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Item 1. Business

2022-03-01 compared with 2021-03-01 · 202 added, 182 removed, 566 unchanged (40% of the section changed)

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We are actively advancing our lead clinical programs, including:

PRGN-3005 and PRGN-3006, which are built on our UltraCAR-T platform;

PRGN-3005, PRGN-3006, and PRGN-3007, which are built on our UltraCAR-T platform;

PRGN-2009 and PRGN-2012, which are based on our AdenoVerse immunotherapy platform;

and AG019, which is built on our ActoBiotics platform.

In addition, we recently completed a Phase 1 study of INXN-4001, a non-viral triple-effector plasmid DNA, which is built on our UltraVector platform.

We have developed a proprietary electroporation device, UltraPorator, designed to further streamline and ensure the rapid and cost-effective manufacturing of UltraCAR-T therapies.

Our UltraPorator device received FDA clearance for manufacturing UltraCAR-T cells in clinical trials in October 2020, and we began dosing patients with UltraCAR-T cells manufactured with UltraPorator in our PRGN-3005 and PRGN-3006 clinical trials in November 2020.

In addition, we have completed a Phase 1 study of INXN-4001, a non-viral triple-effector plasmid DNA, which is built on our UltraVector platform.

We also have a robust pipeline of preclinical programs that we are pursuing in order to drive long-term value creation.

We have developed a proprietary electroporation device, UltraPorator, designed to further streamline and ensure the rapid and cost-effective manufacturing of UltraCAR-T therapies.

UltraPorator has received FDA clearance for manufacturing UltraCAR-T cells in clinical trials, and since November 2020, we have been dosing patients with UltraCAR-T cells manufactured with UltraPorator in our clinical trials.

We exercise discipline in our portfolio management by systematically evaluating data from our preclinical programs in order to make rapid "go" and "no go" decisions.

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A core focus of our research and development programs has been an effort to address the drawbacks associated with conventional cell and gene therapy manufacturing approaches.

To this end, we are developing therapeutic candidates that reduce manufacturing risk by eliminating the need for centralized manufacturing and have invested in internal manufacturing capabilities to de-risk our clinical production.

To this end, we are developing therapeutic candidates that reduce manufacturing risk by eliminating the need for centralized cell therapy manufacturing and have invested in internal manufacturing capabilities to de-risk our clinical production.

Our Clinical Pipeline

Our Healthcare Subsidiaries

Our healthcare business is operated by our wholly owned subsidiaries PGEN Therapeutics, Inc., or PGEN Therapeutics, Precigen ActoBio, Inc., or ActoBio, and Exemplar Genetics, LLC, doing business as Precigen Exemplar, or Exemplar, and also includes our majority ownership interest in Triple-Gene LLC, doing business as Precigen Triple-Gene, or Triple-Gene, as well as equity and royalty interests in therapeutics and therapeutic platforms from companies not controlled by us.

Our Healthcare Business

Our healthcare business focuses on human therapeutics and developing research models and services for healthcare research applications.

Our Biopharmaceuticals segment includes our wholly owned subsidiaries PGEN Therapeutics, Inc., or PGEN Therapeutics, and Precigen ActoBio, Inc., or ActoBio, and our majority ownership interest in Triple-Gene LLC, doing business as Precigen Triple-Gene, or Triple-Gene, as well as royalty interests in therapeutics and therapeutic platforms from companies not controlled by us.

Exemplar Genetics, LLC, doing business as Precigen Exemplar, or Exemplar, is a wholly owned subsidiary which is focused on developing research models and services for healthcare research applications.

Biopharmaceuticals

PGEN Therapeutics

PGEN Therapeutics is a dedicated discovery and clinical stage biopharmaceutical company advancing the next generation of gene and cell therapies using precision technology to target urgent and intractable diseases in immuno-oncology, autoimmune disorders and infectious diseases.

PGEN Therapeutics is a dedicated discovery and clinical stage biopharmaceutical company advancing the next generation of

gene and cell therapies using precision technology to target urgent and intractable diseases in immuno-oncology, autoimmune disorders and infectious diseases.

PGEN Therapeutics operates as an innovation engine, progressing a preclinical and clinical pipeline of well-differentiated therapies toward clinical proof-of-concept and commercialization.

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We deliver gene programs via viral, non-viral, and microbe-based approaches, including Sleeping Beauty , AttSite recombinases, and gorilla adenoviral vectors, from our AdenoVerse library.

Sleeping Beauty is a non-viral transposon/transposase system licensed from the University of Texas MD Anderson Cancer Center that stably reprograms immune cells by inserting specific DNA sequences into the genome.

The Sleeping Beauty system has been shown to promote random integration in the genome without insertion bias, which contrasts with the predilection of lentiviral vectors for integration at transcriptionally active sites.

We believe that this non-viral system may confer benefits including a reduction of the risk of genotoxicity.

The Sleeping Beauty system has been shown to promote random integration in the genome without insertion bias, which contrasts with the predilection of other viral and non-viral methods such as lentiviral vectors and the PiggyBac transposon system for integration at transcriptionally active sites.

We believe that our non-viral system may confer benefits including a reduction of the risk of genotoxicity.

Precigen has made significant improvements to the Sleeping Beauty system by optimizing gene elements, genetic payload capacity, and efficiency of delivery, which provides a system tailored to our multigenic UltraCAR-T platform.

Our AttSite recombinases, which break and rejoin DNA at specific sequences in a unidirectional, irreversible fashion to direct integration of a transgene into the host cell genome, allow for stable, site-specific gene integration.

Genetically engineered adenoviruses (a common group of viruses) called adenovectors that are designed to insert genes into cells are an important part of our technology platforms.

Our AdenoVerse technology platform is composed of a library of engineered adenovector serotypes that yield greater tissue specificity and target selection as compared to known human Ad5 adenovectors.

This includes our gorilla adenovectors, which provide a potential competitive advantage in their large payload capacity, ability for repeat administrations and generation of robust antigen-specific immune responses.

The UltraPorator system includes proprietary hardware and software solutions and potentially represents major advancements over current electroporation devices by significantly reducing the processing time and contamination risk.

UltraPorator is designed for rapid and cost-effective manufacturing of UltraCAR-T therapies and has the potential to enable rapid manufacturing of a range of gene and cell therapies beyond UltraCAR-T.

The final component of our approach to precision medicine is our ability to control gene expression and regulation using the RheoSwitch, kill switches, and tissue-specific promoters.

Genetically engineered adenoviruses (a common group of viruses) called adenovectors that are designed to insert genes into cells are an important part of our technology platforms.

Our AdenoVerse technology platform is composed of a library of engineered adenovector serotypes that yield greater tissue specificity and target selection as compared to known human Ad5 adenovectors.

This includes our gorilla adenovectors, which provide a potential competitive advantage with their large payload capacity, ability for repeat administrations and generation of robust antigen-specific immune responses.

The final component of our approach to precision medicine is our ability to control gene expression and regulation using the

RheoSwitch, kill switches, and tissue-specific promoters.

The RheoSwitch Therapeutic System, our inducible gene switch system, we believe is the most clinically advanced gene switch system and provides quantitative dose-proportionate regulation of the amount and timing of target protein expression in response to an orally available activator ligand, veledimex.

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Of the many immunotherapy approaches, chimeric antigen receptor T, or CAR-T, cell therapies in particular have shown remarkable responses in cancer patients with hematological malignancies.

These therapies rely on the modification of T cells with chimeric antigen receptors to enable those T cells to bind to specific antigens on the patient's tumor cells and kill the tumor cells.

These therapies rely on the genetic modification of T cells to express chimeric antigen receptors and enable these modified T cells to bind to specific antigens on the patient's tumor cells and kill the tumor cells.

Concerns remain, however, regarding complex and lengthy manufacturing processes and the safety profile of CAR-T cell therapies.

Furthermore, current autologous and allogeneic CAR-T cell therapies face challenges in the treatment of solid tumors due to rapid exhaustion and limited persistence of CAR-T cells.

Furthermore, current autologous and allogeneic CAR-T cell therapies face challenges in the treatment of solid tumors due to rapid exhaustion and limited in vivo persistence of CAR-T cells.

Current approaches to CAR-T manufacturing require extensive ex vivo expansion following viral vector transduction to achieve clinically relevant cell numbers.

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Our UltraCAR-T platform is differentiated from the competition, and we believe it has the potential to address the shortcomings of current technologies and disrupt the CAR-T treatment landscape by increasing patient access through shortening manufacturing time from weeks to days, decreasing manufacturing-related costs, and improving outcomes.

We recently introduced our vision for a new UltraCAR-T library approach, which is intended to transform the personalized cell therapy landscape for cancer patients.

Recently we described the advancement of the UltraCAR-T platform to address the inhibitory tumor microenvironment by incorporating intrinsic checkpoint blockade without the need for complex and expensive gene editing techniques.

The next generation of UltraCAR-T utilizes a single multicistronic transposon DNA and the well-established overnight, decentralized manufacturing process of UltraCAR-T.

We have introduced our vision for a new UltraCAR-T library approach, which is intended to transform the personalized cell therapy landscape for cancer patients.

Our goal is to develop and validate a library of non-viral plasmids to target tumor-associated antigens.

