1、 UNITED STATESSECURITIES AND EXCHANGE COMMISSIONWASHINGTON,D.C.20549 FORM 10-K x ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended September 30,2019 OR TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934
2、For the transition period from to Commission File Number:001-37759 OUTLOOK THERAPEUTICS,INC.(Exact name of registrant as specified in its charter)Delaware 38-3982704(State or other jurisdiction ofincorporation or organization)(I.R.S.EmployerIdentification No.)7 Clarke DriveCranbury,New Jersey 08512(
3、Address of principal executive offices)(Zip Code)(609)619-3990(Registrants telephone number,including area code)Securities registered pursuant to Section 12(b)of the Act:Title of each classTrading Symbol(s)Name of each exchange on which registeredCommon StockOTLKThe Nasdaq Stock Market LLCSeries A W
4、arrantsOTLKWThe Nasdaq Stock Market 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 Rule 405 of the Securities Act.Yes No x Indicate by check mark if the registrant is not required to file repor
5、ts pursuant to Section 13 or Section 15(d)of the Act.Yes No x Indicate by check mark whether the registrant(1)has filed all reports required to be filed by Section 13 or 15(d)of the Securities Exchange Act of 1934 during thepreceding 12 months(or for such shorter period than the registrant was requi
6、red to file such reports),and(2)has been subject to such filing requirements for thepast 90 days.Yes x No Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of RegulationS-T(232.405 of this chapter)duri
7、ng the preceding 12 months(or for such shorter period that the registrant was required to submit such files).Yes x No Indicate by check mark whether the registrant is a large accelerated filer,an accelerated filer,a non-accelerated filer,a smaller reporting company,or an emerginggrowth company.See t
8、he definition of“large accelerated filer,”“accelerated filer,”“smaller reporting company,”and“emerging growth company”in Rule 12b-2of the Exchange Act.Large accelerated filer Accelerated filerNon-accelerated filerx Smaller reporting companyx Emerging growth companyx If an emerging growth company,ind
9、icate by check mark if the registrant has elected not to use the extended transition period for complying with any new orrevised financial accounting standards provided pursuant to Section 13(a)of the Exchange Act.x Indicate by check mark whether registrant is a shell company(as defined in Rule 12b-
10、2 of the Exchange Act).Yes No x The aggregate market value of the registrants common stock,held by non-affiliates of the registrant as of March 29,2019(which is the last business day ofregistrants most recently completed second fiscal quarter)based upon the closing market price of such stock on The
11、Nasdaq Capital Market on that date,wasapproximately$18.9 million.As of December 16,2019,the registrant had outstanding 30,103,173 shares of common stock,par value$0.01 per share.DOCUMENTS INCORPORATED BY REFERENCENone.OUTLOOK THERAPEUTICS,INC.ANNUAL REPORT ON FORM 10-KTABLE OF CONTENTS Page Cautiona
12、ry Note Regarding Forward-Looking Statements and Industry DataiiPART I ITEM 1.Business1ITEM 1A.Risk Factors19ITEM 1B.Unresolved Staff Comments55ITEM 2.Properties55ITEM 3.Legal Proceedings55ITEM 4.Mine Safety Disclosures55 PART II ITEM 5.Market for Registrants Common Equity,Related Stockholder Matter
13、s,and Issuer Purchases of Equity Securities56ITEM 6.Selected Financial Data57ITEM 7.Managements Discussion and Analysis of Financial Condition and Results of Operations58ITEM 7A.Quantitative and Qualitative Disclosures about Market Risk71ITEM 8.Consolidated Financial Statements and Supplementary Dat
14、a72ITEM 9.Changes in and Disagreements with Accountants on Accounting and Financial Disclosure100ITEM 9A.Controls and Procedures100ITEM 9B.Other Information100 PART III ITEM 10.Directors,Executive Officers and Corporate Governance101ITEM 11.Executive Compensation105ITEM 12.Security Ownership of Cert
15、ain Beneficial Owners and Management and Related Stockholder Matters113ITEM 13.Certain Relationships and Related Transactions,and Director Independence115ITEM 14.Principal Accounting Fees and Services121 PART IV ITEM 15.Exhibits and Financial Statement Schedules121ITEM 16.Form 10-K Summary124 In thi
