-expressing tumor cells both in vitro and in vivo.

An abstract detailing this ATA3219 preclinical data was presented at the 62 nd ASH Annual Meeting and Exposition in December 2020.

We had a pre-IND meeting with the FDA in October 2020, where we received feedback to guide the IND filing for ATA3219.

We have initiated IND-enabling studies and plan to submit an IND for ATA3219 for patients with B-cell malignancies in the fourth quarter of 2021 or first quarter of 2022.

Additional Programs and Platform Expansion Activities

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For example, in August 2018, we entered into a strategic collaboration with Moffitt.

As part of this relationship, we agreed to collaborate with Moffitt to develop multi-targeted CAR T immunotherapies designed to address cancers with diverse cell types that often become resistant to treatment, such as acute myeloid leukemia, or AML, (ATA2321) and B-cell malignancies (ATA2431), and to make certain milestone and royalty payments associated with the collaboration targets.

In addition, the collaboration includes the use of novel CAR T intracellular co-stimulatory domains that may improve CAR T proliferation when responding to an appropriate antigen and enhance CAR T persistence by reducing T-cell exhaustion.

As part of this relationship, we agreed to collaborate with Moffitt to develop multi-targeted CAR T immunotherapies designed to address cancers with diverse cell types that often become resistant to treatment, such as acute myeloid leukemia (AML) (ATA2321) and B-cell malignancies (ATA2431), and to make certain milestone and royalty payments associated with the collaboration targets.

In addition, the collaboration includes the use of a novel CAR T intracellular co-stimulatory domain that may improve CAR T proliferation when responding to an appropriate antigen and enhance CAR T persistence by reducing T-cell exhaustion.

In addition to our ATA188 program with QIMR, we are also collaborating with QIMR on the development of ATA368 for patients with human papillomavirus (HPV) associated cancers.

We believe our platform will have utility beyond the current set of targets to which it has been directed.

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Our commercial opportunities will be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer side effects or are less expensive than any products that we may develop.

Should our T-cell product candidates be approved for use, we will face substantial competition.

Should any of our T-cell product candidates be approved for use, we will face substantial competition.

In addition to the current standard of care for patients, commercial and academic clinical studies are being pursued by a number of parties in the field of immunotherapy.

Early results from these studies have fueled continued interest in T-cell immunotherapy.

In addition, if approved, our T-cell programs would compete with currently marketed drugs and therapies used for treatment of the indications we are addressing, and potentially with drug candidates currently in development for the same indications.

In addition, if approved, our T-cell programs would compete with currently marketed drugs and therapies used for treatment of the indications we are addressing, and potentially with product candidates currently in development for the same indications.

There are currently no FDA- or EMA-approved products for the treatment of EBV+ PTLD .

However, some marketed products and therapies are used off-label in the treatment of EBV+ PTLD , such as rituximab and combination chemotherapy regimens.

In addition, a number of companies and academic institutions are developing drug candidates for EBV+ PTLD and other EBV-associated diseases including:

Viracta Therapeutics, Inc., which is conducting a Phase 1b/2 clinical study for nanatinostat (formerly named tractinostat, or VRx-3996) in combination with antiviral drug valganciclovir in relapsed/refractory EBV + lymphomas, AlloVir (formerly known as ViraCyte), which has completed a Phase 2 clinical study for Viralym-M (ALVR105), an allogeneic, multi-virus T-cell product that targets six viruses including EBV and is planning to initiate several Phase 3 studies in the next year and Tessa Therapeutics Pte Ltd., or Tessa, which has a preclinical product candidate that is an allogeneic CD30-targeted CAR EBV-specific T-cell therapy.

Drug therapies approved or commonly used for the treatment of NPC include radiation therapy, often given in combination with chemotherapy, and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor, or EGFR.

Surgery for NPC is also occasionally used after chemoradiotherapy or to treat relapsed/refractory NPC.

Several development candidates are being evaluated for NPC.

Tessa is evaluating TT10, an autologous, EBV-specific T-cell product, in a phase 3 clinical study for advanced NPC.

In addition, a number of companies are evaluating immunotherapies in combination with PD1/PDL1 inhibitors for the treatment of head and neck cancers, including NPC.

These include Bristol-Myers Squibb Company’s ipilimumab, relatilimab and daratumumab, Roche Pharmaceuticals’ bevacizumab and AstraZeneca PLC’s tremelimumab.

In addition, a number of companies and academic institutions are developing product candidates for EBV+ PTLD and other EBV-driven diseases including:

AlloVir (formerly known as ViraCyte), which has completed a Phase 2 clinical study for Viralym-M (ALVR105), an allogeneic, multi-virus T-cell product that targets six viruses in allogeneic HSCT recipients with ≥1 treatment-refractory infection, including EBV, and is planning to initiate several Phase 3 studies for CMV, AdV and Virus-Associated Hemorrhagic-Cystitis, as well as a Phase 1b/2 proof of concept trial for the prevention of BKV, CMV, AdV, EBV, HHV06 and JCV;

and Tessa Therapeutics Pte Ltd., which has a Phase 2 autologous and preclinical allogeneic CD30-CAR-T product candidate being evaluated in CD30+ lymphomas.

Multiple Sclerosis

Competition in the MS market is high with at least seventeen therapies, including three generics, approved for the treatment of RRMS in the U.S.

There are many competitors in the RRMS market, including major multi-national fully-integrated pharmaceutical companies and established biotechnology companies.

Most recently, Vumerity™ (diroximel fumarate), marketed by Biogen, and Mayzent ® (siponimod), marketed by Novartis, were approved for the treatment of relapsing forms of MS in the U.S (Vumerity) and EU (Mayzent).

There are numerous development candidates in Phase 3 studies for RRMS including TG Therapeutics’ anti-CD20 monoclonal antibody ublituximab and EMD Serono’s BTK inhibitor, evobrutinib.

Novartis’ anti-CD20 monoclonal antibody ofatumumab and J&J/Janssen’s sphingosine-1-phosphate receptor 1 (S1P1) modulator, ponesimod have completed their Phase 3 studies and have filed (ofatumumab) or plan to file (ponesimod) for regulatory approval in the future.

Celgene’s ozanimod, an S1PR1 and S1PR5 agonist is awaiting FDA and EMA regulatory approval with a Prescription Drug User Fee Act, or PDUFA, date in March 2020, and EMA in the first half of 2020.

Six therapies have been approved for the treatment of PMS.

Ocrevus ® is approved in the U.S.

and EU for the treatment of PPMS.