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If our goal is realized, one or more non-viral plasmids could be selected based on the patient's cancer indication and biomarker profile from the library to build a personalized UltraCAR-T treatment.

After initial treatment, this approach has the potential to allow for redosing of UltraCAR-T targeting the same or new tumor-associated antigens based on the treatment response and the changes in antigen expression of the patient's tumor.

After initial treatment, this approach has the potential to allow for redosing of UltraCAR-T

targeting the same or new tumor-associated antigens based on the treatment response and the changes in antigen expression of the patient's tumor.

The key advantages of UltraCAR-T versus the traditional CAR-T approaches include:

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As a result of this optimization, our UltraCAR-T cells are precision-engineered to produce a homogeneous cell product that simultaneously co-expresses antigen-specific CAR, kill switch, and mbIL15 genes in any genetically modified UltraCAR-T cell.

We recently introduced the next generation UltraCAR-T platform that addresses the inhibitory tumor microenvironment by incorporating a novel mechanism for intrinsic downregulation of one or more checkpoint inhibitor, or CPI, genes.

Our design achieves intrinsic CPI blockade without gene editing and is aimed at avoiding systemic toxicity and the high cost of combining CPI antibodies.

The next generation UltraCAR-T cells simultaneously express CAR, mbIL15, and a kill switch, and incorporates intrinsic CPI blockade using a single multicistronic non-viral transposon.

This design differentiates our UltraCAR-T platform from the approaches used by our competitors and, we believe, reduces the developmental risk as compared to those approaches because product homogeneity is a critical consideration for later stages of clinical development and subsequent commercialization.

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Enhanced persistence and elimination of ex vivo expansion step due to expression of mbIL15

The key driver of improved UltraCAR-T cell performance is mbIL15.

A key driver of improved UltraCAR-T cell performance is mbIL15.

The expression of mbIL15 has been shown to enhance in vivo expansion of UltraCAR-T cells in the presence of tumor antigens and prevent T cell exhaustion to maintain a less differentiated, stem-cell like memory phenotype leading to longer persistence of UltraCAR-T cells.

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Another key differentiator of the UltraCAR-T therapeutic platform is our rapid and decentralized proprietary manufacturing process, which allows us to manufacture UltraCAR-T cells overnight at a medical center's current good manufacturing practices, or cGMP, facility and reinfuse the patient the following day after gene transfer.

This process improves upon current approaches to CAR-T manufacturing, which require extensive ex vivo expansion following viral vector transduction to achieve clinically relevant cell numbers that we believe can result in the exhaustion of CAR-T cells prior to their administration, limiting their potential for persistence in patients.

This process improves upon current approaches to CAR-T manufacturing, which require extensive ex vivo expansion following viral vector transduction that we believe can result in the exhaustion of CAR-T cells prior to their administration, limiting their potential for persistence in patients.

The decentralized nature of the manufacturing process allows us to scale beyond the confines of a dedicated facility.

We are the first company to implement non-viral, rapid, decentralized manufacturing of CAR-T cells in the clinic and have validated our proprietary UltraCAR-T manufacturing process in practice by infusing patients one day after gene transfer at two different sites in our ongoing clinical trials.

We are the first company to validate non-viral, rapid, decentralized manufacturing of CAR-T cells in the clinic by infusing patients one day after gene transfer at two different sites in our ongoing clinical trials.

We have developed a proprietary electroporation device, UltraPorator, designed to further streamline and ensure the rapid and cost-effective manufacturing of UltraCAR-T therapies.

The UltraPorator system, intended to be a viable scale-up and commercialization solution for decentralized UltraCAR-T manufacturing, includes proprietary hardware and software solutions and potentially represents major advancements over current electroporation devices by significantly reducing the processing time and contamination risk.

The FDA has cleared UltraPorator as a manufacturing device for clinical trials of our UltraCAR-T investigational therapies.

We believe our UltraCAR-T manufacturing process will provide a significant potential competitive advantage in the timeline and cost required to manufacture and deliver CAR-T therapies to patients as compared to current treatment approaches that require large, centralized facilities to support manufacturing of a relatively small number of treatments.

We believe development of rapid and successful overnight manufacturing of UltraCAR-T therapies at medical centers signifies a paradigm shift in CAR-T therapy by eliminating manufacturing and timing risks associated with conventional CAR-T therapies, and our intent is for it to take place directly in numerous treatment centers, which can improve the accessibility of our therapies for patients.

PGEN Therapeutics' most advanced programs based on the UltraCAR-T platform include PRGN-3005, which is in a Phase 1/1b clinical trial for patients with advanced ovarian, fallopian tube, or primary peritoneal cancer, and PRGN-3006, which is in a Phase 1/1b clinical trial for patients with relapsed or refractory acute myeloid leukemia, or AML, high-risk myelodysplastic syndromes, or MDS, and chronic myelomonocytic leukemia, or CMML.

PRGN-3006, which is in a Phase 1/1b clinical trial for patients with relapsed or refractory acute myeloid leukemia, or AML, high-risk myelodysplastic syndromes, or MDS, and chronic myelomonocytic leukemia, or CMML;

and PRGN-3007, based on the next generation UltraCAR-T, which has received FDA clearance to initiate a Phase 1/1b clinical trial for patients with advanced receptor tyrosine kinase-like orphan receptor 1-positive, or ROR1, hematological and solid tumors.

PRGN-3005 is a first-in-class, investigational autologous CAR-T therapy that utilizes our UltraCAR-T platform to simultaneously express a CAR targeting the unshed portion of the Mucin 16 antigen, or MUC16, mbIL15, and kill switch genes.

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PRGN-3005 UltraCAR-T cells have shown significantly superior anti-tumor response in mouse models of ovarian cancer compared to mice treated with a saline solution or conventional MUC16 CAR-T cells lacking mbIL15 expression.

Specifically, a single administration of PRGN-3005 one day after non-viral gene transfer showed significantly superior expansion and preferred memory phenotype of UltraCAR-T in vivo and significantly

superior efficacy compared to traditional CAR-T resulting in all PRGN-3005 treated mice becoming tumor-free.

Specifically, a single administration of PRGN-3005 one day after non-viral gene transfer showed significantly superior expansion and preferred memory phenotype of UltraCAR-T in vivo and significantly superior efficacy compared to traditional CAR-T resulting in all PRGN-3005 treated mice becoming tumor-free.

Furthermore, rechallenging these tumor-free mice three months later with ovarian tumors for a second time (to simulate tumor relapse) led to the elimination of tumor burden without additional PRGN-3005 UltraCAR-T treatment.

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The Phase 1 portion of the study is a dual-arm, non-randomized, open-label clinical trial in patients with advanced, recurrent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer.

Patients in this investigator-initiated Phase 1 dose escalation trial receive either intraperitoneal, or IP (Arm A), or intravenous, or IV (Arm B), administration of PRGN-3005 without prior lymphodepletion.

Patients in this investigator-initiated Phase 1 dose escalation trial receive either intraperitoneal, or IP (Arm 1), or intravenous, or IV (Arm 2), administration of PRGN-3005 without prior lymphodepletion.

The primary objectives of the Phase 1 trial are to assess the safety and maximum tolerated dose, or MTD, of PRGN-3005.

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We expect to enroll up to 71 patients total in this study.

In October 2020, we announced the FDA clearance of our UltraPorator system, a proprietary electroporation device and software solution for the scale-up of rapid and cost-effective manufacturing of UltraCAR-T therapies, as a manufacturing device for clinical trials of our investigational UltraCAR-T therapies in compliance with cGMP.

In November 2020, we announced that we have successfully dosed the first patient in the PRGN-3005 Phase 1 trial using UltraCAR-T cells manufactured using the UltraPorator system.

In December 2020, we presented preliminary data from the first six patients treated with PRGN-3005, who were treated at the two lowest dose levels in the IP arm without prior lymphodepletion.

The six patients were treated at either Dose Level 1 (>3x10 4 - ≤ 1 x 10 5 UltraCAR-T cells/kg;

N=3) or Dose Level 2 (>1x10 5 - ≤ 3 x 10 5 UltraCAR-T cells/kg;

Patients had received between 6 and 9 prior therapies before enrolling in the PRGN-3005 study.

Preliminary data from these patients showed that PRGN-3005 was well-tolerated, with no dose-limiting toxicities, or DLTs, neurotoxicities, or cytokine release syndromes reported.

PRGN-3005 UltraCAR-T cells showed encouraging expansion and persistence after low dose IP infusion without lymphodepletion across both dose levels.

In addition, 50 percent (3 out of 6) of the patients experienced regression in total target tumor burden and 33 percent (2 out of 6) patients achieved stable disease according to RECIST v1.1 criteria at their restaging evaluation.

In addition, we believe that our consistent ability to successfully manufacture UltraCAR-T cells at a medical center confirms the validity of our rapid, decentralized approach to manufacturing.

Enrollment is ongoing in the IP arm of the trial, and an expansion phase is planned at the MTD.

We have received clearance from the FDA to initiate dosing in the IV arm of the trial concurrently with the IP arm.

In November 2021, the lead investigator of the PRGN-3005 clinical trial presented additional interim data from the IP arm of the Phase 1 trial at our 2021 R&D Virtual Event.