16、s report,unless otherwise stated or as the context otherwise requires,references to“Outlook Therapeutics,”“Outlook,”“the Company,”“we,”“us,”“our”and similar references refer to Outlook Therapeutics,Inc.(formerly known as Oncobiologics,Inc.)and its consolidated subsidiaries.The Outlook logo,Oncobiolo
17、gics logo and other trademarks or service marks of Outlook Therapeutics,Inc.appearing in this report are the property of Outlook Therapeutics,Inc.This report also contains registered marks,trademarks and trade names of other companies.All other trademarks,registered marks and trade names appearing i
18、nthis report are the property of their respective holders.Convenience translations between Swiss Francs,or CHF,and U.S.dollars provided herein are based on the noon buying rate in New York City for cable transfersin foreign currencies as certified for customs purposes by the Federal Reserve Bank of
19、New York on September 30,2019,or CHF 0.99045=$1.00.We do notrepresent that CHF were,could have been,or could be,converted into U.S.dollars at such rate or at any other rate.CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS AND INDUSTRY DATA This Annual Report on Form 10-K contains forward-looking
20、 statements within the meaning of Section 27A of the Securities Act of 1933,as amended,and Section21E of the Securities Exchange Act of 1934,as amended.Forward-looking statements are based on our managements beliefs and assumptions and on informationcurrently available to our management.All statemen
21、ts other than statements of historical facts are“forward-looking statements”for purposes of these provisions,including those relating to future events or our future financial performance and financial guidance.In some cases,you can identify forward-looking statements byterminology such as“may,”“migh
22、t,”“will,”“should,”“expect,”“plan,”“anticipate,”“project,”“believe,”“estimate,”“predict,”“potential,”“intend,”“continue,”the negative of terms like these or other comparable terminology,in connection with any discussion of future operating or financial performance.These statementsare only prediction
23、s.All forward-looking statements included in this Annual Report on Form 10-K are based on information available to us on the date hereof,andwe assume no obligation to update any such forward-looking statements.Any or all of our forward-looking statements in this document may turn out to be wrong.Act
24、ual events or results may differ materially.Our forward-looking statements can be affected by inaccurate assumptions we might make or by known or unknownrisks,uncertainties and other factors.We discuss many of these risks,uncertainties and other factors in this Annual Report on Form 10-K in greater
25、detail in Item1A under the heading“Risk Factors.”We caution investors that our business and financial performance are subject to substantial risks and uncertainties.This Annual Report on Form 10-K also contains estimates,projections and other information concerning our industry,our business,and the
26、markets for certaindiseases,including data regarding the estimated size of those markets,and the incidence and prevalence of certain medical conditions.Information that is based onestimates,forecasts,projections,market research or similar methodologies is inherently subject to uncertainties and actu
27、al events or circumstances may differmaterially from events and circumstances reflected in this information.Unless otherwise expressly stated,we obtained this industry,business,market and otherdata from reports,research surveys,studies and similar data prepared by market research firms and other thi
28、rd parties,industry,medical and general publications,government data and similar sources.ii PART I Item 1.Business We are a late clinical-stage biopharmaceutical company working to develop the first U.S.Food and Drug Administration,or FDA,-approved ophthalmicformulation of bevacizumab for use in ret
29、inal indications.Our goal is to launch ONS-5010 as the first and only approved bevacizumab in the United States,Europe,Japan and other markets for the treatment of wet age-related macular degeneration,or wet AMD,diabetic macular edema,or DME,and branch retinal veinocclusion,or BRVO.ONS-5010 is an in
30、vestigational ophthalmic formulation of bevacizumab under development to be administered as an intravitreal injection for the treatment of wetAMD and other retinal diseases.Bevacizumab is a full-length,humanized anti-VEGF(Vascular Endothelial Growth Factor)recombinant monoclonal antibody,ormAb,that