Extavia ® (marketed by Novartis) and Betaferon ® (marketed by Bayer AG) are approved in the European Union for the treatment of SPMS when disease is active, or active SPMS.

Mayzent ® (siponimod), marketed by Novartis and Mavenclad ® (cladribine), marketed by EMD Serono, were most recently approved for the treatment of active SPMS in the U.S.

and EU (Mayzent).

In addition, mitoxantrone, which is now generic, is approved to treat SPMS in the U.S.

The SPMS and PPMS markets have active development pipelines and additional novel agents could be approved in the future.

Several development candidates are being evaluated in Phase 3 studies for progressive forms of MS including primary and secondary progressive MS.

These are MedDay’s MD-1003, a concentrated form of biotin, and AB Science’s masitinib, a tyrosine kinase inhibitor.

Medicinova is planning to initiate a Phase 3 study of its PDE inhibitor, ibudilast (MN166) in patients with non-relapsing secondary progressive MS.

Competition in the MS market is high with at least 20 therapies, including four generics or bioequivalents, approved in the U.S.

and EU for the treatment of various forms of MS, including clinically isolated syndrome, relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS).

There are many competitors in the MS market, including major multi-national fully-integrated pharmaceutical companies and established biotechnology companies.

Most recently, Kesimpta ® (anti-CD20 monoclonal antibody), marketed by Novartis, was approved in the U.S.

for the treatment of relapsing forms of MS, and a decision for its approval for treatment of the same indication in the EU is expected in the first half of 2021.

Johnson & Johnson has completed Phase 3 studies of its sphingosine-1-phosphate receptor 1 (S1P1) modulator, ponesimod, and has sought regulatory approval also for relapsing forms of MS in the U.S.

There are numerous development candidates in Phase 3 studies for both relapsing and/or progressive forms of MS and additional novel agents could be approved in either or both indications in the future including TG Therapeutics’ anti-CD20 monoclonal antibody ublituximab, EMD Serono’s Bruton’s tyrosine kinase (BTK) inhibitor, evobrutinib, Roche’s BTK inhibitor, fenebrutinib, Sanofi’s BTK inhibitor, SAR442168 and AB Science’s tyrosine kinase inhibitor, masitinib.

Medicinova is planning to initiate a Phase 3 study of its PDE inhibitor, ibudilast (MN166) in non-active SPMS.

CAR T Program

There are currently two CAR T therapies approved in the U.S.

and EU, Novartis’ Kymriah (tisagenlecleucel) and Gilead/Kite’s Yescarta (axicabtagene ciloleucel).

Bristol-Myers Squibb filed its BLA with the FDA for lisocabtagene maraleucel (liso-cel) in December 2019.

There are more than 100 CAR T’s in development including at least 35 which are allogeneic and off-the-shelf cell therapies.

Depending on the diseases that our CAR T therapies target in the future, we may face competition from both CAR T therapies and other modalities, such as small molecules and antibodies, in the indication of interest.

There are currently four autologous CAR T therapies approved in the U.S.

Novartis’ Kymriah ® (tisagenlecleucel), Gilead/Kite’s Yescarta ® (axicabtagene ciloleucel) and Tecartus TM (brexucabtagene autoleucel) and Bristol-Myers Squibb’s Breyanzi ® (lisocabtagene maraleucel).

Bristol-Myers Squibb has filed a BLA to the U.S.

FDA for idecabtagene vicleucel with bluebird bio.

There are many CAR-mediated cell therapies in development, and, although the majority are autologous, they include allogeneic and off-the-shelf cell therapies.

There are multiple allogeneic CAR platforms being developed with differences in approaches to minimize instances of donor cells recognizing the patient’s body as foreign or rejection of the donor cells by the patient’s body.

These approaches include the use of gene-editing to remove or inhibit the TCR and the use of cell types without a TCR.

The majority of clinical stage allogeneic CAR programs utilize alpha beta T cells as the cell type and gene editing of the T-cell receptor and HLA as the preferred technology approach, however, other strategies are also in development.

Depending on the diseases that we target in the future, we may face competition from both autologous and allogeneic CAR therapies and other modalities (e.g., small molecules, antibodies) in the indication of interest.

Terms of Certain License and Research and Development Collaboration Agreements

2015 MSK License Agreement

In June 2015, we entered into the 2015 MSK License Agreement.

Under the terms of the 2015 MSK License Agreement, MSK granted us a worldwide, exclusive license to certain patent rights, know-how and a library of T cells and cell lines, to research, develop, manufacture and commercialize T-cell products specific to cytomegalovirus, or CMV, EBV or WT1 that comprise or are based on or made using these licensed rights.

We agreed to use commercially reasonable efforts to commercialize the licensed products and, if commercialized, continue active marketing efforts for any commercialized licensed product through the term of the license agreement.

Under the 2015 MSK License Agreement, we are obligated to make milestone payments of up to $33.0 million with respect to the three licensed clinical stage T-cell programs based on achievement of specified development, regulatory and sales-related milestones.

We are also required to make escalating mid to high single-digit royalty payments to MSK based on sales of any licensed products.

Bayer Research, Development and License Agreement

On December 4, 2020, we entered into the Bayer License Agreement, pursuant to which we granted to Bayer an exclusive, field-limited license under the applicable patents and know-how owned or controlled by us and our affiliates covering or related to ATA2271 and ATA3271 (the Licensed Products), in each case, targeting mesothelin.

Under the terms of the Bayer License Agreement, we will be responsible at our cost for all mutually agreed preclinical and clinical activities for ATA2271 through the first in human Phase 1 clinical study in collaboration with MSK , following which Bayer will be responsible for the further development of ATA2271 at its cost.

Bayer will be responsible for the development of ATA3271, except for certain mutually agreed preclinical, translational, manufacturing and supply chain activities to be performed by us relating to ATA3271, in each case at Bayer’s cost.

Bayer will also be solely responsible for commercializing the Licensed Products at its cost.

In December 2020, we received an upfront cash payment of $45.0 million from Bayer for the exclusive license grant, net of applicable withholding taxes, which we believe are recoverable, and an additional $15.0 million upfront reimbursement payment for certain research and process development activities to be performed by us.

We are also entitled to receive (i) up to an additional $5.0 million for additional, specified translational activities under the Bayer License Agreement and (ii) an aggregate of up to $610.0 million in milestone payments upon achieving certain development, regulatory and commercial milestones relating to the Licensed Products.

