Precigen, Inc. (PGEN) 2023年年度報告「NASDAQ」.pdf

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1、Table of ContentsUNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington,D.C.20549 FORM10-K ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended December 31,2023ORTRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT

2、 OF 1934For the transition period from to .Commission file number:001-36042 PRECIGEN,INC.(Exact name of registrant as specified in its charter)Virginia 26-0084895(State or other jurisdiction of incorporation or organization)(I.R.S.Employer Identification Number)20374 Seneca Meadows ParkwayGermantown

3、,Maryland 20876(Address of principal executive offices)(Zip Code)Registrants telephone number,including area code:(301)556-9900Securities registered pursuant to Section 12(b)of the Act:Title of each class Trading Symbol(s)Name of each exchange on which registeredCommon Stock,No Par Value PGENNasdaq

4、Global Select Market Securities registered pursuant to Section 12(g)of the Act:None Table of ContentsIndicate by check mark if the registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.Yes No Indicate by check mark if the registrant is not required to file reports p

5、ursuant to Section 13 or Section 15(d)of the Act.Yes No Indicate by check mark whether the registrant(1)has filed all reports required to be filed by Section 13 or 15(d)of the Securities Exchange Act of 1934 during the preceding 12 months(or for suchshorter period that the registrant was required to

6、 file such reports),and(2)has been subject to such filing requirements for the past 90 days.Yes No Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T(232.405 of this chapter)during the

7、 preceding 12 months(or for such shorter period that the registrant was required to submit such files).Yes No Indicate by check mark whether the registrant is a large accelerated filer,an accelerated filer,a non-accelerated filer,a smaller reporting company,or an emerging growth company.See the defi

8、nitionsof large accelerated filer,accelerated filer,smaller reporting company,and emerging growth company in Rule 12b-2 of the Exchange Act.Large accelerated filer Accelerated filer Non-accelerated filer Smaller reporting company Emerging growth companyIf an emerging growth company,indicate by check

9、 mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standardsprovided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark whether the registrant has filed a report on and attestation to its managemen

10、ts assessment of the effectiveness of its internal control over financial reporting under Section404(b)of the Sarbanes-Oxley Act(15 U.S.C.7262(b)by the registered public accounting firm that prepared or issued its audit report.Indicate by check mark whether the registrant is a shell company(as defin

11、ed in Rule 12b-2 of the Act).Yes No If securities are registered pursuant to Section 12(b)of the Act,indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error topreviously issued financial statements.Yes No Indicate by check m

12、ark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrants executive officersduring the relevant recovery period pursuant to 240.10D-1(b).Yes No As of June 30,2023,the last business day of the regis

13、trants most recently completed second fiscal quarter,the aggregate market value of the registrants common stock held by non-affiliates basedupon the closing price of such shares on the Nasdaq Global Select Market on such date was approximately$177.3 million.As of February 15,2024,248,919,096 shares

14、of common stock,no par value per share,were issued and outstanding.DOCUMENTS INCORPORATED BY REFERENCE:Portions of the registrants Definitive Proxy Statement for its 2024 Annual Meeting of Shareholders are incorporated by reference in Part IIIof this Annual Report on Form 10-K where indicated.Such p

15、roxy statement will be filed with the Securities and Exchange Commission within 120 days of the registrants fiscal year endedDecember 31,2023.Table of ContentsTABLE OF CONTENTS PagePART IItem 1.Business9Item 1A.Risk Factors42Item 1B.Unresolved Staff Comments70Item 2.Properties71Item 3.Legal Proceedi

16、ngs72Item 4.Mine Safety Disclosures72 PART II Item 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities73Item 6.Reserved75Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations75Item 7A.Quantitative and Qual

17、itative Disclosures About Market Risk85Item 8.Financial Statements and Supplementary Data85Item 9.Changes in and Disagreements with Accountants on Accounting and Financial Disclosure85Item 9A.Controls and Procedures85Item 9B.Other Information86Item 9C.Disclosure Regarding Foreign Jurisdictions that

18、Prevent Inspections86 PART III Item 10.Directors,Executive Officers and Corporate Governance87Item 11.Executive Compensation87Item 12.Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters87Item 13.Certain Relationships and Related Transactions,and Director In

19、dependence87Item 14.Principal Accountant Fees and Services87 PART IV Item 15.Exhibits and Financial Statement Schedules88Item 16.Form 10-K Summary90_Precigen,AdenoVerse UltraCAR-T,RheoSwitch,UltraVector,RTS,UltraPorator,ActoBiotics and RheoSwitch Therapeutic System are our and/or our affiliates regi

20、stered trademarks inthe United States and GenVec,ActoBio Therapeutics,AttSite,and Precigen Therapeutics are our and/or our affiliates common law trademarks in the United States are our and/or ouraffiliates common law trademarks in the United States.This Annual Report on Form 10-K,or Annual Report,an

21、d the information incorporated herein by reference contain references to trademarks,service marks,and trade names owned by us or other companies.Solely for convenience,trademarks,service marks,and trade names referred to in this Annual Report and the informationincorporated herein,including logos,ar

22、twork,and other visual displays,may appear without the or symbols,but such references are not intended to indicate,in any way,that we will not assert,to the fullest extent under applicable law,our rights or the rights of the applicable licensor to these trademarks,service marks,and trade names.We do

23、 not intend our use or display of othercompanies trade names,service marks,or trademarks to imply a relationship with,or endorsement or sponsorship of us by,any other companies.Other trademarks,trade names,and service marksappearing in this Annual Report are the property of their respective owners.U

24、nless the context requires otherwise,references in this Annual Report to Precigen,we,us,and our refer toPrecigen,Inc.,3Table of ContentsSpecial Note Regarding Forward-Looking StatementsThis Annual Report contains forward-looking statements within the meaning of the Private Securities Litigation Refo

25、rm Act of 1995,which statements involve substantial risks and uncertainties.Allstatements,other than statements of historical facts,included in this Annual Report,including statements regarding our strategy;future events,including their outcome or timing;future operations;future financial position;f

26、uture revenue;projected costs;prospects;plans;objectives of management;and expected market growth,are forward-looking statements.The words aim,anticipate,assume,believe,continue,could,due,estimate,expect,intend,may,objective,plan,positioned,potential,predict,project,seek,should,target,will,would,and

27、 the negatives of these terms or similar expressions are intended to identify forward-looking statements,although not all forward-looking statements contain these identifying words.Thesestatements may relate to,among other things:(i)the timeliness of regulatory approvals;(ii)our strategy and overall

28、 approach to our business model,our efforts to realign our business,and our abilityto exercise more control and ownership over the development process and commercialization path;(iii)our ability to successfully enter new markets or develop additional product candidates,including the expected timing

29、and results of investigational studies and preclinical and clinical trials,whether with our collaborators or independently;(iv)our ability to consistently manufacture ourproduct candidates or,our products,if approved,on a timely basis or to establish agreements with third-party manufacturers;(v)our

30、ability to successfully enter into optimal strategic relationshipsdirectly or with our subsidiaries and operating companies that we may form in the future;(vi)actual or anticipated variations in our operating results;(vii)actual or anticipated fluctuations incompetitors or collaborators operating re

31、sults or changes in their respective growth rates;(viii)our cash position;(ix)market conditions in our industry;(x)our expectations regarding the size of thepatient populations amenable to treatment with our product candidates;(xi)the volatility of our stock price;(xii)the ability,and the ability of

32、 our collaborators,to protect our intellectual property andother proprietary rights and technologies;(xiii)outcomes of pending and future litigation;(xiv)the rate and degree of market acceptance of any products developed by us,our subsidiaries,or ourpotential collaborators,and competition from exist

33、ing technologies and products or new technologies and products that may emerge;(xv)our ability to retain and recruit key personnel;(xvi)expectations related to the use of proceeds from public offerings and other financing efforts;(xvii)estimates regarding expenses,future revenue,capital requirements

34、,and needs for additionalfinancing;(xviii)our substantial doubt about our ability to continue as a going concern;and(xix)our timeline to commercialization of our product candidates.Forward-looking statements are based on our beliefs,assumptions,and expectations of our future performance,and may also

35、 concern our expectations relating to our subsidiaries and other affiliates.We caution you that the foregoing list may not contain all of the forward-looking statements made in this Annual Report.We may not actually achieve the plans,intentions,or expectations disclosed in our forward-looking statem

36、ents,and you should not place undue reliance on our forward-looking statements.Actualresults or events could differ materially from the plans,intentions,and expectations disclosed in the forward-looking statements we make.We have included important factors in the cautionarystatements included in thi

37、s Annual Report,particularly in Summary of Risk Factors set forth below and Item 1A,Risk Factors,that could cause actual results or events to differ materially fromthe forward-looking statements that we make.Our forward-looking statements do not reflect the potential impact of any future acquisition

38、s,mergers,dispositions,JVs,or investments that we maymake.You should read this Annual Report,the documents that we reference in this Annual Report,the audited consolidated financial statements and related notes thereto included in this Annual Report,theother reports we have filed with the Securities

39、 and Exchange Commission,or SEC,and the documents that we have filed as exhibits to our filings with the SEC completely and with the understandingthat our actual future results may be materially different from what we expect.We do not assume any obligation to update any forward-looking statements,wh

40、ether as a result of new information,future events or otherwise,except as required by law.4Table of ContentsMarket and Industry Data This Annual Report contains industry and market data that are based on general and industry publications,surveys and studies commissioned or conducted by third parties

41、,some of which may not bepublicly available,and our own internal estimates and research.Third-party publications,surveys and studies generally state that they have obtained information from sources believed to be reliable,but do not guarantee the accuracy and completeness of such information.These d

42、ata involve a number of assumptions and limitations and contain projections and estimates of the future performanceof the industries in which we operate that are subject to a high degree of uncertainty.We caution you not to give undue weight to such projections,assumptions and estimates.5Table of Co

43、ntentsSummary of Risk FactorsWe are subject to a variety of risks and uncertainties,including risks that could have a material adverse effect on our business,financial condition,results of operations,and cash flows.The followingsummary of the principal factors that make an investment in our securiti

44、es speculative or risky should not be relied upon as an exhaustive summary of the material risks facing us.You should read thefollowing summary together with the more detailed description of the risks that we deem material described under Risk Factors in Item 1A of this Annual Report and the other i