31、inhibits VEGF and associated angiogenic activity.The study design for our Phase 3 clinical program to evaluate ONS-5010 as an ophthalmicformulation of bevacizumab was reviewed at an end of Phase 2 meeting with the FDA in April 2018,and we filed our investigational new drug application,orIND,with the
32、 FDA in the first quarter of calendar 2019.Our Phase 3 program for ONS-5010 in wet AMD involves two clinical trials,which we refer to as NORSE 1 and NORSE 2,evaluating ONS-5010 againstranibizumab(LUCENTIS).Enrollment in the NORSE 1 study is complete with 61 patients enrolled,all in Australia.The NOR
33、SE 2 study has been initiated andbegan enrolling wet AMD patients in July 2019.The NORSE 2 study is expected to enroll a total of at least 220 patients and is being conducted in the UnitedStates.The endpoint for both studies is a mean increase in baseline visual acuity at 11 months for ONS-5010 dose
34、d on a monthly basis compared to LUCENTISdosed using the alternative PIER clinical trial dosing regimen of three-monthly doses followed by quarterly dosing.Currently,the cancer drug Avastin(bevacizumab)is used off-label for the treatment of wet AMD and other retinal diseases such as DME and BRVO eve
35、n thoughAvastin has not been approved by regulatory authorities for use in these diseases.If the ONS-5010 clinical program is successful,it will support our plans tosubmit for regulatory approval in multiple markets in 2021 including the United States,Europe and Japan.Because there are no approved b
36、evacizumab productsfor the treatment of retinal diseases in such major markets,we are developing ONS-5010 as a novel biologic and not using the biosimilar drug developmentpathway that would be required if Avastin were an approved drug for the targeted diseases.If approved,we believe ONS-5010 has pot
37、ential to mitigate risksassociated with off-label use of bevacizumab.Off-label use of bevacizumab is currently estimated to account for at least 50%of all wet AMD prescriptions in theUnited States.Our Strategy Our goal is to launch ONS-5010 as the first,and only,approved bevacizumab for ophthalmic u
38、se in the United States,Europe,Japan and other markets.In order toachieve this goal,we have adopted a streamlined clinical and regulatory strategy to quickly and efficiently complete the process required to submit a BiologicsLicense Application,or BLA,with the FDA at the earliest opportunity.The key
39、 elements of our strategy include:Leveraging the ophthalmic drug development and commercialization expertise of our leadership team.Members of our executive team haveextensive expertise in developing and commercializing treatments for retinal diseases,such as wet AMD.We intend to leverage their coll
40、ectiveexperience to further the development of,and execute an optimal commercial strategy for,ONS-5010.Engaging with regulatory agencies to establish clear guidelines for potential approval.We have continued our approach to work closely withregulatory authorities to develop and conduct clinical tria
41、ls that we believe will appropriately support approval of our product candidates if our clinicaltrials are successful.As an ophthalmic formulation of bevacizumab,we believe ONS-5010 has a well-defined regulatory pathway.Conducting and efficiently executing clinical trials inside and outside of the U
42、nited States to support potential approval.We have designed our ONS-5010 clinical program to take advantage of reduced costs for clinical trials conducted outside of the United States,as appropriate.We intend to furtherthis strategy,in a manner that will support a BLA submission in the United States
43、 at the earliest opportunity for ONS-5010.1 Reducing and managing costs to minimize additional investment to complete our development programs.We have made the strategic decision tooutsource the commercial manufacturing and future clinical trial supply manufacturing for our product candidates.We bel
44、ieve this will significantlyreduce future overhead costs not directly related to our ONS-5010 program.Our Product Candidate Portfolio Our product candidate portfolio includes our lead product candidate,ONS-5010,which we are actively developing,as well as our biosimilar product candidates,which we on