In addition, we are eligible to receive from Bayer tiered royalties at percentages up to low double digits on worldwide net product sales of the Licensed Products on a country-by-country and product-by-product basis until the later of 12 years after the first commercial sale in such country or the expiration of specified patent rights in such country, subject to certain reductions and aggregate minimum floors.

We also granted Bayer a time limited, non-exclusive right to negotiate a license to additional Atara CAR-T product candidates if we decide to pursue an out-license of such CAR-T product candidates.

Under the terms of the Bayer License Agreement, we are currently negotiating a separate manufacturing and supply agreement with Bayer for the supply of allogenic mesothelin-directed CAR T-cell therapies for clinical trials.

MSK License Agreements

In June 2015, we entered into a license agreement with MSK, under which MSK granted us a worldwide, exclusive license to certain patent rights, know-how and a library of T cells and cell lines, to research, develop, manufacture and commercialize three clinical stage T-cell therapies.

We are obligated to make milestone payments of up to $33.0 million to MSK based on achievement of specified regulatory and sales-related milestones, as well as mid single-digit percentage tiered royalty payments based on future sales of products resulting from the development of the licensed product candidates, if any.

In addition, under certain circumstances, we must make certain minimum annual royalty payments to MSK, which are creditable against earned royalties owed for the same annual period.

We are also obligated to pay a low double-digit percentage of consideration we receive for sublicensing the licensed rights.

The 2015 MSK License Agreement expires for each licensed T-cell product on a licensed product-by-licensed product basis and a country-by-country basis, on the latest of:

(i) expiration of the last licensed patent rights related to a licensed product in a country, (ii) expiration of any market exclusivity period granted by law with respect to a licensed product in a country, and (iii) a specified number of years after the first commercial sale of the licensed product in a country.

Upon expiration of the 2015 MSK License Agreement, the licenses granted to us will become non-exclusive royalty-free, perpetual and irrevocable.

MSK may terminate the 2015 MSK License Agreement if we materially breach the agreement and do not cure this breach within a specified period or if we experience certain insolvency events.

In May and December 2018, we licensed additional CAR T-related technology from MSK.

We are also obligated to pay a low double-digit percentage of any consideration we receive for sublicensing the licensed rights.

The license agreement expires on a licensed product-by-product and country-by-country basis, on the latest of:

(i) expiration of the last licensed patent rights related to a licensed product, (ii) expiration of any market exclusivity period granted by law with respect to a licensed product, and (iii) a specified number of years after the first commercial sale of the licensed product in each country.

Upon expiration of the license agreement, Atara will retain non-exclusive rights to the licensed products.

In May and December 2018, we licensed additional technology from MSK.

We are obligated to make additional milestone payments based on achievement of specified development, regulatory and sales-related milestones as well as mid-single-digit percentage tiered royalty payments based on future sales of products resulting from the development of the licensed product candidates, if any.

QIMR Berghofer License Agreement and Research and Development Collaboration Agreement

In September 2016, we entered into an amended and restated license agreement and an amended and restated research and development collaboration agreement with QIMR Berghofer, each of which amended and restated prior agreements entered into with QIMR Berghofer in October 2015.

We further amended and restated our license agreement and research and development collaboration agreements with QIMR Berghofer in August 2019 to eliminate our license to certain rights related to CMV.

We refer to our August 2019 second amended and restated license agreement with QIMR Berghofer as the QIMR License Agreement and our August 2019 second amended and restated research and development collaboration agreement with QIMR Berghofer as our QIMR Collaboration Agreement.

Under the QIMR License Agreement and QIMR Collaboration Agreement, we possess an exclusive, worldwide license to develop and commercialize allogeneic T-cell programs utilizing technology and know-how developed by QIMR Berghofer.

The QIMR License Agreement provides for various milestone payments of up to $15 million and low to mid single-digit royalty payments to QIMR Berghofer based on future product sales, if any.

QIMR Berghofer License Agreements

In October 2015, we entered into an exclusive license agreement and a research and development collaboration agreement with QIMR Berghofer.

Under the terms of the license agreement, we obtained an exclusive, worldwide license to develop and commercialize allogeneic T-cell therapy programs utilizing technology and know-how developed by QIMR Berghofer.

In September 2016, the exclusive license agreement and research and development collaboration agreement were amended and restated.

Under the amended and restated agreements, we obtained an exclusive and worldwide license to develop and commercialize additional T-cell programs, as well as the option to license additional technology.

We exercised this option in June 2018.

We further amended and restated our license agreement and research and development collaboration agreements with QIMR Berghofer in August 2019 to terminate our license to certain rights related to cytomegalovirus (CMV).

In addition, we further amended and restated our license agreement and research and development collaboration agreements with QIMR Berghofer in August 2020 to terminate our license to certain rights related to BK polyomavirus and JC polyomavirus.

We refer to our August 2020 third amended and restated license agreement with QIMR Berghofer as the QIMR License Agreement and our August 2020 third amended and restated research and development collaboration agreement with QIMR Berghofer as our QIMR Collaboration Agreement.

The QIMR License Agreement provides for various milestone and low to mid single-digit royalty payments to QIMR Berghofer based on future product sales, if any.

Under the terms of the QIMR Collaboration Agreement, we are required to reimburse the cost of agreed-upon development activities related to programs developed under the collaboration.

The QIMR Collaboration Agreement also provides for various milestone payments of up to $7 million to QIMR Berghofer based on achievement of certain developmental and regulatory milestones.

The QIMR Collaboration Agreement also provides for various milestone payments to QIMR Berghofer based on the achievement of certain developmental and regulatory milestones.

We have the right at any time to terminate the QIMR License Agreement , at will, by providing written notice of termination to QIMR Berghofer and paying QIMR Berghofer a break-up fee equal to 50 percent of the amount of the next milestone payment that would be payable to QIMR Berghofer.

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A provisional patent application is not examined for patentability by the U.S.

Patent and Trademark Office, or USPTO, and automatically expires 12 months after its filing date.

Patent and Trademark Office (USPTO), and automatically expires 12 months after its filing date.

As a result, a provisional patent application cannot mature into an issued patent.

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Our global patent estate consists of both solely-owned and in-licensed patents and patent applications, is directed to compositions of matter and/or associated methods, including methods of treatment, and consists of 3 9 patent families having a total of more than 2 7 4 issued patents or patent applications.

Our patents and patent applications (if issued) are expected to expire between 2022 and 2040, not inclusive of any patent term extension that may be available in any associated jurisdiction.