Data from the patients treated in the IP arm showed a favorable safety profile, dose-dependent expansion and persistence in the peripheral blood, and clinical activity as evidenced by a decrease or stabilization of total target tumor burden at the first restaging in a majority of patients.

In addition, the UltraPorator system has enabled us to deliver higher UltraCAR-T doses, and we believe that our consistent ability to successfully manufacture UltraCAR-T cells at a medical center confirms the validity of our rapid, decentralized approach to manufacturing.

In March 2021, we announced FDA clearance to initiate dosing in the IV arm of the Phase 1 dose escalation trial concurrently with the IP arm.

In August 2021, we announced that the FDA has cleared enrollment of patients in Dose Level 3 in the IV arm without the need to follow 3+3 dose escalation through Dose Levels 1 and 2.

In January 2022, we announced the completion of enrollment in the dose escalation phase of both IP and IV arms without lymphodepletion in the ongoing Phase 1 clinical trial.

We have received FDA clearance to incorporate lymphodepletion at Dose Level 3 of the IV arm.

We plan to evaluate lymphodepletion in the IV arm and plan to initiate a multicenter expansion phase of PRGN-3005.

In addition, based on the favorable safety profile of PRGN-3005 to date, we plan to evaluate the potential for redosing in the clinical trial.

PRGN-3006 is a first-in-class, investigational autologous CAR-T therapy that utilizes our UltraCAR-T platform to express a CAR to target CD33, mbIL15 and a kill switch for better precision and control.

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The Phase 1 portion of this study is a dual-arm, non-randomized, dose-escalation clinical trial where PRGN-3006 is delivered via intravenous infusion.

The patient population includes relapsed or refractory AML, higher-risk MDS, and CMML.

In the 3+3 dose escalation phase, patients will be treated in one of the two arms:

patients in Arm 1, or No Lymphodepletion arm, will receive UltraCAR-T cell infusion without prior lymphodepletion, and patients in Arm 2, or Lymphodepletion arm, will receive lymphodepleting chemotherapy prior to UltraCAR-T infusion.

Because our UltraCAR-T cells have the potential for enhanced in vivo expansion and persistence due to expression of mbIL15, we are evaluating the administration of PRGN-3006 in patients without prior lymphodepletion.

The patient population includes relapsed or refractory AML, or r/r AML, higher-risk MDS, and CMML.

In the 3+3 dose escalation phase, patients are treated in one of the two arms:

patients in Cohort 1, or No Lymphodepletion arm, receive UltraCAR-T cell infusion without prior lymphodepletion, and patients in Cohort 2, or Lymphodepletion arm, receive lymphodepleting chemotherapy prior to UltraCAR-T infusion.

The primary objective of this trial is to assess the safety of PRGN-3006 and determine the MTD.

The Phase 1 trial is being conducted in collaboration with Moffitt Cancer Center, a pioneer in CAR-T clinical development.

In October 2020, we announced the FDA clearance of our UltraPorator system as a manufacturing device for clinical trials of our investigational UltraCAR-T therapies in compliance with cGMP.

In November 2020, we announced that we have successfully dosed the first patient in the PRGN-3006 Phase 1 trial using UltraCAR-T cells manufactured using the UltraPorator system.

In December 2020, the Principal Investigator of the PRGN-3006 clinical trial presented clinical progress and preliminary data from the ongoing Phase 1 trial, including a case study of a patient treated at Dose Level 2 of the No Lymphodepletion arm at the 62 nd ASH Annual Meeting and Exposition.

Later in December, we presented additional data to expand upon the preliminary data presented at the ASH Annual Meeting and Exposition.

As of November 10, 2020, the cutoff date for the results, a total of nine patients had been treated in either the No Lymphodepletion arm or the Lymphodepletion arm of the trial.

Of the nine patients treated, six were treated at either the Dose Level 1 (>3x10 4 - ≤ 1 x 10 5 UltraCAR-T cells/kg;

N=3) or the Dose Level 2 (>1x10 5 - ≤ 3 x 10 5 UltraCAR-T cells/kg;

N=3) of the No Lymphodepletion arm, and three were treated at the Dose Level 1 (>3x10 4 - ≤ 1 x 10 5 UltraCAR-T cells/kg;

N=3) of the Lymphodepletion arm.

Preliminary data from these patients showed that PRGN-3006 was well-tolerated, with no DLTs and no neurotoxicity.

Transient grade 1 to 3 cytokine release syndrome was reported in two patients, which was resolved without intervention.

There was low incidence of treatment-related adverse events and serious adverse events, and Grade 3 or greater treatment-emergent adverse events included hematologic events, decreased electrolytes, and infections.

PRGN-3006 UltraCAR-T showed encouraging expansion and persistence in peripheral blood of patients in both No Lymphodepletion and Lymphodepletion arms and across all dose levels.

Furthermore, PRGN-3006 UltraCAR-T cells showed the ability to traffic, expand, and persist in bone marrow.

In addition, we believe that our consistent ability to successfully manufacture UltraCAR-T cells at a medical center confirms the validity of our rapid, decentralized approach to manufacturing.

A case study of the patient with the longest follow-up as of the data cutoff was also presented at the ASH Annual Meeting and Exposition.

The case study patient was a 69 year old female with secondary AML and four prior lines of therapy, including induction chemotherapy, or IC, allogenic hematopoietic stem cell transplantation, or allo-HSCT, hypomethylating agent plus venetoclax, or HMA+VEN.

The patient was refractory to all therapy post allo-HSCT.

The patient had approximately 40 percent peripheral blasts and 47 percent bone marrow blasts at baseline.

The patient was treated at Dose Level 2 in No Lymphodepletion arm with a total of only 24 million UltraCAR-T cells via IV infusion.

Case study findings presented showed that, after a low dose infusion without prior lymphodepletion, PRGN-3006 UltraCAR-T cells demonstrated robust expansion and persistence in blood at seven months post-infusion.

PRGN-3006 UltraCAR-T cells demonstrated trafficking to bone marrow and the ability to expand and persist in bone marrow.

The patient showed a decline in AML blast levels in blood and bone marrow concomitant with UltraCAR-T expansion and persistence and had durable stable disease.

Enrollment is ongoing simultaneously in both the No Lymphodepletion and the Lymphodepletion arms of this Phase 1 trial.

The dose escalation phase of each arm will be followed by a dose expansion phase at the MTD.

PRGN-3006 was granted Orphan Drug designation for the treatment of AML by the FDA.

In November 2021, the Principal Investigator of the PRGN-3006 clinical trial presented clinical progress and interim data from the ongoing Phase 1 trial at our 2021 R&D Virtual Event.

In December 2021, the Principal Investigator presented additional interim data at the 63 rd ASH Annual Meeting and Exposition.

Data showed a favorable safety profile of PRGN-3006 administered in both the No Lymphodepletion and the Lymphodepletion cohorts.

In addition, dose-dependent expansion and persistence of PRGN-3006 in peripheral blood and bone marrow was observed in both the No Lymphodepletion and the Lymphodepletion cohorts with higher peak expansion in the Lymphodepletion cohort compared to the No Lymphodepletion cohort.

Furthermore, data showed encouraging clinical responses in the Lymphodepletion cohort.

In January 2022, we announced the completion of enrollment in the Phase 1 dose escalation trial in both the No Lymphodepletion and the Lymphodepletion cohorts.

We plan to initiate a multicenter expansion phase of the study at Dose Level 3 with lymphodepletion.

We plan to incorporate a repeat dosing regimen in the expansion phase.

Furthermore, we anticipate publication of additional Phase 1/1b data in 2022.

PRGN-3006 has been granted Orphan Drug designation for the treatment of AML by the FDA.

PRGN-3007 is a first-in-class, investigational autologous CAR-T therapy that utilizes the next generation UltraCAR-T platform to express a CAR to target ROR1, mbIL15, kill switch, and a novel mechanism for the intrinsic blockade of the programmed death 1, or PD-1, gene expression.

ROR1 is a type I orphan-receptor that is expressed during embryogenesis and by certain hematological and solid tumors but is undetectable on normal adult tissues.

ROR1 in malignancies is aberrantly expressed in B-cell malignancies such as B-cell acute lymphoblastic leukemia, or B-ALL, diffuse large cell B-cell lymphoma, or DLBCL, chronic lymphocytic leukemia, or CLL, and mantle cell lymphoma, or MCL.

Furthermore, upregulated expression has been detected in various solid tumors, including ovarian cancer, breast adenocarcinomas encompassing triple negative breast cancer, or TNBC, pancreatic cancer, Ewing's sarcoma and lung adenocarcinoma.

The increased expression of ROR1 in hematological and solid tumor malignancies has been associated with tumor proliferation, metastasis and poor clinical outcomes.

The PD-1/programmed death ligand 1, or PD-L1, pathway plays a vital role in how tumor cells evade immune response.

While the blockade of the PD-1/PD-L1 pathway has demonstrated considerable benefit for treating various cancers, the use of systemic CPI can lead to side effects associated with autoimmune response.

The innovative design of PRGN-3007, where the

blockade of PD-1 expression is intrinsic and localized to UltraCAR-T cells, is aimed at avoiding systemic toxicity and the high cost of CPI by eliminating the need for combination treatment.

In preclinical in vitro studies, PRGN-3007 showed significant reduction in PD-1 expression on UltraCAR-T cells compared to control ROR1 CAR-T cells lacking PD-1 blockade.

The downregulation of PD-1 expression on PRGN-3007 resulted in enhanced ROR1-specific cytotoxicity and release of inflammatory cytokines upon co-culture with various ROR1-positive, or ROR1 + , PD-L1 + hematological and solid tumor cells compared to Control ROR1 CAR-T, especially at low effector to target cell ratios.

Single-cell cytokine proteomics showed that the downregulation of PD-1 expression on PRGN-3007 resulted in a significantly higher number of polyfunctional CAR-T cells compared to Control ROR1 CAR-T.

Expression of mbIL15 on PRGN-3007 UltraCAR-T, with or without downregulation of PD-1 expression, resulted in robust expansion in presence of ROR1 antigen, lack of autonomous expansion in absence of ROR1, and durable persistence even in absence of exogenous cytokines in vitro.

PRGN-3007 was selectively and effectively eliminated by the kill switch activator treatment demonstrating functionality of the kill switch, which is intended to improve the safety profile of PRGN-3007.

In preclinical in vivo testing, a single administration of PRGN-3007, only one day after gene transfer, effectively reduced tumor burden and significantly improved overall survival of tumor bearing mice compared to Control ROR1 CAR-T in an aggressive xenograft model of mantle cell lymphoma.

Blood analyses demonstrated sustained downregulation of PD-1 expression, rapid expansion, long-term persistence, and a predominant central memory phenotype of PRGN-3007 in tumor bearing mice.

In October 2021, we announced that FDA has cleared the investigational new drug, or IND, application to initiate the Phase 1/1b clinical trial of PRGN-3007 in advanced ROR1 + hematological and solid tumors.

The Phase 1/1b clinical trial is an open-label study designed to evaluate the safety and efficacy of PRGN-3007 in patients with advanced ROR1 + hematological (Arm 1) and solid (Arm 2) tumors.

The target patient population for Arm 1 includes relapsed or refractory CLL, relapsed or refractory MCL, relapsed or refractory B-ALL, and relapsed or refractory DLBCL.

The target patient population for Arm 2 includes locally advanced unresectable or metastatic histologically confirmed TNBC.

The study will enroll in two parts:

an initial 3+3 dose escalation in each arm followed by a dose expansion at the maximum tolerated dose.

Arm 1 and Arm 2 will enroll in parallel.

The Phase 1 trial will be conducted in collaboration with Moffitt Cancer Center, a pioneer in CAR-T clinical development.

We plan to initiate dosing in the Phase 1 trial of PRGN-3007 in 2022.

"Off-the-shelf" AdenoVerse Immunotherapy

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We have established proprietary manufacturing cell lines and production methodologies from our AdenoVerse immunotherapy platform, which we believe are easily scalable for commercial supply.

We believe that our proprietary gorilla adenovectors, which are part of the AdenoVerse technology, have superior performance characteristics as compared to current competition, including standard human adenovirus serotype 5, or Ad5, rare

human adenovirus types and other non-human primate adenovirus types.

We believe that our proprietary gorilla adenovectors, part of the AdenoVerse technology, have superior performance characteristics as compared to current competition, including standard human adenovirus serotype 5, or Ad5, rare human adenovirus types and other non-human primate adenovirus types.

The key advantages of AdenoVerse immunotherapy platform include:

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The rare and weak pre-existing immunity against gorilla adenovectors may therefore provide an advantage in clinical applications as compared to existing competition.

Inability to replicate

Replication incompetence

Our gorilla adenovectors are engineered and manufactured using a process that ensures the production of replication incompetent adenoviral therapeutic candidates with no cytopathic or cytotoxic effect in normal human cells.

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Our modular cGMP facility with a small footprint was designed with agility and control in mind, focusing on rapid manufacturing and the ability to scale production appropriately to meet early-stage clinical trial needs of gene therapy vectors, especially our AdenoVerse-based therapeutics.

We are able to generate greater than 1,000 doses of early phase

clinical trial material at this facility at an expedited timeline and reduced cost compared to contract manufacturing organizations.

As a result, we feel we are in a position to be in control of meeting our gene therapy manufacturing needs for our early-phase clinical trials.

We are able to generate greater than 1,000 doses of early phase clinical trial material at this facility at an expedited timeline and reduced cost compared to contract manufacturing organizations.

As a result, we feel we are in a position to be in control of meeting our gene therapy manufacturing needs for our

early-phase clinical trials.

PGEN Therapeutics' most advanced programs based on the AdenoVerse immunotherapy platform include:

(i) PRGN-2009, a first-in-class, "off-the-shelf" investigational immunotherapy utilizing the AdenoVerse platform, is designed to activate the immune system to recognize and target human papillomavirus-positive, or HPV+, solid tumors, which is in a Phase 1/2 clinical trial for patients with HPV-associated cancers in collaboration with the National Cancer Institute, or NCI, pursuant to a cooperative research and development arrangement, or CRADA;

and (ii) PRGN-2012, a first-in-class, investigational "off-the-shelf" AdenoVerse immunotherapy designed to elicit immune responses directed against cells infected with HPV type 6, or HPV6, or HPV type 11, or HPV11, which recently received investigational new drug application, or IND, approval from the FDA to initiate a Phase 1 trial in patients with recurrent respiratory papillomatosis, or RRP.

(i) PRGN-2009, a first-in-class, investigational "off-the-shelf" immunotherapy utilizing the AdenoVerse platform, is designed to activate the immune system to recognize and target human papillomavirus-positive, or HPV+, solid tumors, which is in a Phase 1/2 clinical trial for patients with HPV-associated cancers in collaboration with the National Cancer Institute, or NCI, pursuant to a cooperative research and development arrangement, or CRADA;

and (ii) PRGN-2012, a first-in-class, investigational "off-the-shelf" AdenoVerse immunotherapy designed to elicit immune responses directed against cells infected with HPV type 6, or HPV6, or HPV type 11, or HPV11, which is in a Phase 1 trial in patients with recurrent respiratory papillomatosis, or RRP.

PRGN-2009, a first-in-class, "off-the-shelf" investigational immunotherapy, is designed to activate the immune system to recognize and target HPV+ solid tumors.

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PRGN-2009 is in a Phase 1/2 clinical trial for patients with HPV-associated cancers in collaboration with NCI pursuant to a CRADA.

The Phase 1 portion of the study will follow 3+3 dose escalation to evaluate the safety of PRGN-2009 administered as a monotherapy, Arm A, to determine the recommended Phase 2 dose, or R2PD, followed by an evaluation of the safety of the combination of PRGN-2009 at the R2PD and M7824, Arm B.

The Phase 1 portion of the study was designed to follow 3+3 dose escalation to evaluate the safety of PRGN-2009 administered as a monotherapy, Arm A, to determine the recommended Phase 2 dose, or R2PD, followed by an evaluation of the safety of the combination of PRGN-2009 at the R2PD and M7824, Arm B.

The Phase 1 study population includes patients with recurrent or metastatic HPV-associated cancers.

PRGN-2009 will be administered via sub cutaneous injection once every 2 weeks for three administrations and may be continued every 4 weeks for up to one year, as clinically appropriate.

M7824 will be administered on Day 1 and then every 2 weeks.

The Phase 2 portion of the study will evaluate PRGN-2009 as a monotherapy or in combination with M7824 as a neoadjuvant or induction therapy in patients with newly-diagnosed stage II/III HPV16-positive oropharyngeal cancer and patients with newly diagnosed operable stage II/III/IVA/IVB HPV+ sinonasal squamous cell cancer.

In January 2021, we announced preliminary data from the ongoing Phase 1/2 clinical trial of PRGN-2009 in patients with HPV-associated cancers.

Enrollment in the Phase 1 monotherapy dose escalation arm, Arm A, of this trial is complete, and enrollment in the Phase 1 combination arm, Arm B, has been initiated.

A total of six patients were treated in the monotherapy arm.

All patients in the monotherapy arm have received multiple PRGN-2009 administrations to date.

Preliminary data showed that repeated administrations of PRGN-2009 was well-tolerated by these patients with no DLTs.

In addition, preliminary correlative analysis by the NCI of peripheral blood mononuclear cells from three patients treated at the initial dose level showed an increase in HPV16 and/or HPV18-specific T-cell response in 100 percent (3 out of 3) patients.

Furthermore, an increase in the magnitude and breadth of immune response was seen after repeat administration of PRGN-2009.

PRGN-2009 is administered via sub cutaneous injection once every 2 weeks for three administrations and may be continued every 4 weeks for up to one year, as clinically appropriate.

M7824 is administered on Day 1 and then every 2 weeks.

The Phase 2 portion of the study is designed to evaluate PRGN-2009 as a monotherapy or in combination with M7824 as a neoadjuvant or induction therapy in patients with newly-diagnosed stage II/III HPV16-positive oropharyngeal cancer and patients with newly diagnosed operable stage II/III/IVA/IVB HPV+ sinonasal squamous cell cancer.

In November 2021, one of the lead investigators of the PRGN-2009 clinical trial presented clinical progress and preliminary data from the Phase 1 trial at our 2021 R&D Virtual Event.

In November 2021, the Principal Investigator of the PRGN-2009 clinical trial presented additional interim data at the Society for Immunotherapy of Cancer, or SITC, 2021 Annual Meeting.

Phase 1 data showed a favorable safety profile of repeated PRGN-2009 administrations in both the monotherapy and the combination arms.

In addition, there was not a significant neutralizing antibody response to gorilla adenovector post PRGN-2009 treatment, and there was not a significant increase in neutralizing antibody response over time with subsequent additional vaccinations in both the monotherapy and the combination arms.

We believe that the lack of significant neutralizing antibody response highlights the ability to deliver repeated administrations of PRGN-2009, a major differentiation of our AdenoVerse immunotherapy platform.

Phase 1 data showed encouraging clinical activity and patient case studies showed an increase in the HPV16 and/or HPV18-specific immune response after PRGN-2009 administration and an increase in the magnitude and breadth of immune response with respect to repeated administrations of PRGN-2009.

Enrollment in the Phase 1 monotherapy dose escalation arm is complete and enrollment in the Phase 1 combination arm is ongoing in patients with recurrent or metastatic HPV-associated cancers.

In addition, enrollment in the monotherapy arm of the Phase 2 trial, which evaluates PRGN-2009 as a neoadjuvant therapy for newly diagnosed oropharyngeal or sinonasal squamous cell cancer (OPSCC) patients is ongoing.

We expect to report additional Phase 1 data in 2022.

We plan to seek FDA guidance on a rapid regulatory strategy for PRGN-2009 given the positive interim results and significant unmet patient need.

We plan to initiate a Phase 2 study in advanced HPV-associated cancer indications in combination with an approved anti-PD-1 CPI.

PRGN-2012, a first-in-class, investigational "off-the-shelf" AdenoVerse immunotherapy for the treatment of RRP.

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RRP is classified based on age of onset as juvenile or adult.

Approximately 1,500 new cases of RRP are diagnosed each year in the United States.

Juvenile-onset disease has an incidence of 4 per 100,000 and adult-onset RRP has an incidence of 2 to 3 per 100,000.

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In preclinical models, PRGN-2012 has demonstrated strong HPV6 and HPV11-specific T-cell response in RRP patient samples in vitro .

In January 2021, we announced that the FDA had cleared the IND to initiate the Phase 1 clinical trial of PRGN-2012 AdenoVerse immunotherapy in adult patients with RRP.

The Phase 1 study will follow 3+3 dose escalation of PRGN-2012 as an adjuvant immunotherapy following standard-of-care surgical removal of visible papillomatosis disease.

Patients will receive up to four injections of PRGN-2012.

PRGN-2012 is in a Phase 1 clinical trial for adult patients with RRP.

The Phase 1 study is designed to follow 3+3 dose escalation of PRGN-2012 as an adjuvant immunotherapy following standard-of-care surgical removal of visible papillomatosis disease.

Patients receive up to four injections of PRGN-2012.

The primary objective of the study is to determine safety and tolerability and the recommended Phase 2 dose of PRGN-2012.

The study will enroll 3 to 6 subjects at each dose level, and 12 patients will be treated at the MTD.

The study is designed to enroll 3 to 6 subjects at each dose level, and to treat 12 patients at the MTD in the expansion cohort.

PRGN-2012 is being developed in collaboration with the Center for Cancer Research at the NCI through a CRADA.

In November 2021, the Principal Investigator of the PRGN-2012 clinical trial presented preliminary data from the ongoing clinical trial at our 2021 R&D Virtual Event.

Phase 1 data reported showed a favorable safety profile of repeated PRGN-2012 administrations in RRP patients.

In addition, the preliminary Phase 1 data from three RRP patient case studies demonstrated encouraging clinical activity of PRGN-2012 with reduction or elimination in the need for surgical interventions at the most recent follow-up after PRGN-2012 treatment compared to the recent history of surgical interventions for these patients before enrolling in the trial.

PRGN-2012 has been granted Orphan Drug designation for the treatment of RRP by the FDA.

Preclinical Programs

We have a robust pipeline of preclinical programs that we are pursuing in order to drive long-term value creation.

Our pipeline includes a number of product candidates, including UltraCAR-T therapeutics for various cancers, an "off-the-shelf" AdenoVerse immunotherapy for infectious disease, and a multifunctional therapeutic for solid tumors.

We have a robust pipeline of preclinical programs in our core therapeutic areas of immune-oncology, infectious diseases, and autoimmune disorders that we are pursuing in order to drive long-term value creation.

Our pipeline includes a number of product candidates based on UltraCAR-T and "off-the-shelf" AdenoVerse immunotherapy therapeutic platforms.

We expect to continue development of various preclinical programs to identify product candidates for evaluation in clinical trials.

We are evaluating multiple UltraCAR-T candidates for treatment of hematological and solid tumors in preclinical testing.

We recently introduced our vision for a new UltraCAR-T library approach aimed at transforming the personalized cell therapy landscape for cancer patients.

Our goal is to develop and validate a library of non-viral plasmids to target tumor-associated antigens.

We have reported our vision for a new UltraCAR-T library approach aimed at transforming the personalized cell therapy landscape for cancer patients.

Our goal is to develop and validate a library of non-viral plasmids to target tumor-associated antigens using the UltraCAR-T platform.

We are developing PRGN-2013, a preclinical stage asset based on our "off-the-shelf" AdenoVerse immunotherapy platform, to treat chronic hepatitis B virus, or HBV, infection.

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Preclinical studies of PRGN-2013 showed that mice treated with PRGN-2013 saw (i) a more significant cytotoxic T-cell response against more HBV epitopes and (ii) decreased plasma levels of HBsAg, the key marker of chronic HBV infection in mice.

We are also developing immuno-oncology product candidates based on our Multifunctional Therapeutic platform to target solid tumors.

Additional preclinical programs under development include an AdenoVerse cytokine therapy candidate for solid tumors and candidates to target autoimmune disorders.

We also have a number of other potential product candidates in our preclinical pipeline and, consistent with our commitment to actively manage our portfolio programs, we exercise discipline in our portfolio management by systematically evaluating data from our preclinical programs in order to make rapid "go" and "no go" decisions.

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Precigen ActoBio's Therapeutic Platforms

Our ActoBiotics platform is a unique therapeutic platform precisely tailored for specific disease modification with the potential for superior efficacy and safety.

Our ActoBiotics platform is a unique delivery platform precisely tailored for specific disease modification with the potential for superior efficacy and safety.

ActoBiotics combine the advantages of highly selective protein-based therapeutic agents with local delivery by the well-characterized and food-grade bacterium Lactococcus lactis , or L.

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Food-grade bacterium with easy genetic manipulation

ActoBiotics combine the advantages of highly selective protein-based therapeutic agents with local delivery by the well-

characterized and food-grade bacterium with L.

ActoBiotics combine the advantages of highly selective protein-based therapeutic agents with local delivery by the well-characterized and food-grade bacterium with L.

lactis , which has a long history of safe use.

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ActoBio's most advanced internal pipeline candidate, AG019, is a first-in-class disease modifying antigen-specific, investigational immunotherapy for the prevention, delay, or reversal of type 1 diabetes mellitus, or T1D.

AG019 is an easy-to-take capsule formulation of ActoBiotics engineered to deliver the autoantigen human proinsulin, or PINS, and the tolerance-enhancing cytokine human interleukin-10 to the mucosal lining of gastro-intestinal tissues in patients with T1D.

AG019 is an easy-to-take capsule formulation of ActoBiotics engineered to deliver the autoantigen human proinsulin, or hPINS, and the tolerance-enhancing cytokine human interleukin-10 to the mucosal lining of gastro-intestinal tissues in patients with T1D.

We believe this design can reduce T1D pathology by reestablishing immunological tolerance to islet antigens via the production of regulatory T, or Treg, cells.

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Furthermore, AG019 treatment induced accumulation and proliferation of PINS-specific FoxP3 + Treg cells in the pancreas and peripheral lymph nodes.

AG019 is currently in a Phase 1b/2a clinical trial for the treatment of early-onset T1D.

The Phase 1b portion of the study evaluates the safety and tolerability of AG019 monotherapy administered as a single dose and repeated daily doses in adult and adolescent patients.

Enrollment and dosing in the Phase 1b and Phase 2a portions of the study are complete.

portion of the study investigates the safety and tolerability of AG019 in combination with teplizumab, or PRV-031.

In August 2020, we announced that the primary endpoint of assessing safety and tolerability in the Phase 1b monotherapy portion of the study was met and that preliminary results at six months after AG019 monotherapy treatment initiation showed an encouraging trend in the insulin C-peptide levels, a biomarker for T1D disease progression.

In December 2020, we announced additional data from our ongoing Phase 1b portion and initial preliminary data from the Phase 2a portion of our ongoing Phase 1b/2a clinical trial.

The additional data from the Phase 1b monotherapy portion of the trial showed that AG019 continued to be well-tolerated, with no discontinuations due to treatment-emergent adverse events.

From the perspective of clinical activity, this data showed that 58 percent (7 of 12) of patients aged 17 or older receiving the AG019 monotherapy showed stabilization of C-peptide levels during the first six months of treatment and slower decline in C-peptide levels after being treated for 12 months as compared to treatment with placebo.

In addition, a mechanistic analysis performed by an independent research group found the induction of antigen-specific tolerance in conjunction with the reduction of disease-specific T cell responses for adult patients after three months of treatment with AG019.

We believe these results indicate the potential of AG019 to preserve insulin production in early-onset T1D through AG019's capacity to induce antigen-specific immune modulation.

Data from the Phase 2a combination portion with teplizumab showed that the combination was well-tolerated.

This data showed that 70 percent of adult patients (7 of 10) experienced stabilization of C-peptide levels after six months of treatment with a trend toward higher C-peptide levels as compared to baseline levels.

Mechanistic data were consistent with the data shown in the monotherapy trial, which we believe indicates the effect may be attributed to AG019.

We believe preliminary results in the combination trial point to the potential to boost or prolong teplizumab-induced metabolic effects.

No dose-related adverse events or serious adverse events were reported in either portion of this trial.

We have completed a Phase 1b/2a clinical trial of AG019 for the treatment of early-onset T1D.

The Phase 1b open-label portion of the study evaluated the safety and tolerability of AG019 monotherapy administered as a single dose and repeated daily doses in adult and adolescent patients.

The Phase 2a double-blind portion of the study investigated the safety and tolerability of AG019 in combination with teplizumab, or PRV-031.

In June 2021, one of the lead investigators of the AG019 clinical trial presented results from the primary analysis at the Federation of Clinical Immunology Societies (FOCIS) 2021 Virtual Annual Meeting.

In October 2021, one of the lead investigators of the AG019 clinical trial presented additional interim data at the European Association for the Study of Diabetes (EASD) 57th Annual Meeting.

The primary endpoint of both the Phase 1b AG019 monotherapy and the Phase 2a AG019 combination therapy has been met.

AG019 was well-tolerated when administered to adults and adolescents either as monotherapy or in combination with teplizumab.

A single 8-week treatment cycle of oral AG019 as a monotherapy and in combination with teplizumab showed stabilization or increase of C-peptide levels during the first 6 months post treatment initiation in recent-onset T1D.

In an independent analysis performed in a subset of adult and adolescent patients by the Immune Tolerance Network (ITN), a leading independent research group sponsored by the United States National Institutes of Health, AG019 monotherapy and combination therapy induced antigen-specific tolerance in conjunction with the reduction of disease-specific T cell responses.

The extent of these antigen-specific immune modulatory effects in the combination therapy patients was similar to what was seen in AG019 monotherapy patients indicating that this effect may be attributed to the single 8-week treatment cycle of oral AG019.

We have completed the Phase 1b/2a clinical trial of AG019 and analysis of final results is ongoing.

Based on the positive results from the trial we plan to initiate discussions with regulatory agencies for the design of a Phase 2/3 clinical trial of AG019 in T1D.

Precigen Triple-Gene

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Triple-Gene's approach is to develop a holistic treatment for heart failure through improvements in angiogenesis, calcium homeostasis-associated cellular energetics, reductions in inflammatory signals, and the activation/recruitment of stem cells to support heart remodeling.

Triple-Gene's most advanced candidate, INXN-4001, a non-viral triple effector plasmid based on our UltraVector platform designed for the constitutive expression of human S100A1, SDF-1a, and VEGF-165, is engineered to address multiple pathways of heart failure.

Utilizing a single plasmid comprising all three genes, instead of each individual gene on separately delivered plasmids, INXN-4001 can control for delivery and ensure expression of three genes in all transfected cells.

Triple-Gene's most advanced candidate, INXN-4001, a non-viral triple effector plasmid based on our UltraVector platform designed for constitutive expression of human S100A1, SDF-1a, and VEGF-165, is engineered to address multiple pathways of heart failure.

Heart failure represents a significant unmet medical need and a major economic burden worldwide.

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Heart failure is the number one cause of hospitalization in patients aged 65 years and older, and 50 percent of heart failure patients die within five years after diagnosis.

Heart failure is a complex and multifaceted disease most often resulting from the intersection of multiple genetic predispositions with negative environmental factors.

Heart failure is a complex and multifaceted disease most often resulting from the intersection of multiple genetic

predispositions with negative environmental factors.

Existing treatments improve quality of life in the short-term and offer some improvement in long-term survival at high cost and with associated complications.

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Coronary sinus delivery of INXN-4001 in a large animal ischemic heart failure model showed decreased left ventricular end systolic volume and increased absolute mean ejection fraction, which are indicators of myocardial function, as well as no increase in arrhythmias compared to controls.

We recently completed our Phase 1 clinical trial of INXN-4001, which was a first-in-human, open label study designed to evaluate the safety of retrograde coronary sinus infusion, or RCSI, of INXN-4001 in outpatient left ventricular assist device, or LVAD, recipients.

A completed Phase 1 clinical trial of INXN-4001 was a first-in-human, open label study designed to evaluate the safety of retrograde coronary sinus infusion, or RCSI, of INXN-4001 in outpatient left ventricular assist device, or LVAD, recipients.

Twelve stable patients with implanted LVAD for mechanical support of end stage heart failure were allocated into two cohorts of six subjects for infusion of the same amount of INXN-4001 (80mg) in either 40mL or 80mL via RCSI at a rate of 20mL per minute.

The primary objectives of the Phase 1 study are to evaluate the safety of INXN-4001 infusion into the myocardium of LVAD patients and to demonstrate safety and feasibility of RCSI.

Secondary endpoints include improvements in the six minute walk test, or 6MWT, duration and distance and quality of life, as assessed by Kansas City Cardiomyopathy Questionnaire, or KCCQ, responses.

We have completed dosing and follow-up of patients in this trial.

In August 2020, we provided six-month follow-up data from the Phase 1 study of INXN-4001.

Twelve chronic heart failure patients were treated with INXN-4001 in either Cohort 1 (80 mg/40 mL;

n=6) or Cohort 2 (80 mg/80 mL;

n=6), and ten were

evaluated for six-month follow-up.

The study has met the primary endpoints to evaluate safety and feasibility for INXN-4001.

The primary objectives of the Phase 1 study were to evaluate the safety of INXN-4001 infusion into the myocardium of LVAD patients and to demonstrate safety and feasibility of RCSI.

Secondary endpoints included improvements in the six minute walk test, or 6MWT, duration and distance and quality of life, as assessed by Kansas City Cardiomyopathy Questionnaire, or KCCQ, responses.

The Phase 1 trial met the primary endpoints to evaluate safety and feasibility for INXN-4001.

The infusions of INXN-4001 were overall well tolerated, with no adverse events attributed to INXN-4001, whereas one serious adverse event was considered related to the infusion procedure.

Furthermore, preliminary assessment of the secondary endpoints show improvement by at least five points in total KCCQ score, a validated tool qualified by the FDA for Clinical Outcome Assessment, was observed in 50 percent of patients evaluable (5 out of 10) at the six-month follow-up visit, These included four patients treated in Cohort 1 and one patient treated in Cohort 2.

Of the evaluable patients, 50 percent (4 out of 8) had an improvement in the 6MWT (> 50 meters in distance walked) at six months post-infusion compared to pre-treatment baseline.

The Phase 1 trial has now been completed, and analysis of final results is ongoing.

Precigen Exemplar

Exemplar is committed to enabling the study of life-threatening human diseases through the development of MiniSwine Yucatan miniature pig research models and services, as well as enabling the production of cells and organs in its genetically engineered swine for regenerative medicine applications.

Historically, researchers have lacked animal models that faithfully represent human diseases.

As a result, a sizeable barrier has blocked progress in the discovery of human disease mechanisms;

novel diagnostics, procedures, devices, prevention strategies and therapeutics;

and the ability to predict in humans the efficacy of those next-generation procedures, devices, and therapeutics.

Exemplar's MiniSwine models are genetically engineered to exhibit a wide variety of human disease states, which provides a more accurate platform to test the efficacy of new medications and devices.

Furthermore, a preliminary assessment of the secondary endpoints showed improvement in the 6MWT and KCCQ score in a subset of patients.

Partnered Program

We have partnered with Castle Creek Biosciences, Inc.

(formerly Fibrocell Science, Inc.), or Castle Creek, to advance product candidates D-Fi (debcoemagene autoficel), formerly designated FCX-007, for the treatment of recessive dystrophic epidermolysis bullosa, or RDEB, and FCX-013 for the treatment of localized scleroderma.

We have partnered with Castle Creek Biosciences, Inc., or Castle Creek, to advance product candidates D-Fi (debcoemagene autoficel), formerly designated FCX-007, for the treatment of recessive dystrophic epidermolysis bullosa, or RDEB, and FCX-013 for the treatment of localized scleroderma.

In October 2020, Castle Creek announced the dosing of the first patient in the ongoing Phase 3 trial of D-Fi and the dosing of the first patient in the ongoing Phase 1/2 trial of FCX-013.

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Castle Creek retains a license to continue to develop and commercialize the Retained Products within the field of use for so long as Castle Creek continues to pursue such development and commercialization, and we are also entitled to certain royalties with respect to the Retained Products.

We are also required to perform certain drug product manufacturing activities related to the Retained Products.

We were also required to perform certain drug product manufacturing activities related to the Retained Products .

Precigen Exemplar

Historically, researchers have lacked animal models that faithfully represent human diseases.

As a result, a sizeable barrier has blocked progress in the discovery of human disease mechanisms;

novel diagnostics, procedures, devices, prevention strategies and therapeutics;

and the ability to predict in humans the efficacy of those next-generation procedures, devices, and therapeutics.

Exemplar's MiniSwine models are genetically engineered to exhibit a wide variety of human disease states, which provides a more accurate platform to test the efficacy of new medications and devices.

Healthcare Business

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The availability of reimbursement from government and other third-party payers will also significantly affect the pricing and competitiveness of our products.

Our competitors may also obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter

Key product features that would affect our ability to effectively compete with other therapeutics include the efficacy, safety and convenience of our products, as well as the availability of intellectual property protection.

Immuno-oncology

Our lead product candidates include PRGN-3005 for the treatment of ovarian cancer and PRGN-3006 for the treatment of AML, which are built on our UltraCAR-T platform, and PRGN-2009, which is based on our AdenoVerse immunotherapy platform.

Our lead product candidates include PRGN-3005, PRGN-3006, and PRGN-3007, each of which are built on our UltraCAR-T platform, and PRGN-2009, which is based on our AdenoVerse immunotherapy platform.

While we are employing a novel approach, there are a number of competitors pursuing CAR-T cell therapies for the treatment of cancer.

We believe that, among others, Bristol-Myers Squibb, Tmunity Therapeutics, and MaxCyte are developing CAR-T based treatments for ovarian cancer and TCR2 Therapeutics is developing TCR-T based treatment for ovarian cancer.

We believe that Celyad, Mustang Bio, Amgen, Cellectis S.A., and Allogene Therapeutics are also using CAR-T technology to develop product candidates for the treatment of AML.

We believe that INOVIO Pharmaceuticals, AstraZeneca, Transgene SA, and Advaxis Immunotherapies are developing immunotherapies against HPV-associated cancers.

We believe that, among others, Bristol-Myers Squibb, Tmunity Therapeutics, and Anixa Biosciences are developing CAR-T based treatments for ovarian cancer and TCR2 Therapeutics is developing TCR-T based treatment for ovarian cancer.

We believe that Celyad, Mustang Bio, Kite, Amgen, Cellectis S.A., and Allogene Therapeutics are also using CAR-T technology to develop product candidates for the treatment of AML.

We believe that Bristol-Myers Squibb, Lyell Immunopharma, and Oncternal Therapeutics are developing ROR1 CAR-T cells for treatment of ROR1-positive cancers.

We believe that INOVIO Pharmaceuticals, AstraZeneca, Transgene SA, PDS Biotech, and Advaxis Immunotherapies are developing immunotherapies against HPV-associated cancers.

Bristol-Myers Squibb's product candidate, JCAR020, is a MUC16-IL-12 armored T-cell therapy being developed to treat ovarian cancer.

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Tmunity Therapeutics is also developing TmFRα01 CAR-T targeting folate receptor alpha for ovarian cancer.

MaxCyte's MCY-M11 is a mesothelin-specific human mRNA CAR-T cell therapy being developed to treat ovarian cancer.

MCY-M11 is a non-viral approach that uses repeated infusions of mesothelin-specific messenger RNA (mRNA) transfected T cells transiently expressing CAR to permit prospective control of 'on-target/off-tumor' toxicity.

TCR2 Therapeutics' TC-210 targets mesothelin and is based on TCR Fusion Construct T cells, or TRuC-T cells, technology and is manufactured using lentiviral transduction of autologous T cells.

For the treatment of AML using CAR-T therapies, we believe that Celyad and Mustang Bio have product candidates in the most advanced clinical trials.

Celyad's product candidate, CYAD-02, is an NKG2D-based CAR-T with co-expression of a single shRNA targeting NKG2DL, MICA and MICB, that uses the OptimAb manufacturing process, which generates a higher frequency of less differentiated CAR-T cells.

TCR2 Therapeutics' gavocabtagene autoleucel (gavo-cel, formerly TC-210) targets mesothelin and is based on TCR Fusion Construct T cells, or TRuC-T cells, technology and is manufactured using lentiviral transduction of autologous T cells.

Anixa Biosciences is developing an autologous CAR-T treatment targeting follicle stimulating hormone receptor (FSHR) for ovarian cancer.

Regeneron and 2seventy bio are developing bbT4015, an engineered CAR T cell therapy targeting MUC16, which we believe is in preclinical development.

For the treatment of AML using cell therapies, we believe that Celyad, Mustang Bio, Kite, and Fate Therapeutics have product candidates in the most advanced clinical trials.

Celyad's product candidate, CYAD-02, is an investigational NKG2D-based CAR-T with co-expression of a single shRNA targeting NKG2DL, MICA and MICB, that uses the OptimAb manufacturing process, which generates a higher frequency of less differentiated CAR-T cells.

CYAD-02 is in clinical trials for r/r AML or MDS patients.

Mustang Bio's product candidate, MB-102, is an autologous CAR-T cell therapy that is produced by engineering patient T cells to recognize and eliminate CD123-expressing tumors.

Mustang Bio's product candidate, MB-102, is an investigational autologous CAR-T cell therapy that is produced by engineering patient T cells to recognize and eliminate CD123-expressing tumors.

Fate is developing FT538, an investigational, universal, off-the-shelf NK cell cancer immunotherapy derived from a clonal maters iPSC line, which we believe is in a Phase 1 clinical trial for the treatment of AML.

Kite is developing KITE-222, an investigational autologous T cell therapy engineered with a CAR that specifically targets CLL-1 for treatment of AML.

Amgen is developing AMG 553, an FMS-like tyrosine kinase 3, or FLT3, CAR-T cell therapy utilizing autologous T cells genetically modified ex vivo to express a transmembrane CAR to target FLT3 protein on the surface of AML cells irrespective of FLT3 mutational status.

Cellectis S.A.

is also developing UCART123, an allogeneic anti-CD123 CAR-T cell therapy, which utilizes lentivector transduction followed by TALEN-mediated gene editing to eliminate expression of TCRαβ from donor T cells.

is also developing UCART123, an allogeneic anti-CD123 CAR-T cell therapy, which utilizes lentivector transduction followed

by TALEN-mediated gene editing to eliminate expression of TCRαβ from donor T cells.

Vor Biopharma is developing VOR33, an investigational hematopoietic stem cell (HSC) therapy with elimination of CD33 expression via gene-editing, in combination with Mylotarg TM , an anti-CD33 antibody drug conjugate (ADC).

Vor Biopharma is also developing VCAR33, an autologous anti-CD33 CAR-T as a monotherapy and in combination with VOR33, both of which we believe are in preclinical development.

Finally, Allogene Therapeutics' allogeneic CAR-T therapies ALLO-316 and ALLO-819, targeting FLT3 and CD70, respectively, which we believe are in preclinical development for AML, are manufactured using healthy donor T-cells that are engineered using lentiviral transduction to express CAR followed by gene editing to eliminate expression of TCR to reduce the potential of rejection of therapy by a patient's immune system.

Bristol-Myers Squibb is developing JCAR024, a ROR1 CAR-T cell product, which we believe is in a Phase 1 clinical trial for ROR1-positive solid and hematological malignancies.

Lyell Immunopharma is developing LYL797, a ROR1-targeted CAR T-cell product, which we believe recently received FDA clearance to initiate Phase 1 clinical trial for patients with relapsed/refractory TNBC or non-small cell lung cancer, or NSCLC.

Oncternal Therapeutics is developing ONCT-808, a ROR1 targeted autologous CAR-T cell therapy, which we believe is currently in preclinical development, initially as a potential treatment for hematologic malignancies.

In addition to our direct competitors that are using CAR-T therapies specifically for the treatment of ovarian cancer and AML, the CAR-T technology space has significant other competition including from multiple companies and their collaborators, such as Novartis and University of Pennsylvania, Kite and Gilead, Adaptimmune and GSK, Autolus Therapeutics, Poseida Therapeutics, and Bellicum Pharmaceuticals.

We also face competition from non-cell based cancer treatments offered by other companies such as Amgen, AstraZeneca, Incyte, Merck, Abbvie, and Roche.

See "Our Therapeutic Platforms - UltraCAR-T," "Our Product Pipeline - PRGN-3005" and "Our Product Pipeline - PRGN-3006" for a discussion of the features that we believe differentiate UltraCAR-T treatments in general and PRGN-3005 and PRGN-3006 specifically from our competitors.

For the treatment of HPV-associated cancers, we believe that INOVIO Pharmaceuticals, AstraZeneca, and Transgene S.A.

See "PGEN Therapeutics' Therapeutic Platforms" for a discussion of the features that we believe differentiate our UltraCAR-T treatments from our competitors.

For the treatment of HPV-associated cancers, we believe that INOVIO Pharmaceuticals, AstraZeneca, BioNTech SE, PDS Biotechnology, and Transgene S.A.

are developing immunotherapies that are in clinical testing.

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MEDI0457 is a multi-component DNA vaccine that uses different DNA plasmids to express modified sequences for E6 and E7 antigens of HPV16 and HPV18 and immune activator interleukin-12, or IL-12.

developing BVAC-C, which is based on CeliVax technology that uses patient-derived B cells and monocytes transfected with E6/E7 recombination gene of HPV16 and HPV18 and loaded with an adjuvant for HPV-associated cancers.

We believe BioNTech is developing BNT113, an investigational HPV16 E6/7 mRNA vaccine for a form of HPV+ Head and Neck cancer.

We believe PDS Biotechnology is developing PDS-0101, an investigational HPV16 peptide vaccine for various HPV-associated cancers.

Cellid is developing BVAC-C, which is based on CeliVax technology that uses patient-derived B cells and monocytes transfected with E6/E7 recombination gene of HPV16 and HPV18 and loaded with an adjuvant for HPV-associated cancers.

In addition to our direct competitors developing vaccines for treatment of HPV-associated cancers, various development-stage companies are involved in different vaccine and immunotherapy technologies, including Advaxis Immunotherapies, Bavarian Nordic, and Altimmune.

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The results of the preclinical tests and clinical trials, together with detailed information relating to the product's CMC and proposed labeling, among other things, are submitted to the FDA as part of an application requesting approval to market the product for one or more uses, or indications.

When an application is submitted, the FDA makes an initial determination as to

whether the application is sufficiently complete to be accepted for review.

When an application is submitted, the FDA makes an initial determination as to whether the application is sufficiently complete to be accepted for review.

If the application is not, the FDA may refuse to accept the application for filing and request additional information.

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This rolling review is available if the applicant provides and the FDA approves a schedule for the submission of the remaining information and the applicant pays applicable user fees.

However, the FDA's review period for a Fast Track application does not begin until the last section of the marketing application is submitted.

However, the FDA's review period for a Fast Track application does not begin until the last section of the

marketing application is submitted.

In addition, the Fast Track designation may be withdrawn by the FDA if the agency believes that the designation is no longer supported by data emerging in the clinical trial process.

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Numerous federal and state laws and regulations, including state data breach notification laws, state health information and/or genetic privacy laws and federal and state consumer protection laws (e.g., Section 5 of the Federal Trade Commission, or FTC, Act and the California Consumer Privacy Act, or CCPA), govern the collection, use, disclosure, and protection of health-related and other personal information.

Many of these laws differ from each other in significant ways and may not have the same

effect, thus complicating compliance efforts.

Many of these laws differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

Compliance with these laws is difficult, constantly evolving, and time consuming.

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Transition to Our Core Healthcare Business Model

Historically, we developed technology platforms for application across a variety of diverse end markets, including health, food, energy, and environment.

Historically, we developed technology platforms for application across a variety of diverse end markets, including health, food, energy, and the environment.

In January 2020, we announced that we were increasing our focus on our healthcare opportunities, which reflected our most advanced platforms, and in connection therewith, we divested a number of our non-healthcare assets and changed our name to Precigen, Inc.

These transactions included the sale of a number of our non-healthcare assets, or the TS

Biotechnology Sale, to TS Biotechnology Holdings, LLC, or TS Biotechnology, an entity formed by Third Security, LLC, or Third Security.

Kirk, who is the former CEO of Precigen and is currently the Executive Chairman and a member of our board of directors, serves as the Senior Managing Director and Chairman of Third Security and owns 100 percent of the equity interests of Third Security.

These transactions included the sale of a number of our non-healthcare assets, or the TS Biotechnology Sale, to TS Biotechnology Holdings, LLC, or TS Biotechnology, an entity formed by Third Security, LLC, or Third Security.

Kirk, who is our Executive Chairman, serves as the Senior Managing Director and Chairman of Third Security and owns 100 percent of the equity interests of Third Security.

In addition, in January 2020, in a separate transaction, we sold our interest in EnviroFlight, LLC, or EnviroFlight, to Darling Ingredients, Inc., or Darling.

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See "Notes to the Consolidated Financial Statements - Note 4" appearing elsewhere in this Annual Report for a discussion of Intrexon Energy Partners and Intrexon Energy Partners II.

Non-Healthcare Business

Our Non-Healthcare Business

At December 31, 2021, our only non-healthcare business is our established bovine genetics company, Trans Ova Genetics, L.C., or Trans Ova.

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Through extensive research programs and applied science, Trans Ova has developed and implemented new technologies that, we believe, have helped to move the science of bovine genetic improvement forward.

We continue to evaluate the optimal means to utilize these technology assets and Trans Ova's broad customer base and deep industry knowledge to maximize the value of the business.

We are evaluating strategic alternatives to determine the optimal means to utilize these technology assets and Trans Ova's broad customer base and deep industry knowledge to maximize the value of the business for our shareholders, including a potential sale of the business, the development of collaborations with third parties, and other strategic opportunities.

As of December 31, 2021, Trans Ova had 213 production employees.

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The health and safety of our employees is of the utmost importance.

Our essential employees are practicing appropriate safety measures, including social distancing and use of personal protective equipment.

These efforts have permitted us to continue to advance our programs, with the ultimate goal of benefiting patients.

We have implemented safety measures in our facilities for the well-being of our employees and visitors.

These measures have permitted us to continue to advance our programs, with the ultimate goal of benefiting patients.

Commencing in the second half of March 2020, our healthcare business began to experience delays to certain of our clinical trials as a result of COVID-19.

For example, starting in March 2020, ActoBio temporarily suspended the last cohort of the Phase 1b/2a clinical trial for AG019 as a proactive measure to protect the welfare and safety of patients, caregivers, clinical site staff, our employees, and contractors.

For example, starting in March 2020, we temporarily suspended the last cohort of the Phase 1b/2a clinical trial for AG019 as a proactive measure to protect the welfare and safety of patients, caregivers, clinical site staff, our employees, and contractors.

The temporary suspension of the AG019 trial was voluntary and was not related to any patient safety issues in the study.

The voluntary suspension of the AG019 trial was lifted in June 2020, and the study is recruiting patients again.

The voluntary suspension of the AG019 trial was lifted in June 2020, and recruitment in the study resumed.

Additionally, from April to May 2020, enrollment of new patients in our PRGN-3005 Phase 1 trial was temporarily suspended due to a mandated hold on certain early and late-stage clinical trials at the Fred Hutchinson Cancer Research Center in Seattle that was instituted in light of the COVID-19 pandemic.

Recruitment resumed in the PRGN-3005 trial in May 2020.

At this time, we do not expect that these suspensions will result in significant overall delay.

Furthermore, uncertainty regarding the duration and severity of the ongoing pandemic may adversely impact our clinical as well as preclinical pipeline candidates in the future.

Notwithstanding the foregoing, as the COVID-19 pandemic continues to evolve, we may experience additional delays to our clinical trials, including related to enrollment, site closures, reduced availability of key personnel, or our ability to receive the necessary approvals from the FDA or other regulatory agencies to advance our programs.

Although these suspensions did not result in significant overall delay, there is uncertainty regarding the duration and severity of the ongoing pandemic, and we could experience further delays of other pandemic-related events that may adversely impact our clinical as well as preclinical pipeline candidates in the future.

Notwithstanding the foregoing, as the COVID-19 pandemic continues to evolve, we may experience additional delays to our clinical trials, including related to enrollment, site closures,

reduced availability of key personnel, or our ability to receive the necessary approvals from the FDA or other regulatory agencies to advance our programs.

We are also closely monitoring the impact of COVID-19 on other aspects of our business.

While Trans Ova and Exemplar have not experienced any significant impacts as a result of COVID-19 at this time, we are unable to reliably quantify or estimate what future impacts may be.

While Trans Ova and Exemplar have not experienced any significant impacts as a result of COVID-19 at this time, we are unable to reliably quantify or estimate what the future impacts may be.

In addition, we have taken certain steps with respect to our operations of MBP Titan as a result of the impacts of the COVID-19 pandemic and other factors.

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Reportable Segments

As of December 31, 2020, our reportable segments are (i) PGEN Therapeutics, (ii) ActoBio, (iii) Trans Ova, and (iv) the Human Biotherapeutics division.

As of December 31, 2021, our reportable segments were (i) Biopharmaceuticals, (ii) Exemplar, and (iii) Trans Ova.

These identified reportable segments met the quantitative thresholds to be reported separately for the year ended December 31, 2021.

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As of December 31, 2021, we had 191 employees in support of our healthcare operations, of which 137 support our research and development functions including operational and facility activities.

Of these research and development employees, 59 have

advanced degrees, of which 35 are PhDs.

Of these research and development employees, 59 have advanced degrees, of which 35 are PhDs.

Our corporate employees provide support to all of our operating subsidiaries and are responsible for the execution of all corporate functions, including executive, operational, finance, information technology, legal, and corporate communications.

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We are proud of the fact that our domestic healthcare operations and corporate functions include 40 percent of employees in ethnic and racial minority groups and also the fact that 45 percent of the same population of employees are women.

Our recent employee development initiatives included employee training targeting specific areas of interest, executive and manager coaching, and performance management which encompass performance goals and competency evaluations.

We implemented safety protocols in response to the COVID-19 pandemic including increased cleaning protocols, employee preventative measures, contract tracing, and bi-weekly virus testing.

These measures enabled us to have the majority of our research and development employees return to their workplaces by early June 2020.

Our 2021 employee development initiatives included employee training targeting specific areas of interest, executive and manager coaching, and performance management which encompass performance goals and competency evaluations.

We maintained our safety protocols in response to the COVID-19 pandemic including increased cleaning protocols, employee preventative measures, and contract tracing.

In August and September 2021, we instituted a mandatory vaccination policy for all employees of our healthcare operations based in the United States.

Additional Information

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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