45、ly plan to further advance upon entering into a license or co-development agreement with a partner in the major markets.We refer to these legacybiosimilar product candidates as our inactive development portfolio.Active Development Portfolio ONS-5010 Bevacizumab for Ophthalmic Use ONS-5010 is an inve
46、stigational ophthalmic formulation of bevacizumab under development to be administered as an intravitreal injection for the treatment of wetAMD and other retinal diseases.We currently intend to commercialize both vial and pre-filled syringe formulations if approved.Bevacizumab is a full-length,human
47、ized anti-VEGF recombinant mAb that inhibits VEGF and associated angiogenic(the growth of new blood vessels)activity.With wet AMD,abnormally high levels of VEGF are secreted in the eye.VEGF is a protein that promotes the growth of new abnormal blood vessels.Anti-VEGFinjection therapy blocks this gro
48、wth.Since the advent of anti-VEGF therapy,it has become the standard of care treatment option within the retina communityglobally.Previously,we were developing ONS-5010 as a biosimilar(ONS-1045)of the cancer drug Avastin for use in oncology indications.In the ONS-1045 program,ourbevacizumab met the
49、primary and secondary endpoints in a three-arm single-dose pharmacokinetic,or PK,Phase 1 clinical trial(see“Inactive DevelopmentPortfolio-ONS-1045 Bevacizumab(Avastin)Biosimilar”).All the PK endpoints met the bioequivalency criteria of the geometric mean ratios within 90%confidence interval of 80-12
50、5%when compared to both U.S.-and E.U.-sourced Avastin reference products.We are developing ONS-5010 as an ophthalmicformulation of bevacizumab for a BLA filing and not using the biosimilar drug development pathway.The following figure demonstrates the concentration-timeprofile of ONS-1045,U.S.-licen
51、sed Avastin,and E.U.-licensed Avastin as the mean.The vertical line at time zero denotes dosing.These results suggest a highdegree of similarity among the three products.2 Comparative Potency of ONS-1045 versus Avastin(U.S.and E.U.)Market Opportunity Age-related macular degeneration,or AMD,is a comm
52、on eye condition and a leading cause of vision loss among people age 50 and older.Wet AMD is a form of“late stage”AMD and is also called neovascular AMD.In wet AMD,abnormal blood vessels grow underneath the retina.These vessels can leak fluid and blood,which may lead to swelling and damage of the ma
53、cula causing vision loss.With wet AMD,abnormally high levels of VEGF are secreted in the eyes.VEGF is aprotein that promotes the growth of new abnormal blood vessels.Anti-VEGF injection therapy blocks this growth.Since the advent of anti-VEGF therapy,it hasbecome the standard of care treatment optio
54、n within the retina community,globally.Wet AMD is a significant disease worldwide,with an estimated prevalence ofover 2.8 million patients diagnosed in the United States,top five European countries and Japan alone in 2018(GlobalData).Annual revenue from LUCENTIS andEYLEA(two approved anti-VEGF thera
55、pies)was approximately$9.0 billion in 2018.Although bevacizumab is not currently FDA-approved for use in treatingwet AMD,it is believed that bevacizumab currently accounts for at least 50%of all wet AMD prescriptions in the United States,where Avastin is repackagedthrough compounding pharmacies and
56、prescribed off-label.If approved,we believe ONS-5010 has potential to mitigate risks associated with off-label repackagingof bevacizumab.DME is caused by a complication of diabetes called diabetic retinopathy.Diabetic retinopathy is the most common diabetic eye disease and the leading cause ofirreve
57、rsible blindness in working age Americans.Diabetic retinopathy usually affects both eyes and is caused by ongoing damage to the small blood vessels of theretina.The leakage of fluid into the retina may lead to swelling of the surrounding tissue,including the macula.DME is the most common cause of vi
58、sion loss inpeople with diabetic retinopathy.DME can occur at any stage of diabetic retinopathy,although it is more likely to occur in later stages of the disease.There wereapproximately 1.0 million patients with DME in the United States,top five European countries and Japan alone in 2018(GlobalData
59、).In BRVO,retinal vein occlusions occur when there is a blockage of veins carrying blood with needed oxygen and nutrients away from the nerve cells in the retina.A blockage in the main vein of the retina is referred to as a central retinal vein occlusion,or CRVO,while a blockage in a smaller vein is