Our patents and patent applications (if issued) are expected to expire between 202 3 and 20 4 1 , not inclusive of any patent term extension that may be available i n any associated jurisdiction.

Trade Secrets

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We have a vigorous global program of trademark registration and enforcement to maintain and strengthen the value of our trademarks and prevent the unauthorized use of those trademarks.

Our global trademark portfolio consists of seven different trademark families comprised of more than 100 registrations and pending applications.

Our global trademark portfolio consists of six different trademark families comprised of more than 90 registrations and pending applications.

Government Regulation and Product Approval

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Our T-cell immunotherapies, if approved, will be products regulated as biologics.

With this classification, commercial production of our products will need to occur in registered facilities in compliance with current good manufacturing practice, or cGMP, for biologics.

With this classification, commercial production of our products will need to occur in registered facilities in compliance with current good manufacturing practice (cGMP) for biologics.

The FDA categorizes human cell- or tissue-based products as either minimally manipulated or more than minimally manipulated and has determined that more than minimally manipulated products require clinical trials to demonstrate product safety and efficacy and the submission of a BLA for marketing authorization.

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Product Development Process

In the U.S., the FDA regulates pharmaceutical and biological products under the Federal Food, Drug and Cosmetic Act, or FDCA, the Public Health Service Act, or PHSA, and their implementing regulations.

In the U.S., the FDA regulates pharmaceutical and biological products under the Federal Food, Drug and Cosmetic Act (FDCA), the Public Health Service Act (PHSA), and their implementing regulations.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

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generally involves the following:

completion of nonclinical laboratory tests and animal studies according to good laboratory practices, or GLPs, and applicable requirements for the humane use of laboratory animals or other applicable regulations;

completion of nonclinical laboratory tests and animal studies according to good laboratory practices (GLPs), and applicable requirements for the humane use of laboratory animals or other applicable regulations;

submission to the FDA of an IND, which must become effective before human clinical trials may begin ;

approval by an independent Institutional Review Board, or IRB, or ethics committee at each clinical site before the trial is commenced;

performance of adequate and well-controlled human clinical trials according to the FDA’s regulations commonly referred to as good clinical practices, or GCPs, and any additional requirements for the protection of human research patients and their health information, to establish the safety and efficacy of the proposed biological product for its intended use;

approval by an independent Institutional Review Board (IRB), or ethics committee at each clinical site before the trial is commenced;

performance of adequate and well-controlled human clinical trials according to the FDA’s regulations commonly referred to as good clinical practices (GCPs), and any additional requirements for the protection of human research patients and their health information, to establish the safety and efficacy of the proposed biological product for its intended use;

submission to the FDA of a BLA for marketing approval that includes substantial evidence of safety, purity, and potency from results of nonclinical testing and clinical trials;

satisfactory completion of an FDA Advisory Committee review, if applicable;

satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the biological product is produced to assess compliance with cGMP, to assure that the facilities, methods and controls are adequate to preserve the biological product’s identity, strength, quality and purity and, if applicable, the FDA’s current good tissue practices, or GTPs, for the use of human cellular and tissue products;

potential FDA audit of the nonclinical study and clinical trial sites that generated the data in support of the BLA ;

FDA review and approval, or licensure of the BLA.

satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the biological product is produced to assess compliance with cGMP, to assure that the facilities, methods and controls are adequate to preserve the biological product’s identity, strength, quality and purity and, if applicable, the FDA’s current good tissue practices (GTPs) for the use of human cellular and tissue products;

potential FDA inspection of the nonclinical study and clinical trial sites that generated the data in support of the BLA;

FDA review and approval, i.e., licensure of the product candidate that is the subject of the BLA.

Before testing any biological product candidate, including our product candidates, in humans, the product candidate enters the preclinical testing stage.

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An IRB is charged with protecting the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.

The IRB also approves the form and content of the informed consent that must be signed by each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.

The IRB also approves the form and content of the informed consent document that must be signed by each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.

Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.

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Annual progress reports detailing the results of the clinical trials must be submitted to the FDA.

Written IND safety reports must be promptly submitted to the FDA, and the investigators for serious and unexpected adverse events, any findings from other studies, tests in laboratory animals or in vitro testing that suggest a significant risk for human patients, or any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

Written IND safety reports must be promptly submitted to the FDA and to investigators for serious and unexpected adverse events, findings from other studies, laboratory animal testing or in vitro testing that suggest a significant risk for human patients, or any clinically important increase in the rate of a serious suspected adverse reaction over the rate listed in the protocol or investigator brochure.

The sponsor must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting.

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The testing and approval processes require substantial time and effort and there can be no assurance that the FDA will accept the BLA for filing and, even if filed, that any approval will be granted on a timely basis, if at all.

Under PDUFA, as amended, each BLA must be accompanied by a significant user fee.

Under the Prescription Drug User Fee Act, as amended (PDUFA), each BLA must be accompanied by a significant user fee.

The FDA adjusts the PDUFA user fees on an annual basis.

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The FDA may refer applications for novel biological products or biological products that present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

During the biological product approval process, the FDA also will determine whether a Risk Evaluation and Mitigation Strategy, or REMS, is necessary to assure the safe use of the biological product.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making

During the biological product approval process, the FDA also determine s whether a Risk Evaluation and Mitigation Strategy (RE M S ) is necessary to assure the safe use of the biological product.

A REMS is a safety strategy to manage a known or potential serious risk associated with a medicine and to enable patients to have continued access to such medicines by managing their safe use, and could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.

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For immunotherapy products, the FDA also will not approve the product if the manufacturer is not in compliance with the GTPs, to the extent applicable.

These are FDA regulations and guidance documents that govern the methods used in, and the facilities and controls used for, the manufacture of human cells, tissue, and cellular and tissue based products, or HCT/Ps, which are human cells or tissue intended for implantation, transplant, infusion, or transfer into a human recipient.

GTPs are FDA regulations and guidance documents that govern the methods used in, and the facilities and controls used for, the manufacture of human cells, tissue, and cellular and tissue-based products (HCT/Ps), which are human cells or tissue intended for implantation, transplant, infusion, or transfer into a human recipient.

The primary intent of the GTP requirements is to ensure that cell and tissue-based products are manufactured in a manner designed to prevent the introduction, transmission and spread of communicable disease.

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In addition, the FDA may require post marketing clinical trials, sometimes referred to as Phase 4 clinical trials, designed to further assess a biological product’s safety and effectiveness, and testing and surveillance programs to monitor the safety of approved products that have been commercialized.