45、nformationcontained in this Annual Report before investing in our securities.Risks Related to Our Financial Position and Capital NeedsThere is substantial doubt about our ability to continue as a going concern.We have a history of net losses,we may not achieve or maintain profitability,and we will n

46、eed substantial additional capital in the future in order to fund our business.We may incur substantially more debt or take other actions that would intensify the risks discussed above.Risks Related to the Discovery and Development of Our Product CandidatesOur business is dependent on our ability to

47、 advance our current and future product candidates through clinical trials,obtain marketing approval,and ultimately commercialize them.The market opportunities for our product candidates may be smaller than we estimate.The regulatory process of the United States Food and Drug Administration,or FDA,a

48、nd comparable foreign authorities are lengthy,time-consuming,and inherently unpredictable,and wemay be unable to obtain FDA approval of our product candidates.The denial or delay of any such approval would prevent or delay commercialization of our product candidates andadversely impact our potential

49、 to generate revenue,our business,and our results of operations.Clinical development involves a lengthy and expensive process with uncertain outcomes.We may incur additional costs and experience delays in developing and commercializing or beunable to develop or commercialize our current and future p

50、roduct candidates.As an organization,we have limited experience designing and implementing clinical trials and failure to adequately design a trial,conduct a trial in accordance with regulatory requirements,or enroll patients in clinical trials,could result in adverse effects,including but not limit

51、ed to increased or unexpected costs and delayed timelines.Cell and gene therapies are novel,complex,and difficult to manufacture.Interim and preliminary results from our clinical trials that we announce or publish from time to time may change,which could result in material changes in the final data.

52、We have chosen to prioritize certain of our product candidates and,as a result,may expend our limited resources on product candidates that do not yield a successful product,or fail tocapitalize on opportunities that may be more profitable.Risks Related to the Commercialization of Product Candidates

53、and Other Legal Compliance MattersEven if a product candidate receives marketing approval,it may fail to achieve the degree of market acceptance necessary for commercial success.Delays in obtaining regulatory approval of manufacturing processes and facilities or disruptions in manufacturing processe

54、s may delay or disrupt our commercialization efforts.Even if we receive marketing approval of a product candidate,we will be subject to ongoing regulatory obligations and continued regulatory review,which may result in significantadditional expense.As a company,we have never commercialized a product

55、,we currently have no active sales force and we may lack the6Table of Contentsnecessary expertise,personnel and resources to successfully commercialize our product candidates.The successful commercialization of our product candidates will depend in part on the extent to which third-party payers prov

56、ide coverage and adequate reimbursement levels.We are subject to certain United States and foreign anti-corruption,anti-money laundering,export control,sanctions and other trade laws and regulations.Failure to comply with current or future federal,state and foreign laws and regulations and industry

57、standards relating to privacy and data protection laws could lead to governmentalenforcement actions(which could include civil or criminal penalties),private litigation,and/or adverse publicity.Risks Related to Our Business Operations and StrategyWe may rely on third parties to develop and commercia

58、lize some of our product candidates.If we fail to maintain an effective system of internal control over financial reporting,we may not be able to accurately report our financial results or prevent fraud.We may be sued for product liability.Our insurance policies are expensive and protect only from s

59、ome business risks,which leaves us exposed to significant uninsured liabilities.Competitors and potential competitors may develop products and technologies that make ours obsolete or garner greater market share than ours.If we lose key personnel,including key management personnel,or are unable to at

60、tract and retain additional personnel,it could delay our product development programs,harm our researchand development efforts,and we may be unable to continue to commercialize our product candidates.If we experience a significant breach of data security or disruption in our information systems,our

61、business could be adversely affected.The effects of the COVID-19 pandemic have disrupted,and will likely continue to disrupt,our business operations,which could have a material adverse effect on our results of operations,cash flows,and financial position.We may pursue strategic acquisitions and inve

62、stments that could have an adverse impact on our business.Risks Related to Our Intellectual PropertyOur ability to compete may decline if we do not adequately protect our proprietary technologies or intellectual property rights.Litigation or other proceedings or third-party claims of intellectual pr

63、operty infringement,misappropriation or other violation could require us to spend significant time and money and couldprevent us from commercializing our technologies or impact our stock price.Risks Related to Our Common StockOur quarterly and annual operating results may fluctuate in the future.As

64、a result,we may fail to meet or exceed the expectations of research analysts or investors,which could cause ourstock price to decline.Our stock price is volatile,and purchasers of our common stock could incur substantial losses.We do not anticipate paying cash dividends,and accordingly,shareholders

65、will have to rely on any stock appreciation for return on their investment.As of February 15,2024,Randal J.Kirk controlled approximately 39 percent of our common stock and may be able to7Table of Contentscontrol or significantly influence shareholder votes and other corporate actions.Sales of a subs

66、tantial number of shares of our common stock in the public market could occur at any time.This could cause the market price of our common stock to drop significantly,evenif our business is doing well.Our articles of incorporation authorize us to issue preferred stock with terms that are preferential

67、 to those of our common stock.We are subject to anti-takeover provisions in our articles of incorporation and bylaws and under Virginia law that could delay or prevent an acquisition of our Company,even if theacquisition would be beneficial to our shareholders.8Table of ContentsPART IItem 1.Business

68、OverviewWe are a dedicated discovery and clinical-stage biopharmaceutical company advancing the next generation of gene and cell therapies with the overall goal of improving outcomes for patients withsignificant unmet medical needs.We are leveraging our proprietary technology platforms to develop pr

69、oduct candidates designed to target urgent and intractable diseases in our core therapeutic areasof immuno-oncology,autoimmune disorders,and infectious diseases.We have developed an extensive pipeline of therapies across multiple indications.We believe that our array of technology platforms uniquely

70、 positions us among other biotechnology companies to advance precision medicine.Precision medicine is the practice of therapeuticproduct development that takes into account specific genetic variations within populations impacted by a disease to design targeted therapies to improve outcomes for a dis

71、ease or patient population.Our proprietary and complementary technology platforms provide a strong foundation to realize the core promise of precision medicine by supporting our efforts to construct powerful gene programsto drive efficacy,deliver these programs through viral,non-viral,and microbe-ba

72、sed approaches to drive lower costs,and control gene expression to drive safety.Our therapeutic platforms,includingUltraCAR-T,AdenoVerse immunotherapy,and ActoBiotics,are designed to allow us to precisely control the level and physiological location of gene expression and modify biological molecules

73、 tocontrol the function and output of living cells to treat underlying disease conditions.We are actively advancing our lead clinical programs,including:PRGN-3005,PRGN-3006,and PRGN-3007,which are built on our UltraCAR-T platform;PRGN-2009 and PRGN-2012,which arebased on our AdenoVerse immunotherapy

74、 platform.In addition,we have completed a Phase 1b/2a study of AG019,which is built on our ActoBiotics platform.We also have a robust pipeline ofpreclinical programs that we are pursuing in order to drive long-term value creation.We have developed a proprietary electroporation device,UltraPorator,de

75、signed to further streamline and ensure the rapid and cost-effective manufacturing of UltraCAR-T therapies.UltraPorator hasreceived FDA clearance for manufacturing UltraCAR-T cells in clinical trials,and we have been dosing patients with UltraCAR-T cells manufactured with UltraPorator in our clinica

76、l 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.Through this process,webelieve we can more effectively allocate resources to programs that we believe show the most promise and ad

77、vance such programs to clinical trials.To guide our decision-making and operations,we have adopted the following tenets,which form the core of our operating ideology:Financial Discipline.Responsibly allocate capital in an effort to ensure maximum value creation.Active Portfolio Management.Continuous

78、ly evaluate our portfolio and strictly adhere to data-driven go and no go decisions to advance programs with the highest probability of success.Rapid Execution.Advance priority programs quickly to value inflection points.Strategic Partnerships.Seek strategic partnerships to maximize value generation

79、.9Table of ContentsOur StrategyOur strategy is to use our discovery and clinical development infrastructure to continue advancement of our clinical programs with the goal of improving outcomes for patients with significant unmetmedical needs.The key elements of our strategy include:Advancing our lea

80、d clinical stage programs and seeking opportunities to maximize their value.We are actively advancing our lead programs that we believe have significant potentialvalue.We intend to efficiently pursue these programs toward clinical proof-of-concept and commercialization,whether independently or with

81、collaborators.Strategically pursuing our preclinical programs.We have a robust pipeline of preclinical programs that we are pursuing in order to drive long-term value creation.We exercise discipline inour portfolio management by systematically evaluating data from our preclinical programs in order t

82、o make rapid go and no go decisions.Through this process,we believe we can moreeffectively allocate resources to programs that we believe show the most promise and advance such programs to clinical trials.Leveraging our technology and therapeutic platforms across indications.Through the application

83、of our suite of proprietary and complementary synthetic biology technologies,we believewe can create optimized biological processes and overcome the limitations of traditional techniques,leading to precision medicines that are manufactured more efficiently and cost-effectively with superior performa

84、nce.We continually assess the application of these technologies across therapeutic areas to determine where we can develop and provide unique solutionsto challenges facing existing therapies.We have strategically focused our efforts on developing an innovative pipeline of therapies based on our tran

85、sformative UltraCAR-T,and AdenoVerse immunotherapy therapeutic platforms.A corefocus 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 aredeveloping therapeutic candidates th

86、at reduce manufacturing risk by eliminating the need for centralized cell therapy manufacturing and have invested in internal manufacturing capabilities to de-riskour clinical and,in certain cases,commercial production.10Table of ContentsOur Clinical PipelineOur Healthcare BusinessOur Biopharmaceuti

87、cals reportable segment is primarily comprised of the Companys legal entities of Precigen and ActoBio,as well as royalty interests in therapeutics and therapeutic platforms fromcompanies not controlled by us.Our Exemplar reportable segment is comprised of Exemplar Genetics LLC,doing business as Prec

88、igen Exemplar,or Exemplar,our wholly owned subsidiary focusedon developing research models and services for healthcare research applications.11Table of ContentsBiopharmaceuticalsPrecigen is a dedicated discovery and clinical stage biopharmaceutical company advancing the next generation of gene and c

89、ell therapies using precision technology to target urgent and intractablediseases in immuno-oncology,autoimmune disorders and infectious diseases.Precigens Technology PlatformsWe leverage a diverse portfolio of proprietary technology platforms to accelerate research and development efforts to delive

90、r the promise of precision medicine.Precigens innovative technologyplatforms enable us to construct powerful,multigenic programs that we believe will drive efficacy,deliver multigenic constructs using viral and non-viral approaches that we believe will drive lowercosts,and control expression of gene

91、s and performance of therapeutics in vivo for precise targeting of complex malignancies.The following discussion describes the technology platforms that we usefor our approach to precision medicine.We believe that the development of innovative biological products requires a deep understanding of the

92、 complexity of cellular processes and the construction of improved gene programs developed inconditions reflective of the natural environment.We accomplish the design of optimized gene programs for our therapeutic approaches via our UltraVector platform that incorporates advanced DNAconstruction tec

93、hnologies and computational models to design and assemble genetic components into complex gene expression programs.UltraVector-enabled matrices facilitate rapid identificationof components that yield desired gene expression.Our library of characterized genetic components and associated functional ch

94、aracterization data enable construction of gene programs for optimizedexpression of multiple effector genes.Expression of our membrane-bound interleukin-15,or mbIL15,gene improves functional characteristics of certain immune cells,including T-cells,byenhancing their potential for expansion and persi

95、stence.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.SleepingBeauty is a non-viral transposon/transposase system licensed from the University of Texas MD Anderson Can

96、cer Center that stably reprograms immune cells by inserting specific DNA sequencesinto their genome.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-viralmethods such as lentivira

97、l vectors and the PiggyBac transposon system for integration at transcriptionally active sites.We believe that our non-viral system may confer benefits including a reductionof the risk of genotoxicity.Precigen has made significant improvements to the Sleeping Beauty system by optimizing gene element

98、s,genetic payload capacity,and efficiency of delivery,whichprovides 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 directintegration of a transgene into the host cell genome

99、,allow for stable,site-specific gene integration.The UltraPorator system includes proprietary hardware and software solutions and potentiallyrepresents major advancements over current electroporation devices by significantly reducing the processing time and contamination risk.UltraPorator is designe

100、d for rapid and cost-effectivemanufacturing of UltraCAR-T therapies and has the potential to enable rapid manufacturing of a range of gene and cell therapies beyond UltraCAR-T.Genetically engineered adenoviruses(a common group of viruses)called adenovectors that are designed to insert genes into cel

101、ls are an important part of our technology platforms.Our AdenoVersetechnology 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.Thisincludes our gorilla adenovectors,which provi

102、de a potential competitive advantage with their large payload capacity,ability for repeat administrations and generation of robust antigen-specificimmune responses.12Table of ContentsThe final component of our approach to precision medicine is our ability to control gene expression and regulation us

103、ing the RheoSwitch,kill switches,and tissue-specific promoters.TheRheoSwitch Therapeutic System,our inducible gene switch system,provides quantitative dose-proportionate regulation of the amount and timing of target protein expression in response to an orallyavailable activator ligand.We have develo

104、ped kill switches,which allow us to selectively eliminate cell therapies in vivo after their administration,to improve their safety profile.We are developingtissue-specific promoters to only induce gene expression locally in cells or tissues of therapeutic interest.We have leveraged our proprietary

105、and complementary technology platforms discussed above and our expertise in immunology to develop key therapeutic platforms,including UltraCAR-T andAdenoVerse,to address multiple pathways of complex disorders with significant unmet medical needs and to realize our core promise of precision medicine.

106、Precigens Therapeutic PlatformsOff-the-shelf AdenoVerse ImmunotherapyOur AdenoVerse immunotherapy platform utilizes a library of proprietary adenovectors for the efficient gene delivery of therapeutic effectors,immunomodulators,and vaccine antigens.We haveestablished proprietary manufacturing cell l

107、ines and production methodologies from our AdenoVerse immunotherapy platform,which we believe are scalable for commercial supply.We believe thatour proprietary gorilla adenovectors,part of the AdenoVerse technology,have superior performance characteristics as compared to current competition,includin

108、g standard human adenovirus serotype5,or Ad5,rare human adenovirus types and other non-human primate adenovirus types.The key advantages of AdenoVerse immunotherapy platform include:Large genetic payload capacityOur gorilla adenovectors have a larger genetic payload capacity than other viral vectors

109、 that currently dominate the gene therapy field,allowing us to engineer multigenic therapeutic candidates totreat complex diseases.Currently,we are able to engineer up to a 12kb genetic payload using our gorilla adenovectors,providing us with an advantage to express multiple genes in a controlledman

110、ner.Repeat administrationUnlike most competing approaches,our gorilla adenovectors are suitable for repeat administration,which can lead to boosted antibody and T-cell responses.This suitability for repeat administrationstems from the very low to non-existent seroprevalence of and limited immunity t

111、o gorilla adenoviruses in the human population.For example,our gorilla adenovector variant GC46 has been shownto have a seroprevalence of less than 6 percent in the United States,with low seropositive titers.In comparison,the seroprevalence of Ad5 in the United States is estimated to be 58 percent,w

112、ith mostof seropositive individuals having high titers.This high Ad5 seroprevalence limits the effectiveness of Ad5-based adenovectors in clinical studies.The rare and weak pre-existing immunity againstgorilla adenovectors may therefore provide an advantage in clinical applications as compared to ex

113、isting competition.Replication incompetenceOur gorilla adenovectors are engineered and manufactured using a process that ensures the production of replication incompetent adenoviral therapeutic candidates with no cytopathic or cytotoxiceffect in normal human cells.This has been achieved by engineeri

114、ng deletions of two regions essential for replication of the adenoviral genome.The use of a proprietary complementing cell lineprovides the necessary genetic elements for manufacture of AdenoVerse immunotherapy candidates.13Table of ContentsWe believe our AdenoVerse immunotherapy candidates have red

115、uced regulatory and commercialization risk due to their design,which renders them incapable of replicating and therefore lesssusceptible to manufacturing failures.Furthermore,our gorilla adenovector manufacturing process has yielded therapeutic candidates at a very high titer and has reduced the com

116、plexity ofmanufacturing.Durable antigen-specific immune responseGorilla adenovectors have been shown in preclinical studies to generate high-level and durable antigen-specific neutralizing antibodies and effector T-cell immune responses,as well as an ability toboost these antibody and T-cell respons

117、es via repeat administration.cGMP Manufacturing FacilityWe have built internal cGMP manufacturing capabilities for our Adenoverse-based therapeutics in Germantown,Maryland,with the aim to reduce the risks associated with technology transfer andtiming when outsourcing to contract manufacturing organi

118、zations.We are able to execute drug substance manufacturing at this facility in an expedited manner at reduced cost compared to contractmanufacturing organizations.We are expanding our drug substance cGMP manufacturing capabilities at this facility with an aim to support the possible commercial laun

119、ch of our PRGN-2012 asset.We will continue to evaluate internal and external strategies to support cGMP manufacturing needs of our AdenoVerse-based therapeutics.Precigens most advanced programs based on the AdenoVerse immunotherapy platform include:(i)PRGN-2012,a first-in-class,investigational off-t

120、he-shelf AdenoVerse immunotherapy designedto elicit immune responses directed against cells infected with HPV type 6,or HPV6,or HPV type 11,or HPV11,which is in a Phase 1/2 trial in patients with recurrent respiratory papillomatosis,orRRP;and(ii)PRGN-2009,a first-in-class,investigational off-the-she

121、lf immunotherapy utilizing the AdenoVerse platform,is designed to activate the immune system to recognize and target humanpapillomavirus-positive,or HPV+,solid tumors,which is in two Phase 2 clinical trials for patients with HPV-associated cancers.PRGN-2012PRGN-2012 is a first-in-class,investigation

122、al off-the-shelf AdenoVerse immunotherapy for the treatment of RRP.PRGN-2012 is an innovative therapeutic vaccine with optimized antigen designthat uses our gorilla adenovector technology,part of our proprietary AdenoVerse platform,to elicit immune responses directed against cells infected with HPV6

123、 and HPV11.Gorilla adenovectorshave numerous advantages,including the ability for repeat administration,the inability to replicate in vivo,which may improve safety,and the ability to deliver large payload capacity.RRP is a rare,difficult-to-treat and sometimes fatal neoplastic disease of the upper a

124、nd lower respiratory tracts that is caused by infection with HPV6 or HPV11.RRP is classified based on age ofonset as juvenile or adult.RRP prevalence is estimated to be approximately 15,000 to 20,000 patients in the U.S and more than 125,000 patients outside the U.S.,based on our commissionedresearc

125、h.There is no approved therapeutic treatment for RRP and the current standard-of-care is repeated endoscopic debulking with ablation or excision of papillomatous lesions.Surgeries are notcurative and recurrence of papilloma after surgical removal is very common and repeated procedures are required t

126、o debulk and monitor the disease,which exposes patients to anesthetic and surgicalrisks,and emotional distress.Patients with aggressive RRP can undergo hundreds of lifetime surgeries to control their disease.RRP morbidity and mortality results from the effects of papilloma masson the vocal cords,tra

127、chea,and lungs,which may cause voice changes,stridor,airway occlusion,loss of lung volume,and/or post-obstructive pneumonia.Although rare,RRP has the potential formalignant transformation in three to seven percent of adult patients.In addition,more than 90 percent of genital warts are related to HPV

128、6 and HPV11 infection.14Table of ContentsIn preclinical models,PRGN-2012 has demonstrated strong HPV6 and HPV11-specific T-cell response in RRP patient samples in vitro.PRGN-2012 is currently under evaluation in a Phase 1/2 clinical trial.The clinical trial evaluates PRGN-2012 as an immunotherapy fo

129、llowing standard-of-care surgery in adult patients with RRP.We have completed Phase 1 dose escalation and dose expansion portion of the PRGN-2012 Phase 1/2 trial.The Phase 1 clinical trial evaluated safety and efficacy of PRGN-2012 as animmunotherapy following standard-of-care RRP surgery.Trial desi

130、gn included a 3+3 dose escalation cohort followed by a dose expansion cohort to enroll additional patients at the recommendedPhase 2 dose(RP2D).Adult patients with severe,aggressive RRP,defined as greater than or equal to 3 surgeries in the prior 12 months,were eligible for the clinical trial.The Ph

131、ase 1 study enrolled a total of 15 patients at one of the following dose levels with patients receiving four PRGN-2012 administrations(on days 1,15,43 and 85)via subcutaneous injection atone of the two dose levels:(i)Dose Level 1:1 x 10 particle units(PU)/dose;N=3;or(ii)Dose Level 2:5 x 10 PU/dose;N

132、=12.Baseline patient characteristics included a median age of 51 years(range:30 to 73).Ten patients were male and five were female.Patients had an average of 6.2 surgeries(range:3 to 10)in the prior 12-months before enrolling in the trial.111115Table of ContentsThe Phase 1 data demonstrated that the

133、 repeated administrations of PRGN-2012 were well-tolerated with no DLTs.There were no TRAEs greater than Grade 2.All patients received fouradministrations of PRGN-2012 at the intended dose level.TRAEs were all mild and reduced in frequency over the treatment interval.The most common TRAE was injecti

134、on site reaction,whichoccurred in all of the patients.Most other TRAEs occurring in more than one subject were similar to seasonal vaccines and the most common were fatigue,fever,and chills.There was a low-levelincrease in neutralizing antibodies against gorilla adenovector after first administratio

135、n and lack of significant neutralizing antibody response to gorilla adenovector over time with subsequentvaccinations highlights the ability to deliver repeated administrations of PRGN-2012.The Phase 1 efficacy data for Dose Level 1 showed that PRGN-2012 treatment reduced the need for surgeries for

136、100%(3 out of 3)severe,aggressive RRP patients.Patients in Dose Level 1 had a33%(1 out of 3)Overall Response Rate(ORR),defined as greater than or equal to 50%reduction in the surgeries in 12-months post PRGN-2012 treatment completion compared to 12-months pre-treatment.Additionally,PRGN-2012 treatme

137、nt at Dose Level 1 resulted in improvement in average time to recurrence(TTR),which is defined as time from start of treatment to first RRP surgery,post treatment.The Phase 1 efficacy data for Dose Level 2 showed PRGN-2012 treatment significantly reduced the need for surgeries for severe,aggressive

138、RRP patients.At Dose Level 2,50%(6 out of 12)patients had a Complete Response,which is defined as no surgeries needed during the 12-month period following PRGN-2012 treatment completion.Patients in Dose Level 2 had a 58%(7 out of 12)ORR.83%(10 out of 12)of patients treated at Dose Level 2 had reduce

139、d RRP surgeries in 12-months post PRGN-2012 treatment compared to pre-treatment.The number of RRP surgeries in thepatients(N=12)in Dose Level 2 reduced from a median of 5 surgeries(range:3-10)in the 12-months pre-treatment to 0.5 surgeries(range:0-6)in 12-months post PRGN-2012 treatment completion.I

140、n addition,there was a significant improvement in TTR for patients treated with PRGN-2012 at Dose Level 2.We announced in January 2024 that all Complete Responses from Phase 1 trial remaindurable ongoing at more than 2 years after PRGN-2012 treatment.Additionally,PRGN-2012 treatment at Dose Level 2

141、showed significant improvement in anatomical Derkay scores,a tool used for research purposes to quantify RRP severity based on involvementof laryngeal structures,and voice quality,evaluated using the validated Vocal Handicap Index-10(VHI-10),at 24-weeks post PRGN-2012 treatment completion compared t

142、o baseline.The Phase 1 data showed that PRGN-2012 treatment resulted in an increase in HPV 6/11-specific T-cell response in the peripheral blood of RRP patients.A significantly greater expansion of HPV-specific T cell responses after PRGN-2012 treatment were observed in responders compared to non-co

143、mplete responders.16Table of ContentsWe have completed enrollment and dosing in the Phase 2 study of PRGN-2012 with 23 patients enrolled.The Phase 2 trial is anticipated to be completed in the second quarter of 2024.We have announced that the FDA has confirmed that the ongoing Phase 1/2 single-arm s

144、tudy will serve as pivotal and that no additional randomized,placebo-controlled trial will be required tosupport submission of a BLA under an accelerated approval pathway.The FDA has confirmed that the current primary endpoint for the ongoing Phase 1/2 study,which is Complete Response rate(percentag

145、e of patients with no surgical interventions during the 12 months following treatment with PRGN-2012),along with an immunological surrogate marker demonstrating an induction ofHPV-specific T cell responses following PRGN-2012 treatment,is acceptable for the accelerated approval request.Based on the

146、FDA guidance,we plan to initiate a confirmatory study prior tosubmission of the BLA.PRGN-2012 has been granted Breakthrough Therapy Designation and Orphan Drug designation for the treatment of RRP by the FDA.PRGN-2012 has received Orphan Drug Designation for theTreatment of RRP from the European Com

147、mission as well.PRGN-2012 Phase 2 pivotal trial data are anticipated in the second quarter of 2024.We plan to submit a BLA under an acceleratedapproval pathway in the second half of 2024.We are preparing for commercial readiness for a potential launch,if approved,of PRGN-2012 in 2025.PRGN-2009PRGN-2

148、009,a first-in-class,off-the-shelf investigational immunotherapy,is designed to activate the immune system to recognize and target HPV+solid tumors.PRGN-2009 leverages ourUltraVector and AdenoVerse platforms to optimize HPV type 16,or HPV16,and HPV type 18,or HPV18,antigen design for delivery via a

149、proprietary gorilla adenovector with a large geneticpayload capacity and the ability for repeat administrations.Guided by our bioinformatics analysis and in silico protein engineering,PRGN-2009 encodes for a novel,multi-epitope antigen design totarget HPV16 and HPV18 infected cells and potentially d

150、ifferentiates from the competition.PRGN-2009 has been engineered using our AdenoVerse platform to be replication deficient in vivo.HPV infections account for 5 percent of all cancers globally,and 690,000 new cancer cases are attributable to HPV infections per year.HPV infects the squamous cell carci

151、noma.Some cervicalcancers come from HPV infection of gland cells in the cervix and are referred to as adenocarcinomas.HPV-related cancers include cervical,oropharyngeal,anal,penile,vaginal,and vulvar.Nearly44,000 HPV-associated cancers occur in the United States each year.Of these,approximately 25,0

152、00 occur in women and 19,000 occur in men.HPV is considered responsible for more than 90percent of anal and cervical cancers,about 70 percent of vaginal and vulvar cancers,and more than 60 percent of penile cancers.Recent studies indicate that about 70 percent of cancers of theoropharynx also may be

153、 related to HPV.PRGN-2009 is in a Phase 1/2 clinical trial for patients with HPV-associated cancers in collaboration with NCI pursuant to a Cooperative Research and Development Agreement(CRADA).We havecompleted the Phase 1 portion of the trial.The Phase 2 portion of the study is designed to evaluate

154、 PRGN-2009 as a monotherapy in patients with newly-diagnosed stage II/III HPV16-positiveoropharyngeal cancer and patients with newly diagnosed operable stage II/III/IVA/IVB HPV+sinonasal squamous cell cancer.We have completed enrollment in the Phase 2 monotherapy arm withtwenty evaluable patients.17

155、Table of ContentsIn June 2023,the Principal Investigator of the PRGN-2009 clinical study presented Phase 1 data at the 2023 American Society of Clinical Oncology,or ASCO,Annual Meeting.Phase 1 studyenrolled a total of seventeen adult patients(N=6 Arm 1A,N=11 Arm 1B).In the monotherapy arm,patients(N

156、=6)were enrolled in two sequential dose level cohorts with PRGN-2009 delivered viasubcutaneous injection.PRGN-2009 at 5x10 particle units(PU)per dose was selected as the recommended phase 2 dose(RP2D).In the combination arm,PRGN-2009 was administered at theRP2D in combination with bintrafusp alfa.Pa

157、tients received up to 20 doses of PRGN-2009 for a duration of 1.8 to 17.9 months in the monotherapy arm and 0.5 to 23.0 months in the combinationarm.The median age in both arms was 61.The median number of prior lines of therapies in the metastatic setting was 2.5 for the monotherapy arm and 2 for th

158、e combination arm.All patients in themonotherapy arm(N=6)and 10 of 11 patients in the combination arm received prior immune checkpoint blockade(ICB)therapy.PRGN-2009 treatment in both monotherapy and combination arms was well-tolerated.In both study arms,there was a low incidence of PRGN-2009 treatm

159、ent-related adverse events(TRAEs)withonly Grade 1 or 2 TRAEs in the monotherapy arm.TRAEs reported in the combination arm were in line with the safety profile reported for bintrafusp alfa and TRAEs attributable to PRGN-2009 inthe combination arm were Grade 1 or 2.Tumor responses were observed in pat

160、ients after treatment with PRGN-2009 in combination with bintrafusp alfa(Arm 1B),including in ICB-resistant patients.The majority(6/6 Arm 1A,8/10 Arm1B)of patients developed HPV-16 and/or HPV-18 specific immune responses after treatment with PRGN-2009 in both monotherapy and combination arms.There w

161、as a lack of significantneutralizing antibody response to gorilla adenovector over time with subsequent vaccinations.PRGN-2009 combined with bintrafusp alfa resulted in a 30%objective response rate(ORR)in patientswith pretreated recurrent or metastatic(R/M)HPV-associated cancers that were nave or re

162、sistant to checkpoint blockade.1118Table of ContentsA Phase 2 clinical trial designed to evaluate PRGN-2009 in combination with anti-PD1 antibody,pembrolizumab,in adult patients with newly-diagnosed HPV-associated oropharyngeal cancer isongoing in collaboration with NCI pursuant to a CRADA.The prima

163、ry objective of the study is to determine if there is an increase in CD3+tumor infiltrating T cells post treatment compared withpre-treatment.Secondary objectives include safety and overall survival(OS).In addition,we have received FDA clearance of an Investigational New Drug Application,or IND,to i

164、nitiate a Phase 2 randomized,open-label clinical trial of PRGN-2009 in combination withpembrolizumab to treat patients with R/M cervical cancer.Patients in the Phase 2 trial will be randomized 1:1 to the combination of PRGN-2009 and pembrolizumab(cohort 1)or pembrolizumabmonotherapy(cohort 2).Patien

165、ts randomized to the PRGN-2009 plus pembrolizumab cohort will receive PRGN-2009 via subcutaneous(SC)injection(5 x 10 PU every 3 weeks for threeadministrations followed by administration each 6 weeks thereafter).Patients in the PRGN-2009 plus pembrolizumab cohort and pembrolizumab monotherapy cohort

166、will receive pembrolizumab viaintravenous(IV)infusion(400 mg every 6 weeks).Patients randomized to the pembrolizumab monotherapy cohort will be offered the option to crossover to the PRGN-2009 plus pembrolizumabcohort if certain conditions are met.The primary objective of the Phase 2 trial in R/M ce

167、rvical cancer is to assess the objective response rate(ORR)per RECIST v1.1 following treatment with PRGN-2009 in combination withpembrolizumab or pembrolizumab monotherapy.Secondary objectives include the evaluation of safety and tolerability,progression-free survival(PFS),overall survival(OS),best

168、overall responses(BOR),Disease Control Rate(DCR),time to response and duration of response.The Phase 2 trial in R/M cervical cancer is enrolling patients.UltraCAR-TRecent technological advances have revolutionized the field of immunotherapy for the treatment of cancer.Of the many immunotherapy appro

169、aches,chimeric antigen receptor T,or CAR-T,celltherapies in particular have shown remarkable responses in cancer patients with hematological malignancies.These therapies rely on the genetic modification of T-cells to express chimeric antigenreceptors and enable these modified T-cells to bind to spec

170、ific antigens on the patients tumor cells and kill the tumor cells.Concerns remain,however,regarding complex and lengthy manufacturingprocesses 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

171、tumors due to rapid exhaustionand 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 relevantcell numbers.We believe such an ex vivo expansion process can result in the exh

172、austion of CAR-T cells prior to their administration,limiting their potential for persistence in patients afteradministration.Furthermore,lengthy and complex manufacturing of current CAR-T approaches results in high manufacturing costs and long delays in providing the CAR-T treatment to cancerpatien

173、ts.Time is of the essence for advanced cancer patients and even modest delays in treatment can adversely affect outcomes.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 treatm

174、ent landscape byincreasing patient access through shortening manufacturing time from weeks to days,decreasing manufacturing-related costs,and improving outcomes.We advanced the UltraCAR-T platform toaddress the inhibitory tumor microenvironment by incorporating intrinsic checkpoint blockade without1

175、119Table of Contentsthe need for complex and expensive gene editing techniques.The next generation of UltraCAR-T utilizes a single multicistronic transposon DNA and our overnight,decentralized manufacturingprocess of UltraCAR-T.We have introduced our vision for a new UltraCAR-T library approach,whic

176、h is intended to transform the personalized cell therapy landscape for cancer patients.Our goal is to develop and validatea library of non-viral plasmids to target tumor-associated antigens.Enabled by what we believe to be design and manufacturing advantages of UltraCAR-T,coupled with the capabiliti

177、es of theUltraPorator system,we are working to empower cancer centers to deliver personalized,autologous UltraCAR-T treatment with overnight manufacturing to any cancer patient.If our goal is realized,one or more non-viral plasmids could be selected based on the patients cancer indication and biomar

178、ker 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 thepatien

179、ts tumor.The key advantages of UltraCAR-T versus the traditional CAR-T approaches include:Advanced non-viral multigenic delivery systemWe have optimized and advanced the Sleeping Beauty system using our UltraVector DNA construction platform to produce multigenic UltraCAR-T cells.As a result of this

180、optimization,ourUltraCAR-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 modifiedUltraCAR-T cell.We recently introduced the next generation UltraCAR-T platform that addresses

181、the inhibitory tumor microenvironment by incorporating a novel mechanism for intrinsicdownregulation of one or more checkpoint inhibitor,or CPI,genes.This design achieves intrinsic CPI blockade without gene editing and is aimed at avoiding systemic toxicity and the high cost ofcombining CPI antibodi

182、es.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

183、 the20Table of Contentsdevelopmental risk as compared to those approaches because product homogeneity is a critical consideration for later stages of clinical development and subsequent commercialization.We utilize ourprotein engineering and immunology expertise to optimize antigen binding,hinge,and

184、 signaling domains of each CAR based on the target antigen expression profile and cancer indication.We havealso included our proprietary kill switch technology in our UltraCAR-T cells to improve the safety profile.Enhanced persistence and elimination of ex vivo expansion step due to expression of mb

185、IL15A 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 antigensand prevent T-cell exhaustion to maintain a less differentiated,stem-cell like memory phenotype leading to long

186、er persistence of UltraCAR-T cells.This yields an enduring anti-tumor response thathas been shown to outlast conventional CAR-T cells in preclinical studies,which we believe is essential to successfully targeting solid tumors.This design allows us to eliminate the need for ex vivoexpansion prior to

187、administration,a requirement that is a major limitation of current CAR-T treatments.Scalable,rapid,decentralized manufacturing processAnother key differentiator of the UltraCAR-T therapeutic platform is our rapid and decentralized proprietary manufacturing process,which allows us to manufacture Ultr

188、aCAR-T cells overnight at amedical centers 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-Tmanufacturing,which require extensive ex vivo expansion following viral vector transdu

189、ction that we believe can result in the exhaustion of CAR-T cells prior to their administration,limiting theirpotential for persistence in patients.The decentralized nature of the manufacturing process allows us to scale beyond the confines of a dedicated facility.We believe we are the first company

190、 tovalidate 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 believeUltraCAR-T is the only autologous CAR-T platform with manufacturing,quality control release and infusi

191、on back to the patient,occurring in one day.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 UltraPoratorsystem,intended to be a viable scale-up and commercialization s

192、olution for decentralized UltraCAR-T manufacturing,includes proprietary hardware and software solutions and potentially representsmajor advancements over current electroporation devices by significantly reducing the processing time and contamination risk.The FDA has cleared UltraPorator as a manufac

193、turing device forclinical 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 patientsas compared to current treat

194、ment approaches that require large,centralized facilities to support manufacturing of a relatively small number of treatments.We believe development of rapid andsuccessful overnight manufacturing of UltraCAR-T therapies at medical centers signifies a paradigm shift in CAR-T therapy by eliminating ma

195、nufacturing and timing risks associated withconventional 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.21Table of ContentsPrecigens most advanced programs based on the UltraCAR-T platfor

196、m include PRGN-3005,which is in a Phase 1b clinical trial for patients with advanced ovarian,fallopian tube,or primaryperitoneal cancer;PRGN-3006,which is in a Phase 1b clinical trial for patients with relapsed or refractory acute myeloid leukemia,or AML,and high-risk myelodysplastic syndromes,or MD

197、S;andPRGN-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 orphanreceptor 1-positive,or ROR1,hematological and solid tumors.PRGN-3005PRGN-3005 is a first-in-class,investigati

198、onal autologous CAR-T therapy that utilizes our UltraCAR-T platform to simultaneously express a CAR targeting the unshed portion of the Mucin 16antigen,or MUC16,mbIL15,and kill switch genes.+22Table of ContentsMUC16 is an extremely large,type I transmembrane cell surface glycoprotein that plays a ke

199、y role in the pathogenesis of ovarian cancer by promoting an increase in cell proliferation,metastasis,resistance to chemotherapy and immune system evasion by cancer cells.MUC16 is overexpressed on more than 80 percent of ovarian tumors but has limited expression in healthy tissues,making itan attra

200、ctive CAR-T target for ovarian cancer.Other cancers with known overexpression of MUC16 include pancreatic,breast,endometrial,lung,and bladder cancers.MUC16 undergoes proteolyticcleavage in the extracellular domain resulting in shedding of a large portion of extracellular domain,termed CA125,from the

201、 cell surface and leaving only a short,unshed extracellular domaintethered to the cell surface.Therapies that target the region of MUC16 that is shed from the cell surface may have limited effectiveness due to their binding to CA125 in circulation which is notassociated with tumor cells.In order to

202、eliminate binding to circulating CA125,we have designed our MUC16 CAR using an antigen binding domain that specifically binds the unshed portion ofMUC16 and optimized its affinity to preferentially target PRGN-3005 to tumor cells.PRGN-3005 is being evaluated for the treatment of advanced ovarian,fal

203、lopian tube,and primary peritoneal cancers.Advanced ovarian cancer is often fatal,with Stage IV survival rates as low as 20percent,and has limited treatment options.Patients with ovarian cancer represent a large population,with approximately 300,000 patients diagnosed worldwide annually,including 22

204、,000 in theUnited States alone.In preclinical in vitro studies,PRGN-3005 UltraCAR-T cells have shown robust MUC16-specific cytotoxicity of ovarian cancer cell lines,a stem-cell like memory phenotype and significantimprovement in their longevity even in the absence of exogenous cytokines as compared

205、to conventional CAR-T cells.PRGN-3005 UltraCAR-T cells have shown significantly superior anti-tumorresponse in mouse models of ovarian cancer compared to mice treated with a saline solution or23Table of Contentsconventional MUC16 CAR-T cells lacking mbIL15 expression.Specifically,a single administra

206、tion of PRGN-3005 one day after non-viral gene transfer showed significantly superior expansion andpreferred 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

207、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-3005UltraCAR-T treatment.These data demonstrated the potential of UltraCAR-T cells to persist long-term in vivo,prevent CAR-T cell e

208、xhaustion,and mount a durable anti-tumor response with theability to continue to respond upon tumor rechallenge.The Phase 1/1b clinical study of PRGN-3005 is designed to enroll in two phases,an initial dose escalation phase(Phase 1)followed by a dose expansion phase(Phase 1b).We have completed thePh

209、ase 1 dose escalation portion of the PRGN-3005 Phase 1/1b study.The Phase 1 portion of the study is a dual-arm,non-randomized,open-label clinical trial in patients with advanced,recurrentplatinum-resistant ovarian,fallopian tube or primary peritoneal cancer.Patients in the Phase 1 dose escalation tr

210、ial receive either intraperitoneal,or IP(Arm 1),or intravenous,or IV(Arm 2),administration of PRGN-3005 without prior lymphodepletion.Previously we had announced FDA clearance to incorporate a cohort with lymphodepletion at Dose Level 3 of the IV arm in the Phase1 study.The primary objectives of the

211、 Phase 1 trial are to assess the safety and maximum tolerated dose,or MTD,of PRGN-3005.In June 2023,the Principal Investigator of the PRGN-3005 clinical study presented Phase 1 data at the 2023 American Society of Clinical Oncology,or ASCO,Annual Meeting.The presentationincluded the complete data se

212、t for the Phase 1 dose escalation portion of the study.The Phase 1 study enrolled a total of 27 patients(N=12 IP;N=6 IV;and N=9 IV with lymphodepletion).The meanage of patients in the study was 57.4 in the IP arm without lymphodepletion,67.3 in the IV arm without lymphodepletion and 62.7 in the IV a

213、rm with lymphodepletion.Patients were heavilypretreated with a median of greater than or equal to 8 prior lines of therapy across all arms.Patients had significantly advanced stage disease with a high baseline tumor burden with most patientshaving distant metastases,including liver,spleen,bladder an

214、d lung.Patients treated in the non-lymphodepletion cohort and lymphodepletion cohort received a single administration of 1.8 to 50 x 10and 4.4 to 83 x 10 UltraCAR-T cells via IV infusion,respectively.PRGN-3005 was well-tolerated with low incidence of treatment related adverse events(TRAEs),no dose l

215、imiting toxicities(DLTs),and no neurotoxicity.The most common side effects for the IVand IP arms without lymphodepletion were abdominal pain,fever and decreased absolute lymphocyte count(ALC).Serious Adverse Events included five incidences of Cytokine Release Syndrome(CRS),with no incidence of CRS g

216、reater than Grade 2.One patient with CRS required specific intervention which resolved following standard CRS management after 24 hours.There was no use oftocilizumab or dexamethasone or kill switch.PRGN-3005 administered via either IP or IV infusion resulted in a dose-dependent expansion and encour

217、aging persistence in peripheral blood.Best responses in patients treated withoutlymphodepletion were stable disease with complete responses observed in certain individual target lesions.Incorporating lymphodepletion prior to IV infusion led to an encouraging anti-6624Table of Contentstumor activity

218、with a decrease in tumor burden in 67%(6/9)of patients and stable or partial response in 90%of the individual target lesions in these patients.Subsequently,we have initiated the Phase 1b dose expansion study of PRGN-3005 UltraCAR-T at Dose Level 3 with lymphodepletion prior to IV infusion.We previou

219、sly communicated,based onportfolio reprioritization efforts,that we will not add an extensive number of new clinical sites for the Phase 1b study.Instead,we anticipate to activate a new site under the CRADA with the NationalCancer Institute(NCI)to continue the advancement of the Phase 1b dose expans

220、ion study without incurring major clinical/contract research organization(CRO)costs.PRGN-3006PRGN-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 andcontrol.CD33,also

221、 known as Siglec-3,is a single pass transmembrane glycoprotein and a member of the sialic acid-binding immunoglobulin-like lectin super-family.CD33 is an attractive target forimmunotherapy because it is over-expressed on AML blasts and leukemic stem cells,or LSCs,but is not expressed on normal blood

222、 stem cells,also known as hematopoietic stem cells.Approximately 85-90 percent of AML patients express CD33 on their tumor cells.In addition to broad expression on AML blasts,CD33 is expressed on LSCs underlying AML.LSCs are thought tobe more resistant to chemotherapy treatment and to be capable of

223、reinitiating the disease resulting in high relapse rates for AML.In healthy subjects,CD33 is primarily expressed on normal myeloidprecursors,colony-forming cells,monocytes,and maturing granulocytes.Because CD33 is not expressed outside the hematopoietic system or on normal hematopoietic stem cells,i

224、t is an attractivetarget for treatment of AML.AML is among the most common types of leukemia in adults with approximately 20,000 AML patients diagnosed in the United States annually.AML is a heterogeneous disease with 50-70 percentrelapse rates and rapid progression.The prognosis for patients with A

225、ML is poor,with an average five-year survival rate of approximately 25 percent overall,and less than a 5 percent fiveyearsurvival rate for patients older than 65.More than 10,000 cases of higher-risk MDS are diagnosed annually in the United States.Due to the aggressive nature of AML progression,rapi

226、d availability oftreatment is of even greater importance in this patient population,and our non-viral UltraCAR-T manufacturing process would represent a significant potential advantage over current approaches thatrequire long lead times for manufacturing.In preclinical studies,PRGN-3006 demonstrated

227、 robust expansion in the presence of CD33 antigen,lack of autonomous expansion in the absence of CD33 and prolonged persistence in the absence ofexogenous cytokines.PRGN-3006 exhibited target-specific killing of CD33 tumor cells as well as a significant release of inflammatory cytokines such as IFN,

228、upon co-culture with AML tumorcells.PRGN-3006 cells were specifically eliminated by kill switch activator treatment,displaying functionality of the kill switch,which is intended to improve the safety profile of PRGN-3006.Invivo,a single administration of PRGN-3006 UltraCAR-T cells only one day after

229、 gene transfer effectively eliminated the tumor burden and significantly improved overall survival of tumor bearingmice compared to CAR-T cells lacking mbIL15 expression(conventional CAR-T)in an aggressive xenograft model of AML.PRGN-3006 demonstrated engraftment and significantly higherexpansion an

230、d persistence in mice compared to conventional CAR-T cells,which lack mbIL15 expression.+25Table of ContentsThe Phase 1/1b clinical study of PRGN-3006 is designed to enroll in two phases,an initial dose escalation phase(Phase 1)followed by a dose expansion phase(Phase 1b).We have completed Phase1 do

231、se escalation portion of the PRGN-3006 Phase 1/1b study.The Phase 1 portion of this study is a dual-arm,non-randomized,dose-escalation clinical trial where PRGN-3006 is delivered viaintravenous infusion.The patient population includes relapsed or refractory AML,or r/r AML,higher-risk MDS,and CMML.In

232、 the Phase 1 3+3 dose escalation portion,patients are treated in one ofthe 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,receivelymphodepleting chemotherapy prior to UltraCAR-T in

233、fusion.The primary objective of this trial is to assess the safety of PRGN-3006 and determine the MTD.The Principal Investigator of the PRGN-3006 clinical study presented complete Phase 1 data at the 64th American Society of Hematology(ASH)Annual Meeting and Exposition.The presentationincluded the c

234、omplete data set for the Phase 1 dose escalation portion of the study.The study enrolled a total of 26 patients(N=10 non-lymphodepletion;N=16 with lymphodepletion)and included 21patients with r/r AML,2 patients with chronic myelomonocytic leukemia(CMML),and 3 patients with MDS.The median age was 60.

235、5 years(range:32-77).Patients were heavily pre-treated with amedian of 3.5 prior regimens(range:1-9)and 58%of patients(N=15)had prior allogeneic hematopoietic stem cell transplantation(allo-HSCT).Patients treated in the non-lymphodepletion cohortand lymphodepletion cohort received a single administr

236、ation of 1.8 to 50 x 106 and 4.4 to 83 x 106 UltraCAR-T cells via IV infusion,respectively.In both the non-lymphodepletion(Cohort 1)and the lymphodepletion(Cohort 2)cohorts,PRGN-3006 was well-tolerated with no dose-limiting toxicities(DLTs)reported.The majority of treatmentemergent adverse events(TE

237、AEs)were either Grade 1 or 2.There was only one transient Grade 3 CRS reported in each cohort with the Cohort 2 event subsequently downgraded to Grade 1 by theinvestigator.Incidence of immune effector cell-associated neurotoxicity syndrome(ICANS)was rare with one Grade 1 event and one Grade 2 event

238、in Cohort 1 and Cohort 2,respectively.Nopatients experienced a significant increase in serum IL-15,demonstrating that mbIL15 remains tethered to the UltraCAR-T cells as designed and is not released.Excellent dose-dependent expansion and persistence of PRGN-3006 in peripheral blood and bone marrow wa

239、s observed following a single infusion in both the non-lymphodepletion andlymphodepletion cohorts highlighting the ability of UltraCAR-T cells to engraft and survive even in the absence of lymphodepletion.Higher peak expansion(10 fold)in peripheral blood wasobserved in the lymphodepletion cohort com

240、pared to non-lymphodepletion cohort at the same dose level.In the lymphodepletion cohort(Cohort 2),an objective response rate(ORR)of 27%(3 out of 11)was reported for heavily pre-treated r/r AML patients with poor prognosis(median prior treatments:4;range:1-9).Responders received a single PRGN-3006 d

241、ose ranging between 4.4 to 28 x 10 cells following lymphodepletion.A disease control rate(DCR)of 45%(5 out of 11)at day 28 for r/rAML patients and 100%of MDS patients,respectively.One patient with CRi was bridged to allo-HSCT at three months post treatment and remains in a measurable residual diseas

242、e-negative CR 18months post-transplant.Additionally,of the 15 evaluable patients in the lymphodepletion cohort(Cohort 2),60%(9 out of 15)heavily pre-treated patients had a reduction in bone marrow blastsfollowing a single PRGN-3006 infusion,with 4 patients experiencing a substantial decrease to 5%.A

243、nalysis of peripheral blood samples post PRGN-3006 infusion showed gene expression changes consistent with improvement in the immune compartment function for anti-tumor effect inresponders.There was an increase in cytotoxicity,costimulatory signaling,and lymphoid compartment and decreased apoptosis

244、pathway scores in the lymphodepletion cohort on Days 14 and 28 postPRGN-3006 treatment compared to baseline.626Table of ContentsWe have initiated a Phase 1b dose expansion study where PRGN-3006 is being evaluated following lymphodepletion.The Phase 1b dose expansion study of PRGN-3006 UltraCAR-T was

245、 expandedto Mayo Clinic in Rochester,Minnesota,joining the existing Moffitt Cancer Center,Tampa,Florida site enhancing the decentralized manufacturing model.PRGN-3006 has been granted OrphanDrug designation in patients with AML and Fast Track Designation in patients with r/r AML by the FDA.PRGN-3007

246、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 novelmechanism for the intrinsic blockade of the programmed death 1,or PD-1,gene expression.ROR1 is a type I orphan-re

247、ceptor that is expressed during embryogenesis and by certain hematological and solid tumors but is undetectable on normal adult tissues.ROR1 in malignancies isaberrantly expressed in B-cell malignancies such as B-cell acute lymphoblastic leukemia,or B-ALL,diffuse large cell B-cell lymphoma,or DLBCL,

248、chronic lymphocytic leukemia,or CLL,andmantle cell lymphoma,or MCL.Furthermore,upregulated expression has been detected in various solid tumors,including ovarian cancer,breast adenocarcinomas encompassing triple negative breastcancer,or TNBC,pancreatic cancer,Ewings sarcoma and lung adenocarcinoma.T

249、he increased expression of ROR1 in hematological and solid tumor malignancies has been associated with tumorproliferation,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

250、-1/PD-L1 pathway has demonstratedconsiderable 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 ofPD-1 expression is intrinsic and localized to UltraCAR-T cells,is aimed at a

251、voiding 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.Thedownregulation of PD-1 expr

252、ession 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

253、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 orwithout downregulation of PD-1 expression,resulted in robust expansion

254、in presence of ROR1 antigen,lack of autonomous expansion in absence of ROR1,and durable persistence even in absence ofexogenous cytokines in vitro.PRGN-3007 was selectively and effectively eliminated by the kill switch activator treatment demonstrating functionality of the kill switch,which is inten

255、ded to improvethe 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 improvedoverall survival of tumor bearing mice compared to Control ROR1 CAR-T in an aggressive xenogra

256、ft 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.The Phase 1/1b clinical trial is an open-label study designed to evaluate the s

257、afety and efficacy of PRGN-3007 in patients with advanced ROR1 hematological(Arm 1)and solid(Arm 2)tumors.Thetarget 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 populationf

258、or Arm 2 includes locally advanced unresectable or metastatic histologically confirmed TNBC.The study+27Table of Contentswill 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

259、trial is beingconducted in collaboration with Moffitt Cancer Center,a pioneer in CAR-T clinical development.PRGN-3007 manufacturing technology transfer to Moffit Cancer Center was completed forinitiation of the Phase 1 study.We have initiated dosing in the Phase 1 dose escalation portion of the Phas

260、e 1/1b study.Preclinical ProgramsWe have a robust pipeline of preclinical programs in order to drive long-term value creation.Our pipeline includes product candidates based on UltraCAR-T and off-the-shelf AdenoVerseimmunotherapy therapeutic platforms.We expect to continue development of a number of

261、potential product candidates in our preclinical pipeline and,consistent with our commitment to activelymanage 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 godecisions.Through

262、 this process,we believe we can more effectively allocate resources to programs that we believe show the most promise and advance such programs to clinical trials.Precigen ActoBio(ActoBio)ActoBio is pioneering a proprietary class of microbe-based biopharmaceuticals that enable expression and local d

263、elivery of disease-modifying therapeutics.We refer to these microbe-basedbiopharmaceuticals as ActoBiotics.Precigen ActoBios Therapeutic PlatformsActoBioticsOur ActoBiotics platform is a unique delivery platform precisely tailored for specific disease modification with the potential for superior eff

264、icacy and safety.ActoBiotics combine the advantages ofhighly selective protein-based therapeutic agents with local delivery by the well-characterized and food-grade bacterium Lactococcus lactis,or L.lactis.ActoBiotics can be delivered orally in acapsule,through an oral rinse or in a topical solution

265、.We believe ActoBiotics have the potential to provide superior safety and efficacy via the sustained release of appropriate quantities of selecttherapeutic agents as compared to injectable biologics,while reducing the side effects commonly attributed to systemic delivery and corresponding peaks in c

266、oncentration.ActoBiotics work viagenetically modified bacteria that deliver proteins and peptides at mucosal sites,rather than the insertion of one or more genes into a human cell by means of a virus or other delivery mechanism.Byforegoing this insertion,ActoBiotics allow gene therapy without the ne

267、ed for cell transformation.28Table of ContentsThe key advantages of ActoBiotics include:Food-grade bacterium with easy genetic manipulationActoBiotics combine the advantages of highly selective protein-based therapeutic agents with local delivery by the well-characterized and food-grade bacterium wi

268、th L.lactis,which has a longhistory of safe use.ActoBiotics are generated by genetically modifying L.lactis via chromosomal integration through targeted double homologous recombination to express and release a variety ofhighly versatile biological moieties.Multiple therapeutic agents,such as protein

269、s,peptides,and antibodies,can be incorporated into a single ActoBiotics therapeutic,enabling the simultaneoustargeting of multiple pathways in one disease.The L.lactis host is also engineered for environmental containment,thus preventing the spread of bacteria outside the human body.Cost-effective a

270、nd scalable manufacturingWe have established an efficient and reliable cGMP manufacturing process for the production of ActoBiotics that we believe is easily scalable for commercial supply.The manufacturing processinvolves fermentation of genetically modified L.lactis to generate significant quantit

271、ies of the therapeutic agent,followed by concentration and freeze-drying.The process does not require the costlypurification required to produce conventional biologics.Convenient delivery methodActoBiotics can be delivered to the oral cavity through a mouthwash,intestinally via a capsule,or through

272、a topical formula.Physiological dosing is low,and our ActoBiotics product candidates havebeen well-tolerated in preclinical and clinical studies.As compared to conventional biologics,we believe ActoBiotics have the potential to provide superior safety and efficacy via the sustainedrelease of appropr

273、iate quantities of select therapeutic agents while reducing the side-effects commonly attributed to systemic delivery and corresponding peaks in concentration of conventionalbiologics.29Table of ContentsActoBios most advanced internal pipeline candidate,AG019,is a first-in-class disease modifying an

274、tigen-specific,investigational immunotherapy for the prevention,delay,or reversal of type 1diabetes mellitus,or T1D.AG019 is an easy-to-take capsule formulation of ActoBiotics engineered to deliver the autoantigen human proinsulin,or hPINS,and the tolerance-enhancing cytokinehuman interleukin-10 to

275、the mucosal lining of gastro-intestinal tissues in patients with T1D.We believe this design can reduce T1D pathology by reestablishing immunological tolerance to isletantigens via the production of regulatory T,or Treg,cells.T1D represents a highly unmet medical need,with approximately 132,000 patie

276、nts,most commonly children and young adults,diagnosed each year.In T1D,the immune system destroys insulin-producing beta cells in the pancreas,creating a blood glucose imbalance and numerous symptoms,including polyuria,polydipsia,polyphagia,weight loss,lassitude,nausea and blurred vision.Thecurrent

277、treatment standard for T1D consists of exogenous insulin along with diet and lifestyle modification,but no disease-modifying treatment is available.We believe that AG019 has the potentialto address the unmet medical need for disease modifying treatment in T1D.Preclinical studies in mice have shown t

278、hat AG019,in association with a short-term treatment with a low-dose anti-CD3 monoclonal antibody,induced stable reversion to normal blood sugar levelsand reversed the disease in diabetic mice treated at an early stage.Furthermore,AG019 treatment induced accumulation and proliferation of PINS-specif

279、ic FoxP3 Treg cells in the pancreas andperipheral lymph nodes.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 AG019monotherapy administered as a single dose and repeated

280、 daily doses in adult and adolescent patients.The Phase 2a double-blind portion of the study investigated the safety and tolerability of AG019in combination with teplizumab,or TZIELD.The primary endpoint of both the Phase 1b AG019 monotherapy and the Phase 2a AG019 combination therapy was met.AG019

281、was well-tolerated when administered to adults and adolescents eitheras 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

282、treatment initiation in recent-onset T1D.In an independent analysis performed in a subset of adult and adolescent patients by the Immune ToleranceNetwork(ITN),a leading independent research group sponsored by the United States National Institutes of Health,AG019 monotherapy and combination therapy i

283、nduced antigen-specific tolerancein 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 wasseen in AG019 monotherapy patients indicating that this effect may be attr

284、ibuted to the single 8-week treatment cycle of oral AG019.Precigen ExemplarExemplar is committed to enabling the study of life-threatening human diseases through the development of MiniSwine Yucatan miniature pig research models and services.Historically,researchershave lacked animal models that fai

285、thfully 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,

286、and therapeutics.Exemplars MiniSwine models aregenetically 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.+30Table of ContentsAs of December 31,2023,Exemplar had 25 employees.Exemplars primary d

287、omestic production facilities are located in Sioux County and Johnson County,Iowa,and include approximately 57,960square feet of production,lab,and office facilities.Competition:Healthcare BusinessWhile we believe that our novel approach to developing the next generation of gene and cell therapies u

288、tilizing our UltraCAR-T,AdenoVerse immunotherapy or ActoBiotics platform to target themost urgent and intractable challenges in immuno-oncology,autoimmune disorders,and infectious diseases provides us with competitive advantages,our industry is highly competitive and subject torapid and significant

289、technological change.Many of our competitors have significantly greater financial,technical,and human resource capabilities than we do,and certain of our competitors mayalso benefit from local government subsidies and other incentives that are not available to us.In addition,mergers and acquisitions

290、 in the pharmaceutical and biotechnology industries may result ineven more resources being concentrated among a smaller number of our competitors.As a result of the resources available to our competitors,our competitors may be able to develop competingand/or superior technologies and processes,and c

291、ompete more aggressively and sustain that competition over a longer period of time than we can.Product candidates that we successfully develop and commercialize will compete with a range of therapies that are currently approved and any new therapies that may become available in the future.Our abilit

292、y to compete successfully will depend on our ability to develop proprietary technologies that can be used to produce products that reach the market in a timely manner and aretechnologically superior to and/or are less expensive than other products on the market.The availability of reimbursement from

293、 government and other third-party payers will also significantly affectthe 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 couldresult in our competitors establishi

294、ng a strong market position before we are able to enter the market.Key product features that would affect our ability to effectively compete with other therapeuticsinclude the efficacy,safety and convenience of our products,as well as the availability of intellectual property protection.UltraCAR-TOu

295、r lead product candidates include PRGN-3005,PRGN-3006,and PRGN-3007,each of which are built on our UltraCAR-T platform.While we are employing a novel approach,there are a numberof competitors pursuing CAR-T cell therapies for the treatment of cancer.We believe that,among others,Bristol-Myers Squibb,

296、and Anixa Biosciences are developing CAR-T based treatments forovarian cancer and Adaptimmune is developing TCR-T based treatment for ovarian cancer.We believe that Kite,Amgen,Cellectis S.A.,Autolus and Allogene Therapeutics are also using CAR-Ttechnology to develop product candidates for the treatm

297、ent of AML.We believe that 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-associate

298、dcancers.Anixa Biosciences is developing an autologous CAR-T treatment targeting follicle stimulating hormone receptor(FSHR)for ovarian cancer,which we believe is in a clinical trial.ArsenalBiosciences is developing AB-1015 CAR-T,which we believe is in a clinical trial for platinum resistant ovarian

299、 cancer.Adaptimmune is developing ADP-A2M4CD8 TCR T-cell therapy thatcoepxresses CD8 co-receptor alongside the engineered TCR targeting MAGE-A4 which we believe is in a clinical trial.Regeneron and 2seventy bio are developing bbT4015,an engineered CAR T-cell therapy targeting MUC16,which we believe

300、is in preclinical development.For the treatment of AML using cell therapies,we believe that Kite,2seventy bio and Nkarta have product candidates in the most advanced clinical trials.Kite is developing KITE-222,aninvestigational autologous T-cell therapy engineered with a CAR that specifically target

301、s CLL-1 for treatment of AML.We believe that 2seventy bio is developing DARIC33,a pharmacologicallycontrolled CD33-targeted CAR-T therapy which is in a clinical trial for pediatric AML.Nkarta is developing NKX101,an investigational allogeneic NK cell therapy expressing a CAR target NKG2Dligands and

302、mbIL-15.We believe NKX101 is in a clinical trial for AML and MDS.Amgen is developing AMG 553,an FMS-like tyrosine kinase 3,or FLT3,CAR-T cell therapy utilizing autologousT-cells genetically modified ex vivo to express a transmembrane CAR to target FLT3 protein on the surface of AML cells irrespectiv

303、e of FLT3 mutational status.Cellectis S.A.is also developingUCART123,an allogeneic anti-CD123 CAR-T cell therapy,which utilizes lentivector transduction followed by TALEN-mediated gene editing to eliminate expression of TCR from donor T-cells.Vor Biopharma is developing VOR33,an investigational hema

304、topoietic stem cell(HSC)therapy with elimination of CD33 expression via gene-editing,in combination with Mylotarg,an anti-CD33antibody drug conjugate(ADC).Vor Biopharma is also developing VCAR33,an autologous anti-CD33 CAR-T as a monotherapy and in combination with VOR33.We believe Autolus is develo

305、pingAUTO09,an autologous CAR-T targeting CD33,CD123 and CLL-1,is in preclinical development.Finally,Allogene Therapeutics allogeneic CAR-T therapies ALLO-316 and ALLO-819,targetingFLT3 and CD70,respectively,which we believe are in preclinical and discovery stage ofTM31Table of Contentsdevelopment re

306、spectively,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 toreduce the potential of rejection of therapy by a patients immune system.Lyell Immunopharma is developing LYL797,a ROR1-t

307、argeted CAR T-cell product,which we believe recently received FDA clearance to initiate Phase 1 clinical trial for patients withrelapsed/refractory ROR1+TNBC or non-small cell lung cancer,or NSCLC,and other solid tumors.We believe that Lyell is also developing another ROR1 CAR-T candidate,LYL119,whi

308、ch is inpreclinical development for ROR1+solid tumors.Oncternal Therapeutics is developing ONCT-808,a ROR1 targeted autologous CAR-T cell therapy,which we believe is currently in a Phase 1/2study in patients with relapsed/refractory aggressive B cell malignancies.In addition to our direct competitor

309、s that are using CAR-T therapies specifically for the treatment of ovarian cancer and AML,the CAR-T technology space has significant other competitionincluding from multiple companies and their collaborators,such as Novartis and University of Pennsylvania,Kite and Gilead,Bristol-Myers Squibb,Janssen

310、 and Legend Biotech,Adaptimmune,Autolus Therapeutics,Poseida Therapeutics,Gracell and AstraZeneca,and Bellicum Pharmaceuticals.We also face competition from non-cell based cancer treatments offered by other companiessuch as Amgen,AstraZeneca,Incyte,Merck,Abbvie,and Roche.See Precigens Therapeutic Pl

311、atforms for a discussion of the features that we believe differentiate our UltraCAR-T treatments from our competitors.AdenoVerse ImmunotherapyFor our product candidate PRGN-2012 for the treatment of RRP,while we believe our approach for PRGN-2012 is novel based on the design of antigen targeting HPV

312、6 and HPV11 and use of ourgorilla adenovector,we face competition in the treatment of RRP.We believe our main competitor in the field is INOVIO Pharmaceuticals with their investigational DNA vaccine INO-3107 targetingHPV6 and HPV11 antigens.For our PRGN-2009 candidate in HPV-associated cancers,we be

313、lieve that INOVIO Pharmaceuticals,BioNTech SE,PDS Biotechnology,Hookipa Pharma and Transgene S.A.are developingimmunotherapies that are in clinical testing.TG4001 is an investigational therapeutic cancer vaccine candidate using an attenuated and modified poxvirus,or MVA,as a vector expressing the HP

314、V16E6 and E7 proteins and interleukin-2.We believe TG4001 is in a clinical trial in combination with anti-PD-L1 antibody avelumab for anogenital HPV+cancers.INOVIOs lead investigationalcandidate VGX-3100 is a plasmid DNA based vaccine designed to increase T cell immune responses against the E6 and E

315、7 antigens of HPV16 and HPV18.VGX-3100 is in clinical trials forprecancerous cervical dysplasia,vulvar dysplasia,and anal dysplasia.Inovio is also developing INO-3112,a DNA medicine candidate targeting HPV 16/18,combined with a DNA plasmid for IL-12in combination with an anti-PD1 monoclonal antibody

316、 for locoregionally advanced,high-risk,HPV16/18 positive oropharyngeal squamous cell carcinoma.We believe BioNTech is developingBNT113,an investigational HPV16 E6/7 mRNA vaccine.We believe BNT113 in combination with an anti-PD1 monoclonal antibody is in a clinical trial for HPV16+PD1+Head and Necksq

317、uamous cell carcinoma.We believe PDS Biotechnology is developing PDS-0101,an investigational HPV16 peptide vaccine for various HPV-associated cancers.We believe PDS0101 is in clinicaltrials as monotherapy and combination therapy for recurrent/metastatic HPV16+head and neck cancer,pre-metastatic HPV-

318、associated oropharyngeal cancer,and HPV+anal,cervical,head and neck,penile,vaginal,vulvar cancers.We believe Hookipa is developing HB-200,based on two single-vector compounds with arenaviral backbones based on lymphocytic choriomeningitis virus andpichinde virus expressing the same transgene encodin

319、g an HPV16 E7E6 fusion protein,which is in a clinical trial for HPV16+head and neck cancers.Cellid is developing BVAC-C,which is basedon 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

320、-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 immunotherapytechnologies,including Advaxis Immunotherapies,and Bavarian Nordic.We also face competition fro

321、m non-vaccine based approaches being developed by companies such as Kite,Iovance,Bristol-Myers Squibb,and Merck.ActobioWe are using our suite of proprietary and complementary synthetic biology technologies for the preclinical and clinical development of product candidates for the treatment of autoim

322、mune disorders,including T1D.While we believe AG019 is the first disease-modifying treatment for T1D,there are a number of competitors pursuing immunotherapy product candidates to treat T1D.We believethat our primary competitors with respect to the development of immunotherapies for T1D are Sanofi,3

323、2Table of ContentsMidatech Pharma,and MerciaPharma.ExemplarPrecigen Exemplar is providing porcine research models and services that aid scientists in the understanding of human disease mechanisms and development of new therapeutics.We use precisegenome modification to recapitulate numerous human dis

324、eases in our Yucatan MiniSwine platform,which are utilized by our industry and academic clientele for the development of new smallmolecule,gene,and cell therapies.We believe that the primary competitors of Exemplar are smaller privately owned entities.Intellectual PropertyWe apply a multilayered app

325、roach for protecting intellectual property relating to the inventions we have developed internally,as well as those we have acquired from third parties,such as byassignment or by in-license.As we advance technologies,we evaluate and determine under the circumstances what type or types of intellectua

326、l property is appropriate for the technology,includingpatents,trademarks,know-how and trade secret protections.We seek patent protection in the United States and in other countries for our inventions,and we develop and protect our know-how andtrade secrets relating to our platform technologies,as we

327、ll as to our pipeline products including those of our subsidiaries and collaborators.For instance,we pursue protection to switch technologies,gene delivery technologies,and genetic componentry related to our pipeline products.In addition,we seek patents covering specificcollaborators products.We foc

328、us our intellectual property on aspects of our platforms and technologies that provide for the design and creation of cells,vectors and components for our pipeline and the pipelines of ourcollaborators,as well as technologies directed to improve delivery and expression of our pipeline products.Our s

329、uccess depends,in part,upon our ability to obtain patents and maintain adequate protection for our intellectual property relating to our technologies and product pipeline.We have adopted astrategy of seeking patent protection in the United States and in other jurisdictions globally as we deem approp

330、riate under the circumstances,with respect to certain of the technologies used in orrelating to our technologies and product pipeline.For instance,where we believe appropriate,we have counterpart patents and patent applications in other jurisdictions,such as Australia,Canada,China,Europe,Hong Kong,I

331、ndia,Israel,Japan,Korea,and South Africa.In the future,we may file in these or additional jurisdictions as deemed appropriate for the protection of our technologies.As of December 31,2023,we owned or in-licensed patents in the United States and have pending United States patent applications relating

332、 to various aspects of our platforms and technologies,andwe have pursued counterpart patents and patent applications in other jurisdictions around the world,as we have deemed appropriate.We continue to actively develop our portfolio through the filing ofnew patent applications,provisional and contin

333、uations or divisionals relating to our advancing technologies,methods and products as we and our collaborators deem appropriate.We work to maintain protection for our key technologies including:our various switch technologies,with a last to expire patent currently in 2038;our portfolio around various gene deliverytechnologies and their use,with a last to expire patent in 2040;and our portfolio aro