60、 called a branch retinalvein occlusion,or BRVO.Per the American Academy of Ophthalmology,retinal vein occlusions are the second most common retinal vascular disorder afterdiabetic retinopathy.There were an estimated 0.3 million patients with BRVO in the United States,top five European countries and
61、Japan alone in 2018(GlobalData).3 Clinical Development Status The study design for our Phase 3 clinical program to evaluate ONS-5010 as an ophthalmic formulation of bevacizumab was reviewed with the FDA at an end ofPhase 2 meeting in April 2018.We began enrolling patients in the NORSE 2 study in Jul
62、y 2019.NORSE 2 is the second study in the Phase 3 clinical program forONS-5010 for the treatment of wet AMD.We are conducting the NORSE 2 study in the United States.The NORSE 1 study,the first clinical study in the Phase 3clinical trial program for ONS-5010,completed enrollment in Australia in Augus
63、t 2019.If the program is successful,it will support our plans to submit forregulatory approval in multiple markets in 2021,including the United States,Europe and Japan.Because enrollment completed in August 2019,we currentlyexpect to report top line data from NORSE 1 in the third quarter of calendar
64、 2020.For NORSE 2,we expect to report top line data and submit a BLA in the firstcalendar quarter of 2021.We have also received agreement from the FDA on three Special Protocol Assessments,or SPAs,for three additional registration clinical trials for our ongoingPhase 3 program for ONS-5010.The agree
65、ments reached with the FDA on these SPAs cover the protocols for NORSE 4,a registration clinical trial to treat BRVO,and NORSE 5 and NORSE 6,two registration clinical trials to treat DME.We intend to initiate NORSE 4,5 and 6 in 2020 after completion of enrollment inNORSE 2.NORSE 1 NORSE 1 completed
66、enrollment in August 2019 with a total of 61 patients at nine sites in Australia.The study is the first of two ongoing,clinical trials evaluatingONS-5010 against ranibizumab for wet AMD.The endpoint for the study is a mean change in baseline visual acuity at 11 months for ONS-5010 dosed on amonthly
67、basis compared to ranibizumab dosed using the PIER alternative dosing regimen of three monthly doses followed by quarterly dosing.We currently expectto announce a readout of the topline results from NORSE 1 in the third quarter of calendar year 2020.NORSE 2 NORSE 2 is the second of our two required
68、clinical trials evaluating ONS-5010 against ranibizumab for wet AMD.We began enrolling patients in July 2019,andthe study is expected to enroll a total of at least 220 patients at sites in the United States.Patients enrolled in the ONS-5010-002 study will be treated for 11months.The endpoint for the
69、 study is a mean increase in baseline visual acuity of at least five letters at 11 months for ONS-5010 dosed on a monthly basiscompared to ranibizumab dosed using the approved PIER alternative dosing regimen of three-monthly doses followed by quarterly dosing.We currently anticipatefull enrollment f
70、or NORSE 2 in the first quarter of calendar year 2020.Inactive Development Portfolio ONS-3010 Adalimumab(Humira)Biosimilar Humira,the reference product for ONS-3010,is a subcutaneous injectable mAb that binds to tumor necrosis factor alpha,or TNF.TNF belongs to a family ofpro-inflammatory cytokines,
71、or soluble protein mediators,that are key initiators of immune-mediated inflammation in many different diseases,such as rheumatoidarthritis,psoriatic arthritis,psoriasis,ankylosing spondylitis,Crohns disease and ulcerative colitis.Several biologic agents,including Humira,have beendeveloped to inhibi
72、t the inflammatory activity of TNFs in the context of these diseases and are collectively referred to as the anti-TNF class of therapeutics.We have successfully completed a randomized,double-blind,single-dose and single-center Phase 1 clinical trial comparing ONS-3010 to Humira in 198 subjectsreceiv
73、ing a 40mg dose in three treatment arms:ONS-3010,U.S.-Humira and E.U.-Humira.This Phase 1 clinical trial was performed at the Center for Human DrugResearch in Leiden,the Netherlands under the auspices of the Stichting Beoordeling Ethiek Biomedisch Onderzoek.In this trial,ONS-3010 met its primary and