In addition, under the Pediatric Research Equity Act, or PREA, a BLA or supplement to a BLA must contain data to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

In addition, under the Pediatric Research Equity Act (PREA), a BLA or supplement to a BLA must contain data to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The FDA may grant deferrals for submission of data or full or partial waivers.

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Marketing Exclusivity

The Biologics Price Competition and Innovation Act, or BPCIA, amended the PHSA to authorize the FDA to approve similar versions of innovative biologics, commonly known as biosimilars.

The Biologics Price Competition and Innovation Act (BPCIA), amended the PHSA to authorize the FDA to approve similar versions of innovative biologics, commonly known as biosimilars.

A competitor seeking approval of a biosimilar must file an application to establish its molecule as highly similar to an approved innovator biologic, among other requirements.

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In both domestic and foreign markets, sales and reimbursement of any approved products will depend, in part, on the extent to which the costs of such products will be covered by third-party payors, such as government health programs, commercial insurance and managed healthcare organizations.

Third-party payors determine which medications they will cover and establish reimbursement levels.

There may be significant delays in obtaining coverage and reimbursement for newly approved drugs, and coverage may be more limited than the purposes for which the drug is approved by the FDA or comparable foreign regulatory authorities.

Interim reimbursement levels for new drugs, if applicable, may also not be sufficient to cover our costs and may only be temporary.

Reimbursement rates may vary according to the use of the drug and the clinical setting in which it is used, may be based on reimbursement levels already set for lower cost drugs and may be incorporated into existing payments for other services.

Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the U.S.

Coverage and reimbursement policies for drug products can differ significantly from payor to payor as there is no uniform policy of coverage and reimbursement for drug products among third-party payors in the U.S.

Third-party payors in the U.S.

often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies.

There may be significant delays in obtaining coverage and reimbursement as the process of determining coverage and reimbursement is often time consuming and costly which will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage or adequate reimbursement will be obtained.

It is difficult to predict at this time what government authorities and third-party payors will decide with respect to coverage and reimbursement for our drug products.

These third-party payors are increasingly challenging the prices charged for medical products and services and imposing controls to manage costs.

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there have been several recent Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the cost of drugs under Medicare, and reform government program reimbursement methodologies for drugs.

Additionally, in May 2018, the U.S.

presidential administration laid out a “Blueprint” to lower drug prices and reduce out of pocket costs of drugs that contains additional proposals to increase manufacturer competition, increase the negotiating power of certain federal healthcare programs, incentivize manufacturers to lower the list price of their products and reduce the out of pocket costs of drug products paid by consumers.

The Department of Health and Human Services, or HHS, has started the process of soliciting feedback on some of these measures and, at the same time, is immediately implementing others under its existing authority.

In January 2019, the HHS Office of Inspector General proposed modifications to U.S.

federal healthcare Anti-Kickback Statute safe harbors which, among other things, will affect rebates paid by manufacturers to Medicare Part D plans, the purpose of which is to further reduce the cost of drug products to consumers.

Although some of these and other proposals may require authorization through additional legislation to become effective, members of Congress and the presidential administration have indicated that they will continue to seek new legislative or administrative measures to control drug costs.

Additionally, in May 2018, the Trump administration laid out a “Blueprint” to lower drug prices and reduce out of pocket costs of drugs that contained proposals to increase manufacturer competition, increase the negotiating power of certain federal healthcare programs, incentivize manufacturers to lower the list price of their products and reduce the out-of-pocket costs of drug products paid by consumers.

Several final rules have been recently promulgated that seek to implement several of the Trump administration’s proposals.

For example, on November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.

Further, on November 20, 2020, the Centers for Medicare and Medicaid Services (CMS) issued an interim final rule implementing President Trump’s Most Favored Nation executive order, which would tie Medicare Part B payments for certain physician-administered drugs to the lowest price paid in other economically advanced countries, effective January 1, 2021.

On December 28, 2020, the United States District Court in Northern California issued a nationwide preliminary injunction against implementation of the interim final rule.

However, it is unclear whether the Biden administration will work to reverse these measures or pursue similar policy initiatives.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, to encourage importation from other countries and bulk purchasing.

Within the U.S., if we obtain appropriate approval in the future to market any of our product candidates, we may seek approval and coverage for those products under Medicaid, Medicare and the Public Health Service, or PHS, pharmaceutical pricing program and also seek to sell the products to federal agencies.

Further, it is possible that additional governmental action is taken in response to the COVID-19 pandemic.

Within the U.S., if we obtain appropriate approval in the future to market any of our product candidates, we may seek approval and coverage for those products under Medicaid, Medicare and the Public Health Service (PHS), pharmaceutical pricing program and also seek to sell the products to federal agencies.

Medicaid is a joint federal and state program that is administered by the states for low income and disabled beneficiaries.

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Subject to certain payment adjustments and limits, Medicare generally pays for Part B covered drugs based on a percentage of manufacturer-reported average sales price.

Drug products are subject to discounted pricing when purchased by federal agencies via the Federal Supply Schedule, or FSS.

Drug products are subject to discounted pricing when purchased by federal agencies via the Federal Supply Schedule (FSS).

FSS participation is required for a drug product to be covered and paid for by certain federal agencies and for coverage under Medicaid, Medicare Part B and the PHS pharmaceutical pricing program.

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In March 2010, the U.S.

Congress enacted the Patient Protection and Affordable Care Act and the Health Care and Education Reconciliation Act, or the Affordable Care Act, which included changes to the coverage and payment for drug products under government health care programs.

Congress enacted the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (collectively, the Affordable Care Act), which included changes to the coverage and payment for drug products under government health care programs.

Since its enactment, there have been judicial and Congressional challenges to numerous elements of the Affordable Care Act, as well as efforts by both the executive and legislative branches of the federal government to repeal or replace certain aspects of the Affordable Care Act.

For example, the President signed Executive Orders designed to delay the implementation of certain provisions of the Affordable Care Act or otherwise circumvent some of the requirements for health insurance mandated by the Affordable Care Act.

For example, President Trump signed Executive Orders designed to eliminate the implementation of certain provisions of the Affordable Care Act or otherwise circumvent some of the requirements for health insurance mandated by the Affordable Care Act.

In addition, the U.S.

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Court of Appeals for the 5th Circuit upheld a District Court ruling that the individual mandate was unconstitutional and remanded the case back to the Texas District Court to determine whether the remaining provisions of the Affordable Care Act are invalid as well.

Supreme Court is currently reviewing this case, but it is unknown when a decision will be reached.

Although the U.S.

Supreme Court has yet ruled on the constitutionality of the Affordable Care act, on January 28, 2021, President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through May 15, 2021 for purposes of obtaining health insurance coverage through the Affordable Care Act marketplace.

The executive order also instructs certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the Affordable Care Act.

It is unclear how the U.S.

Supreme Court ruling, other such litigation, and the healthcare form measures of the Biden administration will impact the Affordable Care Act and our business.

Health Care Laws

Healthcare providers and third-party payors will play a primary role in the recommendation and prescription of any product candidates for which we obtain regulatory approval.

Our current and future arrangements with third-party payors and customers may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we conduct research and would market, sell and distribute our products.

As a biopharmaceutical company, even though we do not and will not control referrals of healthcare services or bill directly to Medicare, Medicaid or other third-party payors, federal and state healthcare laws and regulations pertaining to fraud and abuse and patients’ rights are and will be applicable to our business.

Restrictions under applicable federal and state healthcare laws and regulations that may affect our ability to operate include the following:

the federal healthcare Anti-Kickback Statute, which governs our marketing practices, educational programs, pricing policies, and relationships with healthcare providers or other entities, by prohibiting, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, 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 for, or the purchase, order or recommendation of, any good or service, for which payment may be made under a federal healthcare program such as Medicare and Medicaid;

federal civil and criminal false claims laws, including the civil False Claims Act, which can be enforced through civil whistleblower or qui tam actions, and civil monetary penalty laws impose criminal and civil penalties against individuals or entities for knowingly presenting, or causing to be presented, to the federal government, including the Medicare and Medicaid programs, claims for payment or approval that are false or fraudulent or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government;

the federal Health Insurance Portability and Accountability Act of 1996 (HIPAA) imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program and also created federal criminal laws that prohibit knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statements in connection with the delivery of or payment for healthcare benefits, items or services;

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (HITECH) also imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information held by covered entities and their business associates and their subcontractors that use, disclose or otherwise process individually identifiable health information as well as their covered subcontractors;

the federal physician sunshine requirements under the Affordable Care Act requires certain manufacturers of drugs, devices, biologics and medical supplies to report annually to CMS information related to payments and other transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members and applicable group purchasing organizations, which will be expanded beginning in 2022, to require applicable manufacturers to report such information regarding payments and other transfers of value to physician assistants, nurse practitioners, clinical nurse specialists, anesthesiologist assistants, certified registered nurse anesthetists and certified nurse midwives during the previous year;

state and foreign laws and regulations that are analogous to the federal laws and regulations described in the preceding subsections of this risk factor, such as state anti-kickback and false claims laws, may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers;

some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government;

some state laws require drug manufacturers to report information regarding pricing and marketing information related to payments and other transfers of value to physicians and other healthcare providers;

some state and local laws require the registration of pharmaceutical sales representatives;

and other state laws require the protection of the privacy and security of health information, which may differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

For example, California enacted the California Consumer Privacy Act (CCPA), effective January 1, 2020, and the California Privacy Rights Act of 2020 (CPRA) was recently approved by California voters;

similar healthcare laws and regulations in the European Economic Area (EEA) and other jurisdictions, the General Data Protection Regulation (EU) 2016/679 (GDPR), which imposes obligations and restrictions on the collection and use of personal information relating to individuals located in the EEA (including health information).

Efforts to ensure that our business arrangements with third parties comply with applicable healthcare laws and regulations will involve substantial costs.

It is possible that governmental authorities will conclude that our business practices do not comply with current or future statutes, regulations or case law involving applicable healthcare laws and regulations.

If our operations are found to be in violation of any of these laws or any other governmental regulations, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, exclusion from government-funded healthcare programs, such as Medicare and Medicaid, disgorgement, additional reporting requirements or oversight if we become subject to a corporate integrity agreement or similar agreement, and the curtailment or restructuring of our operations.

Foreign Regulation

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Certain countries outside of the U.S.

have a process that requires the submission of a clinical study application, or CTA, which is much like an IND in the U.S., prior to the commencement of human clinical studies.

In Europe, for example, a CTA must be submitted to the competent national health authority and to independent ethics committees in each country in which a company intends to conduct clinical studies.

have a process that requires the submission of a CTA, which is much like an IND in the U.S., prior to the commencement of human clinical studies.

In the EU, for example, in accordance with the requirements of the EU Clinical Trials Directive, as implemented in national law by Member States, a CTA must be submitted to the competent national health authority and to independent ethics committees in each country in which a company intends to conduct clinical studies.

Once the CTA is approved in accordance with a country’s requirements, clinical study development may proceed in that country.

In all cases, the clinical studies must be conducted in accordance with GCP and other applicable regulatory requirements.

Under E U regulatory systems, a company may submit marketing authorization applications either under a centralized or decentralized procedure.

In 2014, a new Clinical Trials Regulation 536/2014, replacing the current Directive, was adopted.

The new Regulation will become directly applicable in all EU Member States (without national implementation) once the EU Portal and Database are fully functional.

It is expected that the Regulation will apply in late 2021.

The new Regulation seeks to simplify and streamline the approval of clinical trials in the European Union.

For example, the sponsor shall submit a single application for approval of a clinical trial via the EU Portal.

As part of the application process, the sponsor shall propose a reporting Member State, who will coordinate the validation and evaluation of the application.

The reporting Member State shall consult and coordinate with the other concerned Member States.

If an approval is issued, the sponsor can start the clinical trial in all concerned Member States.

However, a concerned Member State can in limited circumstances declare an “opt-out” from an approval.

In such a case, the clinical trial cannot be conducted in that Member State.

The Regulation also aims to streamline and simplify the rules on safety reporting and introduces enhanced transparency requirements such as mandatory submission of a summary of the clinical trial results to the EU Database .

Under EU regulatory systems, a company may submit marketing authorization applications under centralized or decentralized, or mutual-recognition procedures.

We expect to utilize the centralized procedure, which is compulsory for medicinal products produced by biotechnology or those medicinal products containing new active substances for specific indications such as the treatment of AIDS, cancer, neurodegenerative disorders, diabetes, viral diseases and designated orphan medicines, and optional for other medicines which are highly innovative.

Under the centralized procedure, a marketing application is submitted to the European Medicines Agency, or EMA, where it will be evaluated by the Committee for Medicinal Products for Human Use.

If this committee delivers a favorable opinion, this typically results in the grant by the European Commission of a single marketing authorization that is valid for all E U member states within 67 days of receipt of the opinion.

Under the centralized procedure, a marketing application is submitted to the EMA, where it will be evaluated by the Committee for Medicinal Products for Human Use.

If this committee delivers a favorable opinion, this typically results in the grant by the European Commission of a single marketing authorization that is valid for all EU member states within 67 days of receipt of the opinion.

The initial marketing authorization is valid for five years, but once renewed is usually valid for an unlimited period.

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Orphan drugs in Europe enjoy economic and marketing benefits, including up to 11 years of exclusivity for the approved indication unless another applicant can show that its product is safer, more effective or otherwise clinically superior to the orphan-designated product.

The PRIority MEdicines, or PRIME, initiative was established by the EMA to help promote and foster the development of new medicines in the European Union that demonstrate potential for a major therapeutic advantage in areas of unmet medical need.

The PRIME initiative was established by the EMA to help promote and foster the development of new medicines in the European Union that demonstrate potential for a major therapeutic advantage in areas of unmet medical need.

Benefits from the PRIME designation include early confirmation of potential for accelerated assessment, early dialogue and increased interaction with relevant regulatory committees to discuss development options, scientific advice at key development milestones, and proactive regulatory support from the EMA.

In the EU, companies developing a new medicinal product must agree to a Pediatric Investigation Plan, or PIP, with the EMA and must conduct pediatric clinical trials in accordance with that PIP, unless a deferral or waiver applies, (e.g., because the relevant disease or condition occurs only in adults).

In the EU, companies developing a new medicinal product must agree to a PIP with the EMA and must conduct pediatric clinical trials in accordance with that PIP, unless a deferral or waiver applies, (e.g., because the relevant disease or condition occurs only in adults).

The marketing authorization application for the product must include the results of pediatric clinical trials conducted in accordance with the PIP, unless a waiver applies, or a deferral has been granted, in which case the pediatric clinical trials must be completed at a later date.

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There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our products.

Brexit and the Regulatory Framework in the United Kingdom

Following the result of a referendum in 2016, the United Kingdom left the EU on January 31, 2020, commonly referred to as Brexit.

Pursuant to the formal withdrawal arrangements agreed between the United Kingdom and the EU, the United Kingdom was subject to a transition period until December 31, 2020 (the Transition Period) during which EU rules continued to apply.

A UK-EU Trade and Cooperation Deal (the Deal) that outlines the future trading relationship between the United Kingdom and the European Union was agreed in December 2020 and has been approved by each EU member state and the United Kingdom.

Since a significant proportion of the regulatory framework in the United Kingdom applicable to our business and our product candidates is derived from EU directives and regulations, Brexit has had, and will continue to have, a material impact upon the regulatory regime with respect to the development, manufacture, importation, approval and commercialization of our product candidates in the United Kingdom and the EU.

Great Britain (made up of England, Scotland and Wales) is no longer covered by the EEA’s procedures for the grant of marketing authorizations (Northern Ireland will be covered by the centralized authorization procedure and can be covered under the decentralized or mutual recognition procedures).

A separate marketing authorization will be required to market drugs in Great Britain.

It is currently unclear whether the Medical Healthcare products Regulatory Agency (MHRA) in the United Kingdom is sufficiently prepared to handle the increased volume of marketing authorization applications that it is likely to receive.

Any delay in obtaining, or an inability to obtain, any marketing approvals, would delay or prevent us from commercializing our product candidates in the United Kingdom or the EU and restrict our ability to generate revenue and achieve and sustain profitability.

While the Deal provides for the tariff-free trade of medicinal products between the United Kingdom and the EU there may be additional non-tariff costs to such trade which did not exist prior to the end of the Transition Period.

Further, should the United Kingdom diverge from the EU from a regulatory perspective in relation to medicinal products, tariffs could be put into place in the future.

We could therefore, both now and in the future, face significant additional expenses (when compared to the position prior to the end of the Transition Period) to operate our business, which could significantly and materially harm or delay our ability to generate revenues or achieve profitability of our business.

Any further changes in international trade, tariff and import/export regulations as a result of Brexit or otherwise may impose unexpected duty costs or other non-tariff barriers on us.

These developments, or the perception that any of them could occur, may significantly reduce global trade and, in particular, trade between the impacted nations and the United Kingdom.

It is also possible that Brexit may negatively affect our ability to attract and retain employees, particularly those from the EU.

Orphan designation in Great Britain following Brexit is granted on an essentially identical basis to in the EU, but is based on the prevalence of the condition in Great Britain.

It is therefore possible that conditions that are currently designated as orphan conditions in Great Britain will no longer be and that conditions that are not currently designated as orphan conditions in the EU will be designated as such in Great Britain .

Additional Regulation

As a pharmaceutical company, even though we do not and will not control referrals of healthcare services or bill directly to Medicare, Medicaid or other third-party payors, federal and state healthcare laws and regulations pertaining to fraud and abuse and patients’ rights are and will be applicable to our business.

We are also subject to regulation under the Occupational Safety and Health Act, the Environmental Protection Act, the Toxic Substances Control Act, the Resource Conservation and Recovery Act and other present and potential federal, state or local regulations.

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Our facility is designed to global regulatory standards, and the required facility commissioning and qualification activities to support clinical manufacturing are complete.

Commercial production qualification activities for our facility are progressing well and, together with our contracted manufacturing partner, are aligned with our planned commercial product supply strategy.

In December 2019, we entered into a Commercial Manufacturing Services Agreement, or the Manufacturing Agreement, with Cognate Bioservices, Inc., or Cognate.

The Manufacturing Agreement supersedes the Development and Manufacturing Services Agreement, or the DMSA Agreement, with Cognate dated August 10, 2015, as amended.

The Manufacturing Agreement governs similar manufacturing services provided for under the DMSA Agreement with similar terms.

Specifically, pursuant to the Manufacturing Agreement, Cognate provides manufacturing services for certain of our product candidates.

We are in the process of completing our facility’s commercial production qualification activities for tab-cel ® while building inventory according to our commercial product supply strategy.

We continue to scale our EBV T-cell manufacturing platform to improve product yields from a single donor leukapheresis and have generated data confirming the use of stirred-tank perfusion bioreactors to improve yield and cell growth productivity.

We believe our scale-up technology can potentially be a key enabler to deliver biologic-like cost of goods manufactured and could be leveraged across our portfolio, including our CAR T programs .

There have been transient interruptions in the supply of leukapheresis collections related to the COVID-19 pandemic, which supply raw materials used in our product candidates.

If we are unable to obtain such raw materials or other necessary raw materials in a timely manner, our business operations and manufacturing capabilities could be adversely affected.

In addition to our manufacturing facility, we also work with Cognate BioServices, Inc.

(Cognate) pursuant to a Commercial Manufacturing Services Agreement (the Manufacturing Agreement) that we entered into in December 2019 .

Pursuant to the Manufacturing Agreement, Cognate provides manufacturing services for certain of our product candidates.

The initial term of the Manufacturing Agreement runs until December 31, 2021 and is renewable with Cognate’s approval for an additional one-year period.

We may terminate the Manufacturing Agreement for convenience on six months’ written notice to Cognate, or immediately if Cognate is unable to perform the services under the Manufacturing Agreement or fails to obtain or maintain certain necessary approvals.

The Manufacturing Agreement includes standard mutual termination rights for uncured breach or insolvency, or a force majeure event preventing the performance of services for at least ninety days.

In connection with the entry into the Manufacturing Agreement, we and Cognate also entered into a Fifth Amendment to the DMSA Agreement, which amended the expiration date of the DMSA Agreement to December 31, 2019.

Our current manufacturing strategy is to evaluate each product candidate and determine which site in our manufacturing network provides the phase-appropriate technical, quality and regulatory compliance requirements.

In addition, the long-range supply requirements of our product candidates are evaluated periodically to ensure we are planning manufacturing capacity and capabilities accordingly across our network.

Our manufacturing network is comprised of our own facility and the manufacturing capabilities of our partners, including MSK and an affiliate of QIMR Berghofer, and contract manufacturing organizations, or CMOs, including Cognate.

This strategic approach provides us with the flexibility to support our clinical and commercial production needs, address time or capacity constraints as well as provide supply redundancy, where appropriate.

Our T-cell product candidates require blood-derived starting materials which are received from healthy, consenting third-party donors through FDA- and EMA-compliant collection centers.

Our manufacturing operations are conducted under Code of Federal Regulations Good Manufacturing Practices, or GMPs, as well as Good Tissue Practices, or GTPs.

GTPs are FDA regulations and guidance documents that govern the methods used in, and the facilities and controls used for, the manufacture of human cells, tissues and cellular- and tissue-based products, or HCT/Ps, which are human cells or tissue intended for implantation, transplant, infusion or transfer into a human recipient.

Our manufacturing operations are conducted under Code of Federal Regulations Good Manufacturing Practices (GMPs), as well as Good Tissue Practices (GTPs).

GTPs are FDA regulations and guidance documents that govern the methods used in, and the facilities and controls used for, the manufacture of HCT/Ps, which are human cells or tissue intended for implantation, transplant, infusion or transfer into a human recipient.

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We also have the ability to obtain supply from third parties to ensure we have the necessary blood donated from healthy consenting third-party donors.

Human Capital Management

As of December 31, 2020, we had 437 employees.

We consider our relations with our employees to be good.

We believe that the success of our business will depend, in part, on our ability to attract and retain qualified personnel.

Our human capital strategy is designed to enable successful execution of our business objectives, while fostering a collaborative and innovative culture, that embraces diversity and inclusion.

We monitor our success with insights across human capital metrics such as employee engagement, vacancy rates, time to hire, promotion rates, performance ratings, succession depth, retention, EEO compliance, pay equity, and diversity representation.

The principal purposes of our compensation policies and equity incentive plans are to attract, retain and motivate employees and directors by paying for performance through the granting of stock-based compensation awards and cash-based performance bonus awards.

None of our employees are represented by a labor union or are a party to a collective bargaining agreement and we consider our relations with our employees to be good.

COVID-19 Business Update

We continue to closely monitor the impact of the ongoing COVID-19 pandemic on our business and operations and have taken steps to ensure the health and safety of our employees, staff, clinical site staff and patients and to maintain business continuity.

Based on guidance issued by federal, state and local authorities, we have temporarily transitioned most of our workforce to a remote, work-from-home model, while maintaining essential in-person manufacturing and laboratory functions in order to advance key research, development and manufacturing priorities.

We implemented safety protocols and procedures to support our onsite workforce.

In addition to implementing measures to protect the health and safety of our workforce , our clinical study and operational teams are working closely with clinical sites to ensure the safety of site staff and patients as well as preserve data integrity and access to treatment as appropriate.

Where needed, remote study visits, leveraged tele-medicine, home health care, and other methods have been established to ensure continuity of care for patients while preserving key endpoint data .

To date, the COVID-19 pandemic has not materially impacted our or our partners’ clinical, research and development, regulatory and manufacturing operations or timelines.

We have experienced, and may continue to experience, some transient delays in clinical trial site initiation and patient enrollment in certain of our clinical trials as a result of the evolving impact of the ongoing COVID-19 pandemic.

For example, due to the COVID-19 pandemic, in April 2020 we temporarily paused the screening and enrollment of patients in our RCT for ATA188.

We were able to resume such activities and enrolled the first patient in the study in June 2020.

Our Phase 2 multi-cohort study of tab-cel ® has experienced some delays in clinical trial site initiation activities, but we do not believe this study has been significantly impacted.

Our Phase 3 clinical trial of tab-cel ® in patients with EBV+ PTLD has not been significantly impacted by the ongoing COVID-19 pandemic.

The full extent to which the COVID-19 pandemic may impact our business and operations is subject to future developments which are uncertain and difficult to predict.

Further quarantines, shelter-in-place or similar restrictions and other actions taken or imposed by foreign, federal, state and local governments could adversely impact our or our partners’ clinical, research and development, regulatory and manufacturing operations or timelines.

We continue to monitor the impact of the COVID-19 pandemic on our business and operations and will seek to adjust our activities as appropriate.

In addition, the pandemic could result in significant and prolonged disruption of global financial markets, reducing our ability to access capital, which could in the future negatively affect the financial resources available to us.

For additional information about risks and uncertainties related to the COVID-19 pandemic that may impact our business, financial condition and operations, see the section titled “1A.

Risk Factors” under Part I, Item 1A in this Annual Report on Form 10-K.

Corporate Information

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Available Information

We file Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, proxy statements and other materials with the Securities and Exchange Commission, or SEC.

We file Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, proxy statements and other materials with the Securities and Exchange Commission (SEC).

We make these reports available free of charge through our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the SEC.

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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.

What changed 10-K

Item 1. Business