Ocean Biomedical Inc (OCEA) 2022年年度報告「NASDAQ」.pdf

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1、 UNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington,D.C.20549 FORM 10-K(Mark One)ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended December 31,2022 TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 19

2、34 For the transition period from _to _ Commission File Number:001-40793 Ocean Biomedical,Inc.(Exact name of registrant as specified in its charter)Delaware 87-1309280(State or other jurisdiction ofincorporation or organization)(I.R.S.EmployerIdentification Number)55 Claverick St.,Room 325Providence

3、,RI 02903(Address of principal executive offices)(Zip Code)Registrants telephone number,including area code:(401)444-7375 Securities registered pursuant to Section 12(b)of the Act:Title of each class Trading Symbol(s)Name of each exchange on which registeredCommon stock,par value$0.0001 per share OC

4、EA The NASDAQ StockMarket LLCWarrants,each exercisable for one share of common stockat an exercise price of$11.50 OCEAW The NASDAQ StockMarket LLC Securities registered pursuant to section 12(g)of the Act:None.Indicate by check mark if the registrant is a well-known seasoned issuer,as defined in Rul

5、e 405 of the Securities Act.Yes No Indicate by check mark if the registrant is not required to file reports pursuant 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 Exch

6、ange Act of 1934during the preceding 12 months(or for such shorter period that the registrant was required to file such reports),and(2)has been subject to such filingrequirements for the past 90 days.Yes No Indicate by check mark whether the registrant has submitted electronically every Interactive

7、Data File required to be submitted pursuant to Rule 405 ofRegulation S-T(232.405 of this chapter)during the 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 accel

8、erated filer,a non-accelerated filer,smaller reporting company,or anemerging growth company.See the definitions of“large accelerated filer,”“accelerated filer,”“smaller reporting company,”and“emerging growthcompany”in Rule 12b-2 of the Exchange Act.Large accelerated filerAccelerated filer Non-accele

9、rated filerSmaller reporting company Emerging growth company If an emerging growth company,indicate by check mark if the registrant has elected not to use the extended transition period for complying with any newor revised financial accounting standards provided pursuant to Section 13(a)of the Excha

10、nge Act.Indicate by check mark whether the registrant has filed a report on and attestation to its managements assessment of the effectiveness of its internal controlover financial reporting under Section 404(b)of the Sarbanes-Oxley Act(15 U.S.C.7262(b)by the registered public accounting firm that p

11、repared orissued its audit report.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 thefiling reflect the correction of an error to previously issued financial statements.Indicate by check mark wheth

12、er any of those error corrections are restatements that required a recovery analysis of incentive-based compensation receivedby any of the registrants executive officers during the relevant recovery period pursuant to 240.10D-1(b).Indicate by check mark whether the registrant is a shell company(as d

13、efined in Rule 12b-2 of the Exchange Act).Yes No The aggregate market value of the registrants voting and non-voting common stock held by non-affiliates of the registrant on June 30,2022,based on theclosing price of$10.11 for shares of the registrants common stock as reported by The Nasdaq Stock Mar

14、ket,was approximately$107,166,000.There were 33,774,467 common stock shares of the registrant outstanding on March 29,2023.DOCUMENTS INCORPORATED BY REFERENCE None.OCEAN BIOMEDICAL,INC.ANNUAL REPORT ON FORM 10-KFOR THE FISCAL YEAR ENDED DECEMBER 31,2022 TABLE OF CONTENTS PAGE Explanatory Note3 Cauti

15、onary Note regarding Forward-Looking Statements4 Summary of Risk Factors6 PART I 7ITEM 1.Business7ITEM 1A.Risk Factors67ITEM 1B.Unresolved Staff Comments139ITEM 2.Properties139ITEM 3.Legal Proceedings139ITEM 4.Mine Safety Disclosures139 PART II 140ITEM 5.Market for Registrants Common Equity,Related

16、Stockholder Matters and Issuer Purchases of Equity Securities140ITEM 6.Reserved.142ITEM 7.Managements Discussion and Analysis of Financial Condition and Results of Operations142ITEM 7A.Quantitative and Qualitative Disclosures About Market Risk145ITEM 8.Financial Statements and Supplementary Data145I

17、TEM 9.Changes in and Disagreements with Accountants on Accounting and Financial Disclosure145ITEM 9A.Controls and Procedure145ITEM 9B.Other Information146ITEM 9C.Disclosure Regarding Foreign Jurisdictions that Prevent Inspections.146 PART III 147ITEM 10.Directors,Executive Officers and Corporate Gov

18、ernance147ITEM 11.Executive Compensation157ITEM 12.Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters162ITEM 13.Certain Relationships and Related Transactions,and Director Independence165ITEM 14.Principal Accounting Fees and Services171 PART IV 173ITEM 15.

19、Exhibits and Financial Statement Schedules173ITEM 16.Form 10-K Summary181 EXPLANATORY NOTE Prior to February 14,2023,Aesther Healthcare Acquisition Corp.(“Aesther”)was a special purpose acquisition company formed for the purposeof effecting a merger,stock purchase,reorganization or similar acquisiti

20、on or business combination with one or more businesses.On February 14,2023(the“Closing Date”),subsequent to the end of the fiscal year ended December 31,2022,the fiscal year to which this Annual Report on Form 10-K relates,Aesther completed the previously announced business combination pursuant to t

21、hat certain Agreement and Plan of Merger,dated August 31,2022,asamended on December 5,2022 by Amendment No.1(as amended,the“Business Combination Agreement”),by and among the registrant,AHAC MergerSub,Inc.,a Delaware corporation(“Merger Sub”),Aesther Healthcare Sponsor,LLC(the“Sponsor”),in its capaci

22、ty as purchaser representative,OceanBiomedical Holdings,Inc.,formerly known as Ocean Biomedical,Inc.,a Delaware corporation(“Legacy Ocean”),and Dr.Chirinjeev Kathuria,in hiscapacity as seller representative.As contemplated by the Business Combination Agreement,on the Closing Date,Merger Sub merged w

23、ith and into Legacy Ocean,with LegacyOcean continuing as the surviving entity and a wholly-owned subsidiary of the registrant(the“Merger,”and,together with the other transactions andancillary agreements contemplated by the Business Combination Agreement,the“Business Combination”).In connection with

24、the closing of the BusinessCombination(the“Closing”),we changed our name from“Aesther Healthcare Acquisition Corp.”to“Ocean Biomedical,Inc.”and Legacy Ocean changedits name from“Ocean Biomedical,Inc.”to“Ocean Biomedical Holdings,Inc.”As of the open of trading on February 15,2023,our common stock and

25、 public warrants began trading on the Nasdaq Stock Market LLC(“Nasdaq”)as“OCEA”and“OCEAW,”respectively.Substantially concurrently with the filing of this Annual Report on Form 10-K,we will be filing Amendment No.2 to our Current Report on Form8-K,initially filed on February 15,2023,which will includ

26、e the audited consolidated financial statements of Legacy Ocean for the year ended December31,2022 and related Managements Discussion and Analysis of Financial Condition and Results of Operations and unaudited proforma condensed financialinformation for the Company and Legacy Ocean as of December 31

27、,2022 and for the year then ended.Interested parties should refer to our CurrentReports on Form 8-K for more information.Except as otherwise expressly provided herein,the information in this Annual Report on Form 10-K does not reflect the consummation of theBusiness Combination which,as discussed ab

28、ove,occurred subsequent to the period covered hereunder.As used in this Annual Report on Form 10-K,unless otherwise noted or the context otherwise requires:(i)references to the“Company,”“OceanBiomedical,”“we,”“us,”“our”and similar terms refer to Ocean Biomedical,Inc.(f/k/a Aesther Healthcare Acquisi

29、tion Corp.)and its subsidiaries;(ii)references to“Aesther”are to Aesther Healthcare Acquisition Corp.prior to the close of the Business Combination;(iii)references to“Legacy Ocean”areto Ocean Biomedical Holdings,Inc.(f/k/a Ocean Biomedical,Inc.)prior to the close of the Business Combination;and(iv)r

30、eferences to“Sponsor”are toAesther Healthcare Sponsor,LLC.3 CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS Certain statements in this Annual Report on Form 10-K(“Report”),including the section entitled“Managements Discussion and Analysis ofFinancial Condition and Results of Operations,”are“for

31、ward-looking statements”within the meaning of the United States Private Securities LitigationReform Act of 1995 and are being made pursuant to the safe harbor provisions contained therein.These forward-looking statements relate to currentexpectations and strategies,future operations,future financial

32、 positioning,future revenue,projected costs,prospects,current plans,current objectives ofmanagement and expected market growth,and involve known and unknown risks,uncertainties and other factors that may cause actual results,levels ofactivity,performance or achievements to be materially different fr

33、om expectations,estimates,and projections expressed or implied by these forward-looking statements and,consequently,you should not rely on these forward-looking statements as a guarantee,an assurance,a prediction or a definitivestatement of fact or probability of future events.In some cases,you can

34、identify forward-looking statements through the use of words or phrases such as“may”,“should”,“could”,“predict”,“potential”,“plan”,“seeks”,“believe”,“will likely result”,“expect”,“continue”,“will continue”,“will”,“will be”,“anticipate”,“seek”,“estimate”,“intend”,“plan”,“projection”,“would”,“outlook”

35、,and similar expressions,or the negative version of those words orphrases or other comparable words or phrases of a future or forward-looking nature,but the absence of such words does not mean that a statement is notforward-looking.These forward-looking statements are not historical facts,but instea

36、d they are predictions,projections and other statements about futureevents are based upon estimates and assumptions that,while considered reasonable by the registrant and its management,are inherently uncertain.Theseforward-looking statements are provided for illustrative purposes only and actual ev

37、ents and circumstances are difficult or impossible to predict and willdiffer from assumptions.Forward-looking statements in this Report refer to Ocean Biomedical and include,but are not limited to,statements about:our future financial performance;estimates regarding expenses,future revenue,capital r

38、equirements and needs for additional financing;the success,cost and timing of product development activities and clinical trials of product candidates,including the progress of,andresults from,planned clinical trials;the success,cost and timing of completing IND-enabling studies of preclinical produ

39、ct candidates,and the timing of plannedInvestigational New Drug Application,or IND,submissions for such candidates;plans to initiate,recruit and enroll patients in,and conduct planned clinical trials at the projected pace;the intended benefits of our business model;our ability to acquire licenses or

40、 otherwise obtain new product candidates to add to our portfolio for clinical development;plans and strategy to obtain and maintain regulatory approvals of product candidates;plans and strategy to obtain funding for operations,including funding necessary to complete further development and,upon succ

41、essfuldevelopment,if approved,commercialize any product candidates;the potential benefit of any future orphan drug designations for product candidates;our ability to compete with companies currently marketing or engaged in the development of treatments for fibrosis;plans and strategy regarding obtai

42、ning and maintaining intellectual property protection for product candidates and the duration of suchprotection;plans and strategy regarding the manufacture of product candidates for clinical trials and for commercial use,if approved;plans and strategy regarding the commercialization of any products

43、 that are approved for marketing;the size and growth potential of the markets for product candidates,and our ability to serve those markets,either alone or in combinationwith others;expectations regarding government and third-party payor coverage and reimbursement;success in retaining or recruiting,

44、or changes required in,officers,key employees or directors;officers and directors allocating their time to other businesses and potentially having conflicts of interest with our business,as a result ofwhich they would then receive expense reimbursements;public securities potential liquidity and trad

45、ing;impact from the outcome of any known and unknown litigation;future financial performance,including financial projections and business metrics and any underlying assumptions thereunder;future business or product expansion,including estimated revenues and losses,projected costs,prospects and plans

46、;trends in the healthcare industry;ability to scale in a cost-effective manner;ability to obtain and maintain intellectual property protection;future capital requirements and sources and uses of cash;and impact of competition and developments and projections relating to competitors and industry.4 Ma

47、ny factors may cause actual results to differ materially from these forward-looking statements including,but not limited to:the risk of changes in applicable laws or regulations;the risk of the need and ability to raise additional capital and the terms on which such capital is received;the risk of o

48、ur inability to succeed in clinical development or obtain FDA approval of lead pipeline indications;increased regulatory costs and compliance requirements in connection with drug development;the risk of our potential inability to comply with FDA post-approval requirements;the risk of failure to comp

49、ly with manufacturing regulations or unexpected increases in manufacturing costs;the risk of the inability of our products to achieve broad market acceptance of existing or planned products and services and achievingsufficient production volumes at acceptable quality levels and prices;the risk of in

50、creased competition from other pharmaceutical and biotechnology companies,academic institutions,government agencies,and other research organizations;new FDA approved drugs that compete with us in targeted indications;the risk of failure of third party service providers to comply with contractual dut

51、ies;the risk of failure to comply with international,federal and state healthcare;the impact of COVID-19 on operations including its preclinical studies and clinical trials;risks related to the ongoing COVID-19 pandemic and response,including supply chain disruptions;the possibility that we may be a

52、dversely impacted by other economic,business,and/or competitive factors changes in the markets in which we compete,including with respect to our competitive landscape,technology evolution,or regulatorychanges;the risk that we may fail to keep pace with rapid technological developments to provide new

53、 and innovative products and services ormake substantial investments in unsuccessful new products and services;the risk that the addressable market we intend to target does not grow as expected;the risk of our inability to expand and diversify our manufacturing customer base;changes in domestic and

54、global general economic conditions;the risk of loss of any key executives;the risk of loss of any relationships with key partners;the risk of loss of any relationships with key suppliers;the risk of our inability to protect patents and other intellectual property;the risk of lower than expected adop

55、tion rates;the risk of the inability to develop,license or acquire new therapeutics;the risk of the inability to initiate and increase engagement with distributors;the risk of fluctuations in results of our major manufacturing customers;the risk of our inability to execute our business plans and str

56、ategies,including growth strategies;the risk that we experience difficulties in managing growth and expanding operations;the risk that we may not be able to develop and maintain effective internal controls;the risk of our inability to maintain sufficient inventory and capacity to meet customer deman

57、d;the risk of our inability to deliver expected cost and manufacturing efficiencies;the risk that we will need to raise additional capital to execute our business plan,which may not be available on acceptable terms or at all;the risk of product liability or regulatory lawsuits or proceedings relatin

58、g to our business;the risk of cyber security or foreign exchange losses;general economic conditions and geopolitical uncertainty;future exchange and interest rates;and other risks and uncertainties,including those in the section entitled“Risk Factors”in this Report,and other documents filed or to be

59、 filedwith the SEC by the Company.The foregoing list of factors is not exhaustive.You should carefully consider the foregoing factors and the other risks and uncertainties that aredescribed in the section entitled“Risk Factors”in this Report,which are incorporated herein by reference,as well as othe

60、r documents to be filed by us fromtime to time with the SEC.These filings identify and address other important risks and uncertainties that could cause actual events and results to differmaterially from those contained in the forward-looking statements.Forward-looking statements speak only as of the

61、 date they are made.Readers arecautioned not to put undue reliance on forward-looking statements,and while we may elect to update these forward-looking statements at some point in thefuture,they assume no obligation to update or revise these forward-looking statements,whether as a result of new info

62、rmation,future events or otherwise,except as required by applicable law.We are not giving any assurance that we will achieve our expectations.These forward-looking statements should notbe relied upon as representing our assessments as of any date subsequent to the date of this Report.Accordingly,und

63、ue reliance should not be placed uponthe forward-looking statements.5 SUMMARY OF RISK FACTORS You should read this summary together with the description of each risk factor contained in Item 1A of this Report,as well as other documents tobe filed by us from time to time with the SEC,for a more detai

64、led discussion of certain risks that could materially adversely affect our financial conditionsand the market price of our securities.The following list describes some of our principal risk factors after the Closing of the Business Combination:We have incurred significant net losses since inception

65、and we are expected to continue to incur significant net losses for the foreseeablefuture.We may not be successful in our efforts to use our differentiated business model to build a pipeline of product candidates withcommercial value.We will require substantial additional capital to finance our oper

66、ations.If we are unable to raise such capital when needed,or onacceptable terms,we may be forced to delay,reduce and/or eliminate one or more of our research and drug development programs,futurecommercialization efforts and/or other operations.We are a biopharmaceutical company with a limited operat

67、ing history,and many of our development programs are in early stages ofdevelopment.This may make it difficult to evaluate our prospects and likelihood of success.Our underlying technology is unproven and may not result in marketable products.Because we rely on third-party manufacturing and supply ve

68、ndors,our supply of research and development,preclinical and clinicaldevelopment materials may become limited or interrupted or may not be of satisfactory quantity or quality.Even if a product candidate we develop receives marketing approval,it may fail to achieve the degree of market acceptance byp

69、hysicians,patients,third-party payors and others in the medical community necessary for commercial success.The market opportunities for our product candidates may be relatively small since the patients who may potentially be treated with ourproduct candidates are those who are ineligible for or have

70、 failed prior treatments,and our estimates of the prevalence of our targetpatient populations may be inaccurate.We rely on third parties to conduct all or certain aspects of our preclinical studies and clinical trials.If these third parties do notsuccessfully carry out their contractual duties,meet

71、expected deadlines or comply with regulatory requirements,we may not be able toobtain regulatory approval of or commercialize any potential product candidates.The intellectual property that we have in-licensed has been discovered through government funded programs and thus may be subject tofederal r

72、egulations such as“march-in”rights,certain reporting requirements and a preference for U.S.-based companies.Compliancewith such regulations may limit our exclusive rights,and limit our ability to contract with non-U.S.manufacturers.We have entered into and may enter into license,sublicense or other

73、collaboration agreements in the future that may impose certainobligations on us.If we fail to comply with our obligations under such agreements with third parties,we could lose license or sublicenserights that may be important to our future business.Obtaining and maintaining our patent protection de

74、pends on compliance with various procedural,document submission,fee payment andother requirements imposed by governmental patent agencies,and our patent protection could be reduced or eliminated for non-compliance with these requirements.Our internal computer systems,or those of our collaborators or

75、 other contractors or consultants,may fail or suffer security breaches,which could result in a material disruption of our product development programs.We may encounter difficulties in managing our growth,which could adversely affect our operations.If we lose key management or scientific personnel,or

76、 if we fail to recruit additional highly skilled personnel,our ability to developcurrent product candidates or identify and develop new product candidates will be impaired,could result in loss of markets or marketshare and could make us less competitive.We identified a material weakness in Legacy Oc

77、eans internal control over financial reporting.If our remediation of this materialweakness is not effective,or if we experience additional material weaknesses or otherwise fail to maintain an effective system of internalcontrols in the future,we may not be able to accurately report our financial con

78、dition or results of operations.Even if we receive regulatory approval of any product candidates,we will be subject to ongoing regulatory obligations and continuedregulatory review,which may result in significant additional expense and we may be subject to penalties if we fail to comply withregulato

79、ry requirements or experience unanticipated problems with our product candidates.Ongoing healthcare legislative and regulatory reform measures may have a material adverse effect on our business and results ofoperations.The price of our common stock and warrants may be volatile,and you could lose all

80、 or part of your investment.We are“controlled company”within the meaning of Nasdaq rules and the rules of the SEC.As a result,we qualify for exemptions fromcertain corporate governance requirements that provide protection to shareholders of other companies.Our principal stockholders and management o

81、wn a significant percentage of our Common and are able to exert significant control overmatters subject to stockholder approval.Our issuance of additional capital stock in connection with financings,acquisitions,investments,our stock incentive plans,employeestock purchase plan or otherwise will dilu

82、te all other stockholders.We will incur increased costs as a result of operating as a public company,and our management will devote substantial time tocompliance with its public company responsibilities and corporate governance practices.Our management team has limited experience managing a public c

83、ompany.There can be no assurance that we will be able to comply with the continued listing standards of Nasdaq.Our failure to meet thecontinued listing requirements of Nasdaq could result in a delisting of our common stock and warrants.We qualify as an“emerging growth company”as well as a“smaller re

84、porting company”within the meaning of the Securities Act,and ifwe take advantage of certain exemptions from disclosure requirements available to emerging growth companies,this could make oursecurities less attractive to investors and may make it more difficult to compare our performance with other p

85、ublic companies.6 PART I ITEM 1.BUSINESS.Unless otherwise noted or the context otherwise requires,the disclosures in this Item 1 refer to Ocean Biomedical,Inc.and its subsidiaries following theconsummation of the Business Combination and all references to“we,”“us,”“our,”“Ocean Biomedical,”or the“Com

86、pany,”are to Ocean Biomedical,Inc.Introduction We were originally incorporated in June 2021 as a Delaware corporation under the name“Aesther Healthcare Acquisition Corp.”We were aspecial purpose acquisition company,formed for the purpose of effecting an initial business combination with one or more

87、target companies.On September17,2021(the“IPO Closing Date”),we consummated our initial public offering(the“IPO”or the“Public Offering”).On February 14,2023(the“ClosingDate”),we consummated the previously announced Business Combination(as defined in the Explanatory Note to this Annual Report on Form

88、10-K)pursuant to the Business Combination Agreement,by and among the Company,Merger Sub,Sponsor,in its capacity as purchaser representative,LegacyOcean,and Dr.Chirinjeev Kathuria,in his capacity as seller representative.Pursuant to the Business Combination Agreement,on the Closing Date,MergerSub mer

89、ged with and into Legacy Ocean,with Legacy Ocean continuing as the surviving entity and a wholly-owned subsidiary of the Company.Inconnection with the closing of the Business Combination,we changed our name from“Aesther Healthcare Acquisition Corp.”to“Ocean Biomedical,Inc.”Description of Business We

90、,Ocean Biomedical,are a biopharmaceutical company that seeks to bridge the“bench-to-bedside”gap between medical research discoveriesand patient solutions.We do this by leveraging our strong relationships with research universities and medical centers to license their inventions andtechnologies with

91、the goal of developing them into products that address diseases with significant unmet medical needs.We believe that our differentiatedbusiness model positions us to capture inventions created at these institutions that might otherwise fail to be commercialized to benefit patients.Our teamof accompl

92、ished scientists,business professionals and entrepreneurs brings together the interdisciplinary expertise and resources required to develop andcommercialize a diverse portfolio of assets.We are organized around a licensing and subsidiary structure that we believe will enable us to create mutualvalue

93、 for us and potential licensing partners.We believe this structure,combined with the networks of our leadership team,allows us to opportunisticallybuild a continuous pipeline of promising product innovations through our existing and potential future relationships with research institutions.Our goal

94、isto optimize value creation for each of our product candidates,and we intend to continuously assess the best pathway for each as it progresses through thepreclinical and clinical development processincluding through internal advancement,partnerships with established companies and spin-outs or initi

95、alpublic offeringsin order to benefit patients through the commercialization of these products.Our current active assets are licensed directly or indirectlyfrom Brown University and Rhode Island Hospital.Our scientific co-founders and members of our board of directors,Dr.Jack A.Elias and Dr.Jonathan

96、Kurtis,are both affiliated with Brown University and with Rhode Island Hospital.Our Pipeline Our pipeline consists of preclinical programs.We anticipate moving certain preclinical product candidates in our oncology,fibrosis and/orinfectious disease platforms,all licensed exclusively from Brown Unive

97、rsity and Rhode Island Hospital,into the clinic in the next 12 to 18 months.7 Our programs in oncology and fibrosis are based on discoveries of disease pathways and of related drug targets emerging from pioneering work inthe field of chitinase biology by our scientific co-founder and member of our b

98、oard of directors,Jack A.Elias,M.D.,former Dean of Medicine and currentSpecial Advisor for Health Affairs to Brown University.In oncology,our product candidates are based on Dr.Elias findings that a protein called chitinase 3-like-1,or Chi3l1,is a key driver of multipledisease pathways,including tho

99、se involved in primary and metastatic tumor development.In animal models of both lung cancer and glioblastoma,inhibition of Chi3l1 resulted in significant tumor reduction,and the reduction was even greater when the inhibition of Chi3l1 was combined with immunecheckpoint inhibitors,which are used as

100、immuno-therapies to stimulate the bodys immune response against cancer.Neutralizing antibodies against Chi3l1have been developed that are highly avid,specific,react with mouse,human and monkey Chi3l1 and are effectively expressed and humanized.We aredeveloping a mono-specific antibody,or mAb,and two

101、 bi-specific monoclonal antibodies,or BsAbs,product candidates targeting Chi3l1 for the treatmentof non-small cell lung cancer,or NSCLC,which affects approximately 460,000 people in the United States,and of glioblastoma multiforme,or GBM,ausually lethal form of brain cancer that affects approximatel

102、y 28,000 people in the United States.The median survival for individuals diagnosed with GBMis approximately 15 months and the five year survival rate is just 8%for those aged 45-54 and 5%for those aged 55-64.Our product candidate in fibrosis is based on a drug target investigated by Dr.Elias and clo

103、sely related to the Chi3l1 oncology target describedabove.Dr.Elias found that an enzyme called chitinase 1,or Chit1,is a key driver of fibrosis.Fibrosis is observed in an estimated 50%of all diseases.Fibrosis in the lungs tends to be progressive and can reduce their function.In animal models of idio

104、pathic pulmonary fibrosis,or IPF,and Hermansky-Pudlak syndrome,or HPS,inhibition of Chit1 showed statistically significant reduced levels of fibrotic markers.We are developing a small moleculeproduct candidate targeting Chit1 for the treatment of IPF,a debilitating lung disease affecting approximate

105、ly 160,000 people in the United States,and ofHPS,an ultra-rare disease affecting approximately 1,800 in the United States.In infectious diseases we are developing therapeutic and vaccine candidates against malaria,a mosquito-borne disease that kills 500,000 childrenunder the age of five globally eac

106、h year,that infects 200-300 million people annually worldwide,and for which 3.4 billion people worldwide are at risk.Our product candidates in malaria are based on the discovery by Jonathan Kurtis,M.D.,Ph.D.,Chair of Pathology and Laboratory Medicine and Directorof the M.D./Ph.D.Program at Brown Uni

107、versity,of two novel malaria antigens,PfSEA-1 and PfGARP(as defined below).In non-human primate modelsof malaria,vaccination with PfGARP resulted in an 11.5-fold reduction of parasites in blood compared to controls.In in-vitro models,our therapeuticantibody candidate against PfGARP reduced parasite

108、count by 99%compared to controls.We have three product candidates based on these new antigens:(1)a malaria vaccine candidate against PfSEA-1 and/or against PfGARP;(2)a humanized mAb malaria product candidate against PfGARP;and(3)a smallmolecule malaria product candidate,also against PfGARP.Important

109、ly,Dr.Kurtis antigen discoveries described above were enabled by his development of our Whole Proteome Differential Screeningtarget discovery platform(the“WPDS”platform).We believe the WPDS platform may enable us to discover new targets for other infectious diseases in thefuture.The WPDS platform le

110、verages the fact that the immune system,when exposed to an infectious disease such as malaria,will often naturally producea wide array of antibodies to try fighting the infection.Only a small subset of these antibodies may prove effective,and the WPDS platform is designed toidentify these antibodies

111、 and their corresponding antigens.We believe that such antibodies and antigens could inform the development of therapeutic and/orvaccine candidates against the particular infectious disease.Prior to in-licensing our product candidates,the preclinical developments of the oncology,fibrosis and malaria

112、 programs described above have,to date,been funded through grants to our licensors totaling$105.6 million.8 The table below summarizes our product candidate pipeline,target indications,estimated addressable patient populations,and stage of development.Our Team Our scientific co-founders and members

113、of our board of directors are Dr.Elias and Dr.Kurtis.Our executive chairman and co-founder is ChirinjeevKathuria,M.D.,an investor and entrepreneur who has co-founded and driven the initial public offerings,or IPOs,of companies in various industriesincluding healthcare.Our chief executive officer,Eli

114、zabeth Ng,brings a proven track record of building successful portfolios in biopharma companiesincluding Merck&Co.,Inc.,Gilead Sciences,Inc.and BioMarin Pharmaceuticals,Inc.Our team brings expertise in science,medicine,agile drugdevelopment,pharma strategy,and innovation management.Collectively,memb

115、ers of the team have evaluated more than 3,500 innovations;been involvedin more than 80 drug discovery/development programs,17 clinical development programs,and 8 approved drugs;have secured more than$120 million inventure capital funding;and have been involved in the launch of 8 biotech or life sci

116、ences companies and 3 IPOs.In addition,beyond our day-to-dayleadership team,our scientific co-founders and members of our scientific advisory board and board of directors,Dr.Elias and Dr.Kurtis,have authored orco-authored more than 350 papers,secured more than$110 million in grant funding,and are li

117、sted as inventors in more than 50 patents.Our Strategy and Competitive Strengths Our goal is to facilitate the flow of academic discoveries from bench-to-bedside by efficiently carrying out the translational and clinicaldevelopment required to advance them commercially.The number of potential opport

118、unities at research universities and medical centers is large(in 2018they filed over 26,000 invention disclosures and spent over$71 billion in research)but only a small fraction of these opportunities is currently tapped byventure capitalists or pharmaceutical companies.There is a growing yet still

119、small number of accelerator programs and incubators aiming to bridge thebench-to-bedside gap at specific institutions;however,the gap remains wide and we believe this presents an attractive opportunity for us to become anindustry leader by addressing a need to accelerate the advancement of therapeut

120、ics that can address significant unmet medical needs.The core elements that we believe differentiate our business model include:Harnessing inventions and technologies from research universities and medical centers.We search for opportunities wherever theycan be found,and we believe“hidden gems”can b

121、e uncovered by our team.We are experienced at identifying and sourcing breakthroughdiscoveries at academic and research institutions,including our current partnerships with Brown University and Rhode Island Hospital.We know how to assess and test their scientific merits and commercial relevance,and

122、we have extensive experience working with theseinstitutions and licensing their assets.For example,our leadership team has evaluated thousands of innovations,taken multiple productsthrough IND filings and into clinical development,and been involved in the launch of 8 biotech companies.Developing new

123、 drug therapies through an operationally efficient,evidence-based and milestone-driven approach.Once we selectan asset for development,we pursue what we believe are appropriate development strategies that we aim to execute efficiently byleveraging contract research and contract manufacturing organiz

124、ations,or CROs and CMOs,respectively,and other drug developmentexperts and consultants.We aim to rapidly and efficiently advance our product candidates to objective critical decision points.We directresources toward the opportunities that we believe are the most promising,and we discontinue programs

125、 that do not meet ourperformance thresholds.We are skilled at objectively directing internal resources,and at leveraging external resources(such as CROs andCMOs),in order to progress product candidates in accordance with well-defined criteria for advancement within a lean cost structure.Building a d

126、iverse portfolio of product candidates.We are evidence-based and program agnostic,meaning that our resources aredriven strictly by program progress and milestone achievements.Our approach is to develop multiple diverse programs in parallel.Oursuccess is not dependent on any one particular program,di

127、sease area or indication,which mitigates business risk,and allows us theflexibility to opportunistically develop product candidates,regardless of therapeutic area.We believe that this model ensures that weremain focused on assets with the most promise.The unifying theme in our portfolio is to addres

128、s significant unmet medical needs bycommercializing innovative therapeutic products,if approved.Providing attractive economic upside to our partners at research universities and medical centers.We have a structure whereinOcean Biomedical houses each of its programs in a subsidiary.We believe this st

129、ructure is optimal to provide attractive economicincentives to the discovering institution and its researchers.Our subsidiary structure is intended to enable us to offer equity in futureprograms to the licensing institution and the researchers who discover our product candidates.We believe this stru

130、cture will make us apartner of choice for both institutions and researchers and aligns our interests with theirs toward the goal of maximum returns.Employing a multi-disciplinary approach to drug discovery and development across our programs.Our business model is based onbringing together the approp

131、riate disciplines and expertise needed for each of our programs and leveraging learnings across programs anddisease areas.Common ties between many diseases are becoming apparent and similar therapeutic strategies are increasingly beingapplied to different diseases.For example,our oncology and fibros

132、is programs are both based upon chitinase biology.Another example isthe confluence of thinking about immunology and oncology therapeutic approaches which led to the advent of immune checkpointinhibitors.Exploiting multiple commercialization options to maximize each programs value.Throughout the deve

133、lopment of our productcandidates,we continually assess that programs potential paths to market,and we will endeavor to maximize commercial value throughvarious options,including internal advancement,partnerships with established companies,and spin-outs or IPOs.We believe that ourstructure and operat

134、ional strategy enables us to assess and pursue the course that maximizes outcomes for patients and value for ourshareholders.Leadership team comprised of academic,scientific and business innovators.We have assembled an industry-leading,multi-disciplinary team consisting of physicians,scientists and

135、business leaders with significant experience in progressing product candidatesfrom early-stage research through clinical trials,regulatory approval and ultimately to commercialization.We believe our differentiated business model enables us to advance the commercialization of our products,if approved

136、,and will allow us toreplicate our licensing partnerships through aligned incentive structures with research universities and medical centers.9 Feeding our Pipeline:Harnessing Innovations from Research Centers Our innovative business model is aimed at translating biomedical inventions from research

137、universities and medical centers into products that webelieve have the potential to dramatically improve patients lives.Unlike many biotech companies,our success is not dependent on any one particularprogram or disease.Our current pipeline is already well-diversified and our access to innovations fr

138、om academic and medical institutions allows us theflexibility to opportunistically develop product candidates,regardless of therapeutic area.We believe our sources of medical discoveries include not onlyresearch universities and medical centers but also companies with assets that are not core to the

139、ir business model.We use highly selective criteria and stringent due diligence for selecting assets for development.Picking the right assets requires unbiased andobjective science/technology and market assessments that are not affected by institutional legacies,not blinded by research myopia or acad

140、emic necessities,and not influenced by“herd mentalities.”We seek to develop technologies that meet our stringent selection criteria and which are amenable to ourcontrolled de-risking process that we believe can lead to clear and timely value inflection points and milestones.We intend to keep our foc

141、us on projectsand technologies that demonstrate clear progress towards becoming commercially viable products.Our business model aims to diversify our approachaway from a single vector of technology research or science,and instead to pursue a variety of promising research avenues simultaneously and c

142、osteffectively.As explained previously,we believe that we can address the resourcing challenges inherent in such diversity and that the diversity itself is anadvantageous business strategy.Our model for identifying,structuring and developing assets is based on the following tenets:We believe we have

143、 a disciplined process for identification,selection and prioritization of programs:We believe that only well-defined science can be monetized successfully.Independent analyses of pharmaceutical research and development productivity indicatethat ill-defined science is a major cause of low success rat

144、es and eventual failure of programs.We believe that there is no substitute for athorough science/technology assessment upfront as it is essential to have a clear understanding of the science and a clear vision of how atechnology becomes a product before starting the development effort.Our approach t

145、o selecting programs is opportunistic:We seek opportunities based on solid science,well-characterized drugmechanisms of action,and targets with true disease-modifying potential that can address significant unmet medical needs.While manysuch opportunities may be found at leading universities and medi

146、cal centers,we search for promising technologies wherever they can befound.We believe that such technologies can be located at institutions across the world.We are open to evaluating programs at any stageof development.We are purposely opportunistic and agnostic as to therapeutic area.Our strategy i

147、s to bring the appropriate and the mostcurrent expertise to bear as needed for each program.We aim for efficient therapeutic development operations:Once we select an asset for development,we leverage our years ofexperience in drug development to create appropriate development strategies.We aim to ex

148、ecute such strategies efficiently by leveragingCROs and other drug development experts and consultants.The development process is managed by our experienced team with supportfrom leaders and experts in the relevant disease areas.We aim to rapidly and efficiently advance our product candidates to obj

149、ectivecritical decision points.We direct resources toward the opportunities that we believe are the most promising,and we discontinueprograms that do not meet performance thresholds.Each development program is carried forward with what we believe to be the rightbalance of effort from our centralized

150、 resources and personnel,through which we share certain support functions across variousprograms,combined with specialist external providers as appropriate.This combination is designed to ensure that each program has theappropriate level and type of resources required to execute its unique developme

151、nt strategy while minimizing fixed costs at the programlevel.10 We believe our structure supports our strategic aims:We are structured in a manner where Ocean Biomedical currently houses eachprogram in a wholly-owned subsidiary.This structure is designed to leverage a main feature of our business mo

152、del in which eachprogram is derived from our acquisition of a license to assets from a research university or similar institution.This structure is intended toallow us to provide attractive economic incentives to the institution and its relevant investigators.We intend in the future,as newprograms a

153、re licensed in by us,to grant a certain percentage of the ownership in the new subsidiaries we create for such programs,targeting 20%in aggregate,to the institution and to the researchers.This model is also designed to align our interests with those of ourpartners and to facilitate our access to the

154、 particular programs scientific expertise and know-how.We believe this approach will make usthe partner of choice or licensee of choice for institutions and researchers because we aim to act with greater speed and to provide betterpotential upside when compared to pharmaceutical companies or venture

155、-backed biotechnology companies with whom the institutionmight also consider partnering.We believe that our diversified pipeline approach provides us with meaningful advantages:Unlike biotechnology companies thatare focused on a narrow set of assets,on a single platform,or on a particular therapeuti

156、c area,we are advancing a diverse portfolio ofseveral programs in parallel.In so doing,we aim to avoid the duplication of resources,the extra costs and the lack of valuable cross-pollination that would likely exist if each program were pursued as independent assets.We are evidence-based and program

157、agnostic,where deployment of program resources are driven strictly by program progress and milestone achievements.We believe that our diverse,multi-program business model and our access to a robust pipeline of opportunities helps us to remain focused on the most promisingassets.We believe this focus

158、 differentiates us advantageously from biotech companies that,by purposely being focused,have bet theirfortunes on a limited number of programs.We aim to create optionality for maximum impact and value creation in each program:Throughout the development of anyprogram we continuously assess that prog

159、rams potential paths to market and monetization.We anticipate that such paths may include:(a)taking a candidate all the way through to potential approval and product launch via internal funding;(b)externalizing developmentwith a strategic partner that we believe is better suited to progress a progra

160、m;and(c)spinning out or taking a candidates subsidiarypublic.We believe that our structure and operational strategy enables us to objectively assess and choose the option that maximizespotential value for patients and for our shareholders.Our Structure:Supporting Innovation We are structured in a ma

161、nner where Ocean Biomedical houses each program in a subsidiary.We currently house our programs in four wholly-owned subsidiaries and intend to grant a certain percentage of the ownership in future subsidiaries,typically 20%in aggregate,to the institution and to therelevant researchers.This anticipa

162、ted organizational structure for future subsidiaries is unique in the market and we believe it will make us the partner ofchoice for institutions and inventors.Currently,research universities and medical centers(institutions)have two primary options to commercialize their biomedical innovations andt

163、echnologies:licensing to pharma,or licensing to startups that are usually founded or co-founded by the researchers(the inventors)behind the innovations.Most commonly,the IP policy of U.S.institutions specifies that economic value received from licenses is split equally among the institution,the indi

164、vidualinventor(s),and their department or school.Licensing to a large pharmaceutical company is appealing due to the vast resources it may employ to pursue commercial development and thepotential for large up-front and milestone payments.However,these companies often only license innovations later i

165、n their development.Therefore,licenses to large pharmaceutical companies are relatively rare.Researchers often choose to license their innovations to startups because(i)they see greater economic upside(as compared to only receiving afraction of what their institution receives),(ii)they view a startu

166、p as a way to retain more control over the development of their innovation and(iii)astartup may be the only option given the challenges of licensing to larger companies.The researcher typically takes a non-operating role as a scientificfounder of the startup,and holds between a 10%and 20%equity stak

167、e in the enterprise,which will be subject to dilution over time.11 We can provide the resources and capital of a pharma licensee while also providing the more compelling economic upsides of a startup.Eachpatent portfolio that we license in from an institution(capturing the discoveries of one or more

168、 researchers)are housed,or in the future will be housed in aseparate unit or subsidiary which we title a program.We can provide the institution and the researchers a share in the potential economic upside of thatparticular program regardless of how that economic upside comes about.The proposed share

169、 we envision is a 20%total in such subsidiaries withapproximately 10%to the institution and approximately 10%to the researchers,a significantly higher stake than they would typically be able to hold in astartup venture.We believe institutions and their researchers will prefer Ocean Biomedical to lau

170、nching a startup because Ocean Biomedical eliminates thechallenge of needing to raise capital and hire a team,and provides a greater share in the upside.Likewise,we believe Ocean Biomedical will be a preferredchoice as opposed to licensing to large pharmaceutical companies because receiving a percen

171、tage of any economic value,regardless of how it is derived,isoften more attractive than relying on fixed milestone payments or single-digit royalties.We believe our approach will give us preferred access to innovations at research universities and medical centers,and that this in turn will benefitou

172、r shareholders.Our Pipeline Funnel Process Our core competencies for acquiring and developing pipeline programs include:(1)identifying,assessing and selecting inventions andtechnologies(from research universities and medical centers)that we may directly or indirectly license and commercialize;(2)in-

173、licensing selectedinventions and technologies;and(3)developing those inventions and technologies into potential therapeutic products aimed at addressing unmet medicalneeds.Step One:New Program Identification,Assessment and Selection Our close relationships with research universities and medical cent

174、ers,along with their individual researchers,technology transfer offices,accelerator programs and entrepreneurship centers,provide us with access to biomedical inventions and technologies that we may directly or indirectlylicense and commercialize.Our multi-disciplinary Opportunity Assessment Committ

175、ee,or OAC,is responsible for new program identification,assessmentand selection and for ensuring adherence to our due diligence process.The OAC is expected to be comprised of Dr.Jonathan Kurtis(Scientific Co-founder),Elizabeth Ng(Chief Executive Officer),Daniel Behr(Executive Vice President,Head of

176、External Innovation and Academic Partnerships andSecretary),Sharon Talcott(Vice President of Strategic Partnerships),and Gurinder Kalra(Chief Financial Officer and Treasurer).The OAC applies ourdisciplined and rigorous due diligence process to identify,assess quantitatively,and select those inventio

177、ns and technologies based on criteria we believeensures that each asset selected to enter our pipeline is consistent with our mission and commercialization objectives.Our criteria are listed below,and wescore and weigh each criterion through a combination of data analytics,experience and judgment.Ro

178、bust and verifiable science that can lead to predictable outcomes Well-characterized mechanisms with potential to be disease modifying Development path with timely and achievable milestones/value inflection points Solid and dominating intellectual property/patent position Knowledge transfer assuredn

179、ess(inventors available and approachable)Potential for multiple products/applications Potential to address significant unmet medical needs Product advantages that are“must-haves”for patients,practitioners,and payors Manufacturing and scale-up feasibility Attractive market/competitive dynamics Favora

180、ble pricing and reimbursement with good gross margin potential 12 Step Two:Executing License Agreements After a new program is selected via the process outlined above,or in some cases as part of the selection process,we endeavor to negotiate andexecute a license agreement with the relevant universit

181、y or medical center.Our team has negotiated and executed dozens of such license agreements,bothas licensee and as licensor.As mentioned previously,we believe our business model may make us the licensee of choice for institutions and researchers because we aim toact with greater speed and to provide

182、better potential upside when compared to the companies or spin-out startups to whom the institution might alsoconsider licensing.In particular,by housing each program in a subsidiary,we can grant a certain percentage of that subsidiarys ownership(targeting 20%in aggregate)to the institution and to t

183、he relevant researchers.We believe that receiving such percentage of economic value,regardless of how it is derived,will be more attractive to the institution than relying on the fixed milestone payments and single-digit royalties that are customary in other licenseagreements.Additionally,we believe

184、 that individual researchers will find it more attractive to have a direct stake in a programs economic value as opposedto receiving a share(typically one third)of whatever economic value their institution would receive in customary license agreements.Lastly,we believeinstitutions and their research

185、ers will prefer our approach over launching a startup because we eliminate the challenge of raising venture capital andsecuring a team,and because the percent equity ownership we can offer is likely to be higher than the single-digit figures that usually result after the typicaldilution in startups.

186、By offering a percentage ownership in a programs subsidiary in lieu of the alternative license fees,milestone payments and royalties,we believeour license agreements(and the associated negotiation)will be greatly simplified while also being more attractive to our licensors and their individualresear

187、chers.Step Three:Product Development,and Commercialization We are an asset-focused company with an operating model designed for agile,capital efficient,and scalable therapeutic product development.Wehave a structure wherein Ocean Biomedical houses each drug development program or therapeutic platfor

188、m in a subsidiary.Each of these programs mayinclude multiple product candidates or assets.This structure helps to ensure that we align interests and that we gain access to the particular programsscientific expertise and know-how.The results and outcomes of one subsidiary do not directly affect other

189、s,and because our subsidiaries(or assets)aredecoupled,success is not dependent on any one particular asset.We can thereby evaluate each assets preclinical,translational and clinical developmentprogress objectively,which we believe enables us to allocate resources and capital throughout our portfolio

190、 based on each assets evidence-based progressand continued scientific and commercial merits.The continued merits of an asset are periodically assessed using some or all of the criteria outlined abovewhich we use to assess potential new programs.We are agnostic as to which assets deliver success and

191、believe this allows us to maintain focus on thosewhich continue to show most potential.Our product development and commercialization process reflects the disciplined and objective asset-centric philosophy described above.Thisprocess has the following features:Evidence-based and science-driven decisi

192、on making at each stage of translational and clinical development:For each productcandidate,key milestones or decision points are set based on their ability to validate technical and commercial viability,and feasibility,asviewed from industry and regulatory lenses.We support each product candidate w

193、ith the interdisciplinary expertise and resources to reachthese key decision points.We review progress on an on-going basis and constantly re-assess whether the program warrants continuedinvestment i.e.,we recognize the dynamic nature of these product candidates and we re-evaluate them based on deve

194、lopment progress,risk factors,and market dynamics.Lean and agile translational development operations:Each program is managed by our centralized team of experienced productdevelopment leaders who enlist the support of relevant external resources including CROs,CMOs,domain experts,consultants,etc.Web

195、elieve this approach is most cost-effective for clinical and commercial development and that it allows us to minimize overhead whilegiving us the flexibility to tap into the most relevant and current talent for each program without having to rely on large teams ofpermanent hires.13 In addition,our R

196、esearch Review Committee,or RRC,which is expected to be comprised of Dr.Jack A.Elias(Scientific Co-founder),Dr.Jonathan Kurtis(Scientific Co-founder),Elizabeth Ng(Chief Executive Officer),and Dr.Inderjote Kathuria(Chief Strategy Officer)will be responsible forthe research,translational and preclinic

197、al efforts leading to filing an IND and moving a product candidate into human clinical trials.Our Development Review Committee,or DRC,which is expected to be comprised of Dr.Jonathan Kurtis(Scientific Co-founder),Elizabeth Ng(Chief Executive Officer),and Inderjote Kathuria(Chief Strategy Officer)wil

198、l be responsible for managing all clinical development efforts,includingprogress monitoring,allocation of resources,and continuous re-evaluation of a product candidates merits.Both these committees will work in collaboration with our OAC described previously to ensure that each product candidate tha

199、t enters ourpipeline as well as existing ones continue to meet the criteria we have outlined above.Our Therapeutic Programs Oncology Product Candidates for NSCLC and GBM Our oncology product candidates for NSCLC and GBM:OCX-253 anti-Chi3l1 Single-target mAb(NSCLC)OCX-410 anti-Chi3l1/PD-1 Bi-specific

200、 antibody(NSCLC)OCX-909 anti-Chi3l1/CTLA-4 Bi-specific antibody(GBM)Our product candidates in our oncology program are based on a drug target pioneered by Dr.Elias.His research demonstrated that a protein calledchitinase 3-like-1,or Chi3l1,is a key driver of multiple disease pathways in primary and

201、metastatic tumor development demonstrating an 85-95%reductionin primary and metastatic tumor burden in multiple animal models.Animal models of lung cancer and glioblastoma,a type of brain cancer,showed thatinhibition of Chi3l1 resulted in statistically significant tumor reduction even more so when c

202、ombined with immunotherapies to stimulate the bodys ownimmune response against cancer.Our oncology development pipeline consists of:(a)an antibody therapeutic product candidate inhibiting Chi3l1;(b)a bi-specific antibody product candidate inhibiting Chi3l1 plus PD-1,a checkpoint inhibitor protein;an

203、d(c)a bi-specific antibody product candidate inhibitingChi3l1 plus CTLA-4,another checkpoint inhibitor protein.These product candidates are targeting non-small cell lung cancer,or NSCLC,which accountsfor about 85%of all lung cancers globally and affects about 460,000 people in the United States and

204、595,000 people in Europe,and glioblastomamultiforme,or GBM,a brain cancer that kills approximately 60%of patients within 12 to 18 months from the time of diagnosis and for which newtreatment therapies are needed.Non-Small Cell Lung Cancer Lung cancer is the most common cancer worldwide,accounting fo

205、r 2.1 million new cases and 1.8 million deaths in 2018.In the United States,lung cancer is the third most common and the deadliest malignancy.Approximately 541,000 people in the United States today have been diagnosed withlung cancer at some point in their lives.It is estimated that 229,000 new case

206、s of lung cancer are diagnosed annually in the United States,representingabout 13%of all cancer diagnoses.NSCLC is the most common type of lung cancer,accounting for approximately 85%of new lung cancer cases.14 NSCLC continues to rank among the cancers with the lowest five-year survival rates and ha

207、s one of the largest disease burdens in terms ofdisability-adjusted life years.Staging is a way of describing the severity and extent of a cancers growth and spread.The stage of NSCLC is based on a combination of severalfactors,including the size and location of the primary tumor and whether it has

208、spread to the lymph nodes and/or other parts of the body.There are five stages for NSCLC:stage 0 and stages I through IV.In general,an earlier stage of NSCLC is linked with a better outcome.Unfortunately,a significant proportion of patients,in the order of 40%to 50%,are still diagnosed with hard-to-

209、treat stage IV disease.There are currently five main ways to treat NSCLC:surgery,radiation therapy,chemotherapy,targeted therapy and immunotherapy.The use ofthese treatment options for NSCLC is based mainly on the stage of the cancer,but other factors,such as a persons overall health and lung functi

210、on,as wellas certain traits of the cancer itself,such as its molecular characteristics,are also important.Treatment decisions often follow either formal or informal guidelines.Treatment options can be ranked or prioritized into lines of therapy:first-line therapy,second-line therapy,third-line thera

211、py,and so on.First-line therapy,sometimes called induction therapy,primary therapy or front-line therapy,is the first therapy that will likely be attempted.If a first-line therapy either fails to produce sufficient antitumor response or produces intolerable sideeffects,additional therapies may be su

212、bstituted or added to the treatment regimen,known as second-line or third-line treatments.Often,multiple therapiesmay be administered simultaneously,known as combination therapy or polytherapy.Surgery is usually the first choice for early stage disease followed by radiation and chemotherapy.Targeted

213、 therapies and immunotherapy are themain options in advanced disease,in stages III and IV.Targeted therapy is a treatment that targets the cancers specific genes,proteins or the tissue environment that contributes to cancer growth andsurvival.This type of treatment blocks the growth and spread of ca

214、ncer cells and limits damage to healthy cells.Immunotherapy is designed to boost the bodys natural antitumor immune defenses.Lung cancers often contain genetic mutations that are seen as“non-self”by the hosts immune system because they are not seen in normal cells and tissues.The human immune system

215、 is designed to attack andeliminate cells and tissues that it detects as foreign or“non-self.”However,in many patients with cancer these desired antitumor responses are suppressedby the tumor and surrounding cells.This is done by activating one of a number of immune checkpoint inhibitor pathways,or

216、ICPI pathways.An example of the multiple ICPI pathways that have been discovered that has received significant attention in lung cancer is the programmeddeath-1/PD-ligand 1,or PD-1/PD-L1,pathway.In many patients with lung cancer,the immune cells and nearby cells,such as macrophages express,PD-1and t

217、he tumor cells express its binding partner PD-L1.When PD-L1 binds PD-1,it activates pathways that suppress the hosts antitumor immune response.On the other hand,therapeutics(usually antibodies)have been developed that prevent these PD-1/PD-L1 interactions.These therapies boost the hostsantitumor res

218、ponses which augments its ability to attack the tumor.Because there are multiple ICPI pathways,assays that determine which pathway(s)isactivated in a given tumor have been and are being developed.This allows the therapeutic intervention to be directed to the ICPI pathway that is mostimportant in a g

219、iven individual.Importantly,immunotherapy has been generally regarded as revolutionizing the treatment of NSCLC,with immunotherapies targeting the PD-1/PD-L1 pathway now emerging as standard-of-care in some settings.However,despite the advent of these new therapies for NSCLC,there continues to bea n

220、eed for other therapeutic options because only approximately 15%of patients respond to these interventions.In addition,among those that initiallyimprove,the responses are often not durable and diminish over time.In many cases,tumors evolve compensatory mechanisms that circumvent thebeneficial effect

221、s of an individual immunotherapy.Thus,a significant unmet medical need in NSCLC are treatment options that either restore orcomplement,the efficacy of anti PD-1/PD-L1 and other ICPI-based therapies.15 A general overview of immunotherapy and antibodies is presented below under the caption“A Primer on

222、 Antibodies,Antigens and TargetedTherapies.”We believe that OCX-253,our mono-specific mAb against Chi3l1,if approved,will likely be used individually or in combination withimmunotherapies,such as anti-PD-1 therapeutics.Our belief is based on the observation that OCX-253 modulates multiple oncogenic

223、pathways,orsignaling networks used by cancer cells to control the growth and progression of tumors,in addition to its ability to modulate ICPI pathways.Should OCX-253 become a marketed treatment,we would anticipate it being initially used primarily in later-stage cancers,as with most recently approv

224、ed oncologytherapeutics.OCX-253 may progress towards being used for earlier stage cancers,and/or in combination with other medications,as clinician andregulatory agency experience with the drug grows and as our understanding of the needs of individual patients deepens.OCX-410,our bi-specific antibod

225、y,is designed to combine the mechanism of actions of OCX-253 and anti-PD-1 therapeutics.We believe this is apromising combination because studies by Dr.Elias have demonstrated that this bi-specific antibody recruits immune cells,such as CD8+cytotoxic T cellsthat kill tumor cells,and the physical int

226、eraction of these activated T cells to tumor cell membranes.If approved,we anticipate that OCX-410 will likelyenter the market as a second-line therapy in patients with stage III or IV lung cancer who have failed anti PD-1/PD-L1 immunotherapies.We believe thatOCX-410 may eventually be used as a firs

227、t-line treatment for patients with later stage NSCLC.Glioblastoma Multiforme GBM is an aggressive type of cancer that can occur in the brain or spinal cord,the components of the central nervous system,or CNS,and is themost common brain tumor in adults.GBMs are a type of astrocytoma,meaning that they

228、 arise from the star-shaped cells,known as astrocytes,in the CNS.Normally,these cells form a key component of the blood brain barrier,or BBB,a network of cells,proteins,and structural components that controls whichsubstances can get into the central nervous system,or CNS,and which cannot.Astrocytes

229、also normally help support nerve cells and carry nutrients tothem.Brain tumors are graded on an I to IV scale based on how fast they grow.Grade I brain tumors are the least aggressive.They grow very slowly andrarely spread into nearby tissues.Grade IV are the most aggressive.GBMs are grade IV astroc

230、ytomas.They grow quickly and often spread into nearbybrain tissue.They rarely metastasize or spread to other parts of the body.GBM is a rare disease,with a prevalence of 1-9 out of 100,000 individuals.The prevalence in the United States is estimated to be approximately28,000 diagnosed individuals,an

231、d the annual incidence is estimated to be between 6,000 and 10,000.Primary GBM accounts for 90%of cases,mostlyoccurring in older individuals,while secondary GBM develops more slowly and occurs in relatively younger patients.No curative therapies exist for GBM and the treatment landscape has not chan

232、ged in recent years.A significant proportion,approximately 25%,ofthe GBM prevalent population is not actively treated due to rapid disease progression and an extremely poor prognosis.Surgery is standard-of-carefollowed by radiation and follow-up with chemo.If that does not work,then physicians may t

233、ry a second line approach,such as switching chemomonotherapies.However,these second line therapies are rarely effective.Our bispecific antibody candidate,OCX-909,is designed to combine the mechanism of actions of OCX-253 with an anti-CTLA-4 component.CTLA-4 is a protein receptor that functions as an

234、 immune checkpoint that binds to molecules called B7.1 and B7.2 to suppress antitumor immuneresponses in a manner similar to PD-1.We believe OCX-909 may produce antitumor response particularly in GBM because CTLA-4 is expressed in anexaggerated manner in many GBM tumors.If approved,we envision OCX-9

235、09 being potentially utilized as an alternative to surgery,or in the treatmentregimen in both the neoadjuvant(before surgery)and adjuvant(after surgery)settings for patients with GBM.16 A Primer on Antibodies,Antigens and Targeted Therapies One way the bodys immune system attacks foreign substances

236、is by making large numbers of antibodies.An antibody is a protein that binds to aspecific antigen.An antigen is a molecule that is foreign to the human body;examples include viruses,bacteria,and tumor cells.Antibodies have a distinct“Y”shape.Each upper arm of the“Y”is uniquely structured to bind to

237、a specific part of a particular antigen,called anepitope.Once bound to the antigen,an antibody triggers other parts of the immune system to destroy the cells containing the antigen.Monoclonal antibodies,or mAbs,are antibodies that are designed and made as therapeutics to bind to specific antigen tar

238、gets such as those presentin a particular type of cancer cell,virus,or other pathogen.When mAbs are used in this manner they are referred to as targeted therapies.Therapeuticantibodies can also be engineered to recognize two epitopes simultaneously,making them“bispecific.”Bispecific antibodies,or Bs

239、Abs,can bind directly tosurface antigens to kill the cells containing the antigens and they can also help ramp up the immune system to make it more effective against those cells.The Chitinase Biology Behind Our Oncology Project Candidates Dr.Elias has focused a significant amount of his research ove

240、r the last decade on a gene family called the 18 glycosyl hydrolases and its chitinaseand chitinase-like proteins,or CLP.The chitinases and CLP both bind chitin,a polysaccharide that is a major structural component of the exoskeletons ofinsects and other arthropods and the cell walls of fungi.The ch

241、itinases are true enzymes that cleave chitin into smaller saccharide units.In contrast,theCLPs bind to but do not cleave chitin.Chitin,Chitinases,and Chitinase-Like-Proteins Chitinase-3-like-1,or Chi3l1,also known as YKL-40,the prototypic CLP,was initially described as a soluble product of an osteos

242、arcoma cell lineand has since been found in several different laboratory cell lines and animal tissues.In humans,Chi3l1 is found on the cell surface,inside cells and in thecirculation.It plays a major role in tissue injury,inflammation,tissue repair and remodeling responses in healthy individuals.It

243、 is produced by a variety ofcells including epithelial cells and macrophages in response to cytokines,lipids,oxidant injury and other stimuli.It then feeds back to inhibit tissue injuryby inhibiting cell death and apoptosis while stimulating fibroproliferative repair.The levels of circulating and ti

244、ssue Chi3l1 are increased in many human visceral cancers and animal tumor models including lung cancer andglioblastoma.In visceral tumors elevated serum levels of Chi3l1 correlate with a poor prognosis and shorter disease-free intervals and survival.Studies inanimal models have also demonstrated tha

245、t the inhibition of Chi3l1 can dramatically reduce tumor burden.Consequently,Chi3l1 is now appreciated to be asensitive biomarker and an attractive therapeutic target for these malignancies.We intend to take advantage of both of these properties because theinhibition of Chi3l1 is a major focus in OC

246、X-253,410 and 909,and we intend to use Chi311s properties as a biomarker to identify relevantpopulations for clinical trials of these product candidates.17 Chi3l1 interacts with several different cell-surface proteins to mediate its cell and tissue responses.Studies by Dr.Elias and others havedemons

247、trated that Chi3l1 binds to and signals via a number of cell surface receptors(proteins that pass signals between the outside and inside of cells)including the interleukin-13 receptor-2 and CRTH2.They have also demonstrated that IL-13R2 is the alpha subunit of multimeric receptor complexesthat can i

248、nclude galectin 3 and CD44 as subunits.Chi3l1 can also interact with receptor tyrosine kinases,integrins V3 and V5/syndecan 1complexes,and the receptor for advanced glycation end products.These receptors activate a number of signaling pathways including MAPK kinases,Protein Kinase B/Akt and the Wnt/

249、-catenin pathways and induce the production of VEGF intermediaries.As a result of these complex receptor-ligandinteractions it is now known that Chi3l1 regulates oncogenesis via a number of mechanisms.Dr.Elias has demonstrated that Chi3l1 stimulates malignantresponses by inhibiting tumor cell death,

250、stimulating tumor cell proliferation,stimulating the B-Raf protooncogene,and stimulating the phosphorylation ofcofilin.He has demonstrated that Chi3l1 also inhibits key antineoplastic pathways including those mediated by the tumor suppressors phosphatase andtensin homolog,or PTEN,and p53 thereby rem

251、oving intracellular controls against unregulated cell growth.These molecules taken together form the tumormicroenvironment,a localized set of conditions that supports the evolution and growth of tumors.In summary,Chi3l1 contributes to neoplasia,or the uncontrolled and abnormal growth of cells or tis

252、sues that is the hallmark of cancer,byregulating various pro-and anti-oncogenic pathways as shown in the illustration below:Chi3l1 and its Roles in Disease Biology Dr.Elias and other investigators have also found a direct link between Chit1 and fibrotic diseases,such as IPF and HPS.This finding is t

253、he basisfor our anti-Chit1 small molecule therapeutic product candidate,OCF-203,detailed later.18 OCX-253Anti-Chi3l1 mAb for Lung Cancer Recent published studies have demonstrated that the levels of circulating Chi3l1 are elevated in many malignancies including cancers of theprostate,colon,rectum,ov

254、ary,kidney,breast,as well as GBM and malignant melanoma.In these diseases,the levels of Chi3l1 frequently correlate directlywith disease progression and inversely with disease-free interval and survival.This is particularly striking in lung cancer where preclinical and clinicalstudies demonstrated t

255、hat the serum and tissue levels of Chi3l1 are increased and are associated with adverse outcomes,such as poor prognosis and shortersurvival.Dr Elias and colleagues have found that Chi3l1 plays a critical role in the pathogenesis of primary and metastatic lung cancer in murine modelsthat have the sam

256、e genetic mutations that are seen in human disease including activating mutations of the K-Ras oncogene.In murine models primary lungcancer is induced in mice that have activating mutations of Kras(the G12 D mutation)and null mutations of the tumor suppressor p53.Dr Elias andcolleagues have addition

257、ally demonstrated that Chi3l1 is able to replace null mutations of p53 in the generation of primary lung cancer in murine modelsthat only have activating mutations of the K-Ras oncogene.They also demonstrated that Chi3l1 is induced during pulmonary melanoma and pulmonarybreast cancer metastasis in m

258、urine models of these diseases and that Chi3l1 induction is required for the generation of a metastasis permissive pulmonarymicroenvironment.As shown below,both primary tumor growth and metastatic spread were both significantly inhibited via immune inhibition of Chi3l1using therapeutic antibodies(Fi

259、g.1).These antibody findings are the basis for Ocean Biomedicals OCX-253 program in NSCLC.We plan to initiallyfocus on a subset of patients who exhibit elevated levels of circulating Chi3l1 as they are anticipated to be the patient population most likely to respond tothis product candidate.However,t

260、he treatable patient population may eventually expand as a consequence of the many critical pathways OCX-253 appearsto impact(as described and shown in the figure above)and as our understanding of chitinase biology grows.Figure 1:In Animal Models,Antibodies Against Chi3l1 Show Reduction in Primary a

261、nd Metastatic Tumors OCX-410 and OCX-909Anti-Chi3l1/PD-1 and Anti-Chi3l1/CTLA-4 Bispecific Antibodies for NSCLC and GBM Novel immunotherapeutic approaches have improved the prognosis for a number of cancers over the past decade.Cancer cells have unstablegenomes and as a result accumulate genetic mut

262、ations that are not seen in normal cells and tissues.These non-self mutations generate non-self proteins thatcan be recognized and reacted to by the immune system.Normal white blood cells,particularly T lymphocytes,learn to recognize these novel antigens andkill the cells that express them.Under nor

263、mal circumstances,immune responses are activated to deal with pathogens and non-self antigens but are theninhibited to prevent overexuberant,injury-inducing,immune responses.This immune inhibition is often mediated by immune checkpoint inhibitorpathways.Unfortunately,some tumors evolve to take advan

264、tage of these regulatory pathways to evade endogenous antitumor immune responses.Forexample,tumor cells may produce the regulatory protein cell death ligand 1,or PD-L1 or cluster of differentiation proteins 80 or 86.These proteins interactwith their corresponding receptors on T cells,PD-1 and CTLA-4

265、,respectively,to turn off the immune system response to the cancer.Multiple approvedimmunotherapies disrupt the connection between PD-1 or CTLA-4 and their ligands to restore immune activity against susceptible cancers.19 Dr.Elias has demonstrated in widely accepted mouse models of fibrosis that PD-

266、1 and its ligands,PD-L1 and PD-L2,are induced in melanomametastases by Chi3l1,and that Chi3l1 can stimulate these checkpoint inhibitors,thereby encouraging tumor growth.Further work by Dr.Elias hasdemonstrated that bispecific antibodies that bind to both Chi3l1 and PD-1(or CTLA-4)dramatically improv

267、e the responses seen in cocultures of T cellsand tumor cells with more tumor cells undergoing cell death when treated with the bispecific antibody than cells treated with mono-specific antibodiesagainst the same targets,either individually or in combination(Fig.2).These studies also demonstrated tha

268、t these effects were mediated by an enhancedinduction of CD8+cytotoxic T cells that kill the tumor cells and an enhanced ability of these cytotoxic cells to bind to tumor cell membranes in culturestreated with the bispecific antibody compared to cultures treated with mono-specific antibodies against

269、 the same targets,administered either individually orin combination.These observations suggest that the proximity of the Chi3l1 and PD-1(or CTLA-4)targets in the tumor microenvironment play a role intheir vulnerability to this precision immunotherapy 9(Fig.3).Thus,we hypothesize that even patients w

270、hose tumors have been resistant to anti-PD-1 oranti-CTLA-4 antibody therapy may benefit from our bi-specific antibody product candidates that are designed to bind both Chi3l1 and immune checkpointtargets simultaneously.These bi-specific antibodies against Chi3l1 and PD-1 or CTLA-4 are the basis for

271、our OCX-410 and OCX-909 programs,respectively.Figure 2:In vitro Experiments Show Improved Killing of Glioblastoma Tumor Cells with OCX-909 Bi-Specific Anti-Chi3l1/Anti-CTLA-4 Antibody.*=p0.01 Figure 3:Mechanism of Action of OCX-410 We are planning to initially target checkpoint inhibitor positive NS

272、CLC with OCX-410 and GBM with OCX-909 due to the previously publishedimportance of these checkpoint inhibitors for these tumor types as well as Dr.Elias supporting data in preclinical models of these diseases.We intend toevaluate whether checkpoint inhibitor upregulation is critical for the activity

273、 of OCX-410 and OCX-909 in humans,and we intend to evaluate the responseseen in checkpoint inhibitor negative patients as well.The outcome of these studies may help us to better identify our potential target patient population.20 Oncology Product Candidates Clinical Development Plan All three therap

274、eutic antibody product candidates,OCX-253,OCX-410,and OCX-909,have been optimized against their respective targets,andwe are beginning efforts to develop,through the establishment of manufacturing and supply relationships with third parties,a production system capable ofsupporting clinical use.A cri

275、tical step in production is the creation of a master cell bank,or MCB,a depository where genetically identical antibody-producing cells are stored,by a CMO.The MCB is critical for production of consistent therapeutics through clinical development and,potentially,commercial production.We have collabo

276、rated on the first steps of MCB production for OCX-253 with Lonza Group AG,a global contract manufacturingorganization and have completed development of 8 research cell lines that produce OCX-253 in February 2021.Initial assessments indicate that any ofthese cell lines could possibly be used to gene

277、rate clinical and commercial grade OCX-253.Additional evaluations are under way to determine which of the8 cell lines is preferred for the generation of the cGMP MCB and the generation of clinical drug material.We anticipate producing sufficient drug materialto begin IND-enabling safety studies in 2

278、H 2023.The OCX-410 and OCX-909 programs are expected to begin MCB generation in 2H 2023/1H 2024.Weanticipate filing IND applications with the FDA for product candidates in 2023/2024.We intend to model our Phase 1/2 clinical trials of OCX-253 and OCX-410 after Mercks pembrolizumab KEYNOTE-001 trial(N

279、CT01295827).This design is expected to allow for combined initial safety and efficacy endpoints using a single ascending dose,or SAD,strategy followed by a repeatdose regimen to identify tumor responses through generally accepted Response Evaluation Criteria in Solid Tumors,or RECIST,criteria and ti

280、me to tumorprogression.Using RECIST criteria as the primary endpoint of the initial clinical trial will measure whether tumors shrink in response to treatment andallows for a relatively quick determination of whether our product candidates are likely to provide benefit in a larger,more extensive piv

281、otal trial.The timeto the tumor progression endpoint will likely be a secondary endpoint in these first trials but is the generally accepted primary endpoint for registrationaltrials in NSCLC.GBM The OCX-909 program for GBM has the additional challenge of successfully delivering the protein therapeu

282、tic product candidate to the brainwhere the Blood Brain Barrier or BBB has questionable permeability.The BBB is a stretch of less-permeable blood vasculature in the CNS,as compared tothe rest of the body.Its purpose is to carefully screen the entry and exit of molecules between the CNS and bloodstre

283、am.The BBB is a difficult hurdle tocross using small molecules delivered to the periphery,and consistent peripheral delivery of protein-based therapeutics,such as antibodies,to the brain hasso far been elusive.Patients suffering from GBM may have a partially disrupted BBB due to changes in the vascu

284、lature associated with the tumors or theirrecent surgery,but the inconsistency of these disruptions may add considerable challenge to the development of a peripherally delivered medicament.We plan to bypass the BBB using a number of approaches,alone or in combination.The first approach is intracereb

285、ral-ventricular,or ICV,delivery of OCX-909.We intend to make use of a port-reservoir system,such as an Ommaya reservoir,which is a small,plastic,coin-shaped device placedunder the scalp and connected to a catheter placed in one of the brains ventricles.This would allow direct delivery of OCX-909 int

286、o the cerebral spinalfluid,or CSF,pool in the ventricles at the center of the brain.The size of the ICV space changes throughout the day,particularly during sleep,effectivelypumping CSF,and the drug it contains,throughout the brain.Though placement of an Ommaya reservoir is somewhat invasive,it is f

287、requently used inpatients suffering from brain cancers,and we anticipate many of our patients will likely already have one in place.We intend to model our Phase 1/2 clinical trial after the Phase 1/2 clinical trial of Johnson and Johnsons Zarnestra sponsored by M.D.AndersonCancer Center(NCT00050986)

288、.The envisioned clinical trial plan involves a dose escalation SAD/multiple ascending dose,or MAD,strategy followed bycontinued assessments of safety parameters and efficacy using six-month progression free survival as the primary endpoint.We anticipate also monitoringtumor size during this trial us

289、ing radiology techniques in the interest of acquiring efficacy data more rapidly than the primary endpoint is likely to provide.21 Our Phase 3 clinical trial for OCX-909 is tentatively planned to follow the example of Mercks CENTRIC trial of Cilengitide(NCT00689221).The CENTRIC trial used overall su

290、rvival as the approval endpoint leading to a study duration over five years.We intend to continue to work with theoncology community to develop novel validated biomarkers,which could allow for accelerated trials in GBM.We are optimistic that these novel tools mayallow for accelerated trials in the G

291、BM space which could speed the transition of OCX-909 to the market.We intend to seek orphan drug designation forOCX-909 in GBM and may also request priority review.Fibrosis Product Candidate for IPF and HPS:OCF-203 anti-Chit1 Small Molecule Overview of Fibrotic Diseases An important protective mecha

292、nism for tissue regeneration and wound healing is the formation of extracellular matrix,or ECM,a non-cellularportion of a tissue produced and secreted by cells and functions mainly to provide support for tissues.Fibrosis is a pathologic condition where an excessive accumulation of ECM leads to organ

293、 disfunction and failure.Fibrotic diseases constitute amajor health problem worldwide and encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis,or SSc,scleroderma and nephrogenic systemic fibrosis,as well as numerous organ-specific disorders i

294、ncluding pulmonary,cardiac,liver and kidney fibrosis.The United States government estimates that 45%of deaths in the United States can be attributed to fibrotic disorders.Fibrosis is a factor invarious tissue and organ diseases as shown in the figure below.Figure 4 Idiopathic Pulmonary Fibrosis IPF

295、is a chronic,progressive,and fibrotic interstitial lung disease of unknown cause,which occurs primarily in older adults.It results inirreversible loss of lung function with high morbidity and mortality rates.Median survival is three-to-five years following diagnosis.22 IPF is a rare disease with an

296、estimated prevalence ranging from 10-to-60 per 100,000 in the United States and 1.3 to 32.5 per 100,000 in Europedepending on country,age,and risk factors.There is an estimated prevalence of approximately 160,000 in the United States,with most cases occurring inindividuals over the age of 50 years.T

297、he United States incidence rate is approximately 55,000 cases per year,and the incidence is rising due to a growingelderly population and increased disease awareness and detection.In practice,patients are diagnosed and categorized into three categories,as shown below,based on disease severity:mild,m

298、oderate,and severe.Their disease may be characterized based on two lung function measures:FVC,or forced vital capacity,and diffusing capacity of the lung for carbonmonoxide,or DLCO,Figure 5 Current therapeutic standard-of-care utilizes Roches Esbriet(pirfenidone)or Boehringers Ofev(nintedanib).Pirfe

299、nidone and nintedanib slowpulmonary function loss with only modest deceleration of disease progression and no reversal,and their severe side effects(e.g.,nausea,vomiting,diarrhea)cause many patients to avoid or discontinue these therapies.These drugs are primarily used in the moderate patient segmen

300、tboth mild andsevere patients view the negative side effect profile as outweighing the benefits.Despite the side effects,it is estimated that approximately 58%of patientsdiagnosed with IPF take one of these therapeutics and,together,they generated global sales of approximately$3.0 billion in 2019.We

301、 believe that atherapy with even a modest improvement in side effect profile would likely see more utilization.Hermansky-Pudlak Syndrome HPS is a rare,inherited genetic disorder which occurs when a child inherits defective genes from both parents.Although HPS is ultra-rare from aworldwide perspectiv

302、e,it has a much higher prevalence in Puerto Rico where the prevalence is roughly 1 in 1,800 in the northwest region of the island,oran estimated 1,500 patients,accounting for more than 50%of the worldwide HPS population.HPS effects approximately 1 to 9 people per 1 millionindividuals worldwide outsi

303、de of Puerto Rico.The disease onset occurs as early as age 30,and the lifespan of patients with some of the most severe diseasesubtypes usually does not exceed 40 to 50 years.HPS is diagnosed through a combination of identifying signs of albinism,evaluation of patient blood,and/or genetic testing;ho

304、wever,early diagnosis of PF in HPS patients presents the same challenges as IPF diagnosis.There is an unmet need for therapeutics to treat HPS-related pulmonary fibrosis,or HPS-PF,patients.There is no approved drug therapy,and notreatment except potential lung transplantation.The only pharmacologica

305、l option for patients is off-label use of Esbriet,which may slow diseaseprogression but only in patients who retain significant residual lung function.Published clinical studies of Esbriet and Ofev suggest that bleeding is morelikely with Ofev,so its use is generally avoided in the HPS patient popul

306、ation.23 We believe that OCF-203,if approved,has potential to address the need for a HPS therapeutic due to its novel therapeutic approach.It is also ourbelief that developing this product candidate for HPS may allow us to enter the broader fibrotic disease space in an expedited manner by pursuing a

307、n ultra-rare disease indication before potentially broadening to adjacent indications.The Chitinase Biology Behind Our Fibrosis Product Candidate Previously,we described Dr.Elias research on chitinase enzymes and CLP,and his discovery of the key role that a CLP called Chi3l1 plays incancer.Dr.Elias

308、also discovered that a chitinase called Chit1,also known as chitotriosidase,plays a central role in inflammation and in fibrotic diseasessuch as IPF and HPS.Chit1 is expressed in an exaggerated manner in IPF where it correlates inversely with Smad 7.Chit1 is also a critical biomarker andtherapeutic

309、target in Scleroderma-associated interstitial lung disease.This finding is the basis for our anti-Chit1 small molecule therapeutic productcandidate,OCF-203.OCF-203Small Molecule Candidate for IPF and HPS In animal models,Dr.Elias and his colleagues showed that Chit1 is a master regulator of transfor

310、ming growth factor beta 1,an extensively-published biochemical pathway relevant to inflammation,tissue modeling,and fibrosis,and that it mediated fibrosis response through various mechanismsdescribed below.Animal models of IPF exhibit similar pathology to that of humans,allowing for relevant testing

311、 of molecular mechanisms and potentialtherapeutics in these models.Transgenic laboratory animals developed in the Elias laboratory to over-express Chit1 were shown to be far more susceptibleto lung fibrosis than their wild type counterparts,which further demonstrates the role of Chit1 as a factor in

312、 IPF.Using high throughput screening,Dr.Elias identified a small molecule candidate for the OCF-203 program that prevented and reducedinflammation and fibrosis in the bleomycin mouse model of IPF(Fig.5).Importantly,the molecular mediators of fibrosis,fibronectin,Col1A1,andCol3A1,were also substantia

313、lly reduced in the IPF model animals that had received the OCF-203 candidate.Results were similar in a mouse model of HPS(Fig.6),suggesting that the OCF-203 molecule could benefit this patient population as well.The biochemical pathways known to be impacted by Chit1inhibition imply that there may be

314、 benefit of this product candidate for the potential treatment of other fibrotic diseases such as non-alcoholic-steatohepatitis,or NASH,and lysosomal storage disorders.Figure 6:OCF-203 Lead Candidate Treatment Reduces Observed Markers of Fibrosis in an Animal Model of IPF 24 Figure 7:OCF-203 Lead Ca

315、ndidate Treatment of the Bleomycin HPS-1 Mouse Model results in Normalized Levels of Fibrotic Markers No significant toxicity has been observed at therapeutic doses in the animal studies with the OCF-203 lead to date.This candidate molecule hasbeen previously evaluated(by unrelated parties)in Japan

316、in the mid-1960s for potential use as an antibiotic though approval was never pursued.Whilethe clinical data from these studies is not suitable for current regulatory filings,we believe it may support the safety observations seen in Dr.Elias recentanimal studies and also provides invaluable informat

317、ion as to the behavior of this molecule and its derivatives that we can potentially use in the design offuture clinical development work.Additionally,we believe OCF-203s safety observations in animal studies may be further supported by past publishedliterature which estimates that 6%of humans do not

318、 produce Chit1 and,though they may be more susceptible to infection by chitin-containing parasites,this deficiency may provide greater longevity and reduced age-related disease burden as compared to people who produce Chit1 normally.Taken together,these findings suggest that therapies that focus on

319、inhibiting Chit1 may be well tolerated in patients.This is of import to IPF and HPS given that there areno currently approved drug therapies for HPS,and the currently approved therapies for IPF,pirfenidone and nintedanib,both carry a significant risk ofsevere side effects,as described previously.Fib

320、rosis Programs Clinical Development Plan We have identified opportunities in the structure of OCF-203 that we believe may be able to improve the expected risk/benefit ratio for patients.We intend to embark on a limited structure-activity-relationship,or SAR,study and plan to begin IND enabling studi

321、es in 2023.We plan to submit our INDapplication to the FDA in the second half of 2023.Clinical Development Clinical development of OCF-203 is expected to initiate with a single Phase 1/2 clinical trial in IPF that we plan will be followed by later stageclinical development for IPF and HPS in paralle

322、l.We intend to conduct a Phase 1/2 SAD/MAD trial in patients with IPF that is modeled after the Phase 2portion of the Galapagos PINTA trial(NCT03725852).Our Phase 1/2 clinical trial is expected to be designed to provide human proof of concept datademonstrating the cessation of fibrosis progression,w

323、hich would allow for the initiation of Phase 3 clinical trials in both IPF and HPS.The Phase 3 clinicaltrial of OCF-203 for the prevention of fibrotic progression in IPF will likely be modeled after the Genentech ASCEND trial(NCT01366209),while thePhase 3 clinical trial of OCF-203 for the prevention

324、 of fibrotic progression in HPS will likely be modeled after the National Human Genome ResearchInstitute,or NHGRI,trial in HPS patients(NCT00001596).Both the Genentech and NHGRI trials were evaluating pirfenidone.We intend to seek orphandrug designation for OCF-203 in HPS.Infectious Diseases Product

325、 Candidates for Malaria ODA-570 Vaccine for the Prevention of P.falciparum Infection ODA-611 anti-PfGARP mAb for the Treatment of Symptomatic P.falciparum Infection ODA-579 anti-PfGARP Small Molecule for the Treatment of Symptomatic P.falciparum Infection 25 Infectious diseases,caused by infection w

326、ith viruses,bacteria,fungi or parasites are the primary cause of more than 12.5%of all deathsworldwide.Efforts to reduce this death toll are hampered by drug resistant pathogens and,for many pathogens,a lack of effective vaccines.As detailedbelow,our infectious disease program is designed to address

327、 this significant unmet medical need and will initially focus on malaria,the greatest singleagent killer of children worldwide.Please see the section entitled“Description of Business Our Therapeutic Programs Malaria Background:Epidemiology and Lifecycle”below.ODA-570malaria vaccine Using the WPDS pl

328、atform,Dr.Kurtis has identified PfGARP and PfSEA-1 as parasite antigens that are recognized by antibodies in the plasma ofchildren who are relatively resistantbut not in those who are susceptibleto malaria caused by P.falciparum.PfSEA-1 is a parasite antigen with a mass of 244 kilodaltons,which has

329、no significant similarity to proteins of known function.PfSEA-1 displaysminimal sequence variation in the region we cloned(amino acids 810 to 1083)across hundreds of parasite strains.Antibodies made in mice immunizedwith recombinant PfSEA-1 have been shown to inhibit parasite growth by 58%to 74%acro

330、ss three parasite strains compared with controls(Fig 8).Similarly,purified human antibodies to PfSEA-1 have also been shown to significantly inhibit parasite growth in laboratory studies.In both cases,anti-PfSEA-1 antibodies trapped parasites within the red cell,preventing their egress,and led to pa

331、rasite death.Figure 8.Antibodies to PfSEA-1 kill parasites.Polyclonal anti-PfSEA-1 antibodies in mice inhibit parasite growth by 74%in vitro.Ring stage 3D7parasites were cultured in the presence of anti-PfSEA-1 mouse sera at 1:10 dilution.Negative controls included no anti-sera and pre-immune mouse

332、sera.Red blood cells(RBC).In vaccine challenge experiments in mouse models of malaria infection,immunization with a recombinant protein encoding the P.berghei ANKA(a lethal mouse malaria strain)ortholog of PfSEA-1,or PbSEA-1,or antibodies to PbSEA-1 conferred marked protection against a lethal P.ber

333、ghei ANKAchallenge as evidenced by up to a 75%reduction in parasitemia seven days after challenge.In all five experiments performed,by day seven to eight afterchallenge,control mice had high parasitemia with associated morbidity,whereas none of the vaccinated mice had high parasitemia or overt morbidity.Inexperiments with long-term follow-up,both active immunization with rPbSEA-1 and passive trans