74、secondary endpoints,demonstrating a similar PK profile,as well as an immunogenicity profile equivalent to both U.S.-and E.U.-Humira across all three treatmentarms.ONS-3010 was well-tolerated and demonstrated a favorable safety profile,which was similar to the safety profile for both U.S.-and E.U.-Hu
75、mira anddemonstrated a lower injection site reaction rate than both U.S.-and E.U.-Humira.4 Regulatory Status and Development Plan Prior to commencement of our Phase 1 clinical trial in 2014,we received feedback from both FDA and the European Medicines Agency,or EMA,which providedguidance for the des
76、ign of the clinical trial and our similarity testing approach.Since completion of the Phase 1 clinical trial,we had additional regulatory meetingswith the FDA and the EMA,as well as other national regulatory agencies such as the Medicines and Healthcare Products Regulatory Agency,or MHRA,theSwedish
77、Medical Products Agency,and the Canadian regulatory agency,Health Canada,to obtain further guidance on the Phase 3 clinical trial design in plaquepsoriasis and the general similarity development plan for registration.We have out-licensed all of the emerging markets development rights to third partie
78、s.Futuredevelopment of ONS-3010 as a biosimilar for Humira in the United States and other developed markets will only occur if we secure a development partner or sellthose development rights completely.ONS-1045 Bevacizumab(Avastin)Biosimilar Avastin,the reference product for ONS-1045,is a mAb admini
79、stered by infusion that interferes with tumor growth by binding to VEGF,a protein that stimulatesthe formation of new blood vessels and is approved for use in the United States,Europe and elsewhere for the treatment of various forms of cancer.We have completed a randomized,double-blind,single-dose a
80、nd single-center Phase 1 clinical trial comparing ONS-1045 to U.S.-licensed Avastin and E.U.-licensed Avastin in 135 subjects.This Phase 1 trial was performed at the Center for Human Drug Research in Leiden,the Netherlands under the auspices of theStichting Beoordeling Ethiek Biomedisch Onderzoek.PK
81、 data,safety and immunogenicity were collected for a total of 98 days after a single 2.0 mg/kg dose.Inthis trial,ONS-1045 met its primary and secondary endpoints demonstrating a similar PK profile,as well as an immunogenicity profile equivalent to both U.S.-and E.U.-Avastin.Safety was comparable acr
82、oss all three groups.Immunogenicity was low with only one subject in the E.U.-licensed Avastin arm developing ananti-drug antibody,or ADA,at day 98.No neutralizing antibodies were detected in any arm.The results of the Phase 1 trial(shown in the figure included under“Active Development Portfolio ONS
83、-5010 Bevacizumab for Ophthalmic Use”)suggest a high degree of similarity between the three products.Regulatory Status and Development Plan Prior to the commencement of the Phase 1 clinical trial in 2015,we received feedback from both the FDA and the EMA,which provided guidance for the clinicaltrial
84、 design and similarity testing approach.We have completed the next series of our regulatory interactions to obtain further guidance on our confirmatory trialdesign.Based on input from the FDA,EMA,MHRA and the Danish Health and Medicines Agency,we believe we have designed the appropriate confirmatory
85、trial.We have outlicensed all of the emerging markets development rights to third parties.Future development of ONS-1045 as a biosimilar for Avastin in theUnited States and other developed markets will only occur if we secure a development partner or sell those development rights completely.Commerci
86、alization,Sales and Marketing We currently own all of the development and commercialization rights to ONS-5010.Our commercialization strategy is to maximize the revenue potential of ONS-5010,which could potentially include marketing it ourselves if approved,as well as seeking and securing licensing
87、opportunities to fund its continueddevelopment.If approved,we believe that ONS-5010 will be entitled to 12 years marketing exclusivity against biosimilar competition.For many years,anti-VEGF therapy has been the standard of care for many ophthalmic diseases,including wet AMD,DME and BRVO.However,alt
88、houghmultiple branded drugs have been approved for these indications(e.g.,LUCENTIS,EYLEA and BEOVU),they are very expensive.Doctors who wish to treattheir retinal patients with a less expensive anti-VEGF drug often use bevacizumab.But because there is no FDA-approved ophthalmic formulation ofbevaciz
89、umab,doctors must use repackaged bevacizumab(Avastin)provided by compounding pharmacists.Despite clinicians widespread acceptance and use ofbevacizumab to treat ophthalmic diseases such as wet AMD,DME and BRVO,no manufacturer has previously sought approval from FDA of bevacizumab forthese purposes.T
90、he repackaged bevacizumab for ophthalmic use that is provided by compounding pharmacies can carry known risks of contamination(including silicone oildroplet contamination from syringes)and inconsistent potency,with potentially severe consequences,as leading retinal societies have reported.For these
91、reasons,the retina community and payors have shown interest in the development of an ophthalmic formulation of bevacizumab that could be an on-label alternative torepackaged bevacizumab from compounding pharmacists.5 To meet this retinal market need,we are developing ONS-5010 as an investigational o
92、phthalmic formulation of bevacizumab.If approved,it will provide an FDA-approved and European Agency-approved,viable treatment option across the spectrum of anti-VEGF ophthalmic drugs that treat wet AMD,DME and BRVO.Additionally,if approved,it would avoid the safety,sterility,potency,availability an
93、d syringe drawbacks that can occur with repackaged bevacizumab fromcompounding pharmacies.Additionally,if ONS-5010 is approved and commercialized,we expect to price it responsibly to help mitigate the high cost of on-label treatment for retinaldiseases.Both in the U.S.and globally,the high cost of t
94、reating retinal diseases such as wet AMD,DME and BRVO can result in patients receiving an insufficientnumber of treatments,or potentially no treatment at all.Our commercial strategy includes a focus on becoming the step therapy of choice for retinal diseases forbranded and long acting options.where
95、an anti-VEGF therapy is indicated.Step therapy is a type of prior authorization for drugs that begins treatment for amedical condition with the most preferred drug therapy and progresses to other therapies only if necessary.By ensuring the consistent availability of safe,sterile and fully potent on-
96、label bevacizumab for intravitreal injection,at a responsible price,ONS-5010,ifapproved,has the potential to become the anti-VEGF cornerstone of care for retinal diseases.It may also provide synergies with future long-acting agents andadjunct therapies for advanced treatment of wet AMD,DME and BRVO.
97、ONS-5010 has the potential,if approved and commercialized with a responsible pricingstrategy,to help lower the aggregate costs of treating retinal diseases for the overall healthcare system.To provide additional resources to fund the ONS-5010 program,in addition to pursuing potential strategic colla
98、borations and partnerships for ONS-5010,we alsointend to continue to pursue potential strategic collaborations,and partnerships with biotechnology and pharmaceutical companies in the United States and otherregions for our clinical stage biosimilar assets,or even the outright sale of the development
99、rights of these assets outside of the emerging markets territoriespreviously licensed.Currently,we have a joint participation agreement in place for ONS-3010 with Zhejiang Huahai Pharmaceutical Co.,Ltd.,or Huahai,wherebywe share post-Phase 1 development costs with Huahai,and proportionately share th
100、e revenues from commercialization of ONS-3010 in the United States,Canada,European Union,or E.U.,Japan,Australia and New Zealand.We could also be required to form a joint venture to further develop and commercialize ONS-3010with Huahai in the agreed countries,if so,requested by Huahai.However,we do
101、not have any other development and commercialization agreements for the UnitedStates or for major ex-U.S.markets,such as the E.U.and Japan.For emerging markets opportunities,in 2012 and 2013,we established early country-specific partnerships for ONS-3010 and ONS-1045 in China with Huahai,inIndia wit
102、h IPCA Laboratories Limited,or IPCA,and in Mexico with Laboratories Liomont,S.A.de C.V.,or Liomont,and in September 2017 we entered into anagreement with BioLexis Pte.Ltd.,or BioLexis,our controlling stockholder,providing for the license of rights to ONS-3010 and ONS-1045 in emerging marketsexcludin
103、g China,India and Mexico.To date,these agreements have collectively provided an aggregate of$29.0 million in payments as of September 30,2019.Collaboration and License Agreements We enter into collaboration and license agreements in the ordinary course of our business.We have in-licensed certain tec
104、hnology from Selexis SA,or Selexis,that we used to research and develop our product candidates.For product candidates developed using the Selexis technology,we enter into commercial licenseagreements with Selexis that give us rights to commercialize,file investigational new drugs,or INDs and enter i
105、nto collaborative arrangements with third partiesfor the further development and commercialization of such biosimilar product candidates.6 MTTR Strategic Partnership Agreement(ONS-5010)In February 2018,we entered into a strategic partnership agreement with MTTR,LLC,or MTTR,to advise on regulatory,cl
106、inical and commercial strategy andassist in obtaining approval of ONS-5010,our bevacizumab therapeutic product candidate for ophthalmic indications.Under the terms of the agreement,we paidMTTR a$58,333 monthly consulting fee through December 2018.Beginning January 2019,the monthly fee increased to$1
107、05,208 per month,and then,afterlaunch of ONS-5010 in the United States,will increase to$170,833 per month(the amount of which is reduced by 50%in the event net sales of ONS-5010 arebelow a certain threshold million per year).We also agreed to pay MTTR a tiered percentage of the net profits of ONS-50
108、10 ranging in the low-to mid-teens,withthe ability to credit monthly fees paid to MTTR.In March 2018,we amended the MTTR agreement and agreed to pay a one-time fee of$268,553 to MTTR bySeptember 2020 if certain regulatory milestones are achieved earlier than anticipated.In June 2019,we entered into
109、a further amendment of our strategicpartnership agreement with MTTR pursuant to which we increased the aggregate monthly payments to MTTR under the existing agreement from$105,208 to$170,724 through December 2019 by adding an additional monthly retainer of$115,516,and an offset of$50,000 to the exis
110、ting monthly retainer while theadditional monthly retainer is in effect.MTTR earned an aggregate$1,744,933 and$602,629 during the years ended September 30,2019 and 2018,respectively,which includes monthly consulting fees and expense reimbursement.Unless earlier terminated,the MTTR agreement expires,
111、on a country-by-country basis,upon the later of expiration of any regulatory exclusivity in such countryand,in certain major market countries,ten years after launch of ONS-5010 in such major market country,and in all other countries in the territory,ten years afterlaunch of ONS-5010 in any country i
112、n the territory.Either party may terminate the MTTR agreement upon the uncured material breach of the agreement by theother party or upon a bankruptcy or insolvency of the other party.Additionally,we are permitted to terminate the MTTR agreement in the event of certain specifieddevelopment or commer
113、cial failures of ONS-5010 and may terminate either the entire MTTR agreement or with respect to certain consultants in the event thatcertain consultants are not able to perform their obligations under the MTTR Agreement,and a suitable replacement consultant is not found.Additionally,in theevent of a
114、 change of control of our company or sale of our rights to ONS-5010,MTTR will be entitled to additional consideration equal to its profit-sharing percentage multiplied by the value of the applicable transaction that relates to ONS-5010(subject to certain adjustments).In November 2018 we appointed Te
115、rry Dagnon as our Chief Operating Officer and Jeff Evanson as our Chief Commercial Officer.Although each is an executiveofficer of our company,they are providing services to us pursuant to our strategic partnership agreement with MTTR,are compensated by MTTR,and each has anownership interest in MTTR
116、.See also Item 13“Certain Relationships and Related Transactions,and Director IndependenceMTTR LLC-ONS 5010 StrategicPartnership Agreement.”Selexis Humira(ONS-3010),Avastin(ONS-5010 and ONS-1045)and Herceptin(ONS-1050)In October 2011,we entered into a research license agreement with Selexis,whereby
117、we acquired a non-exclusive license to conduct research internally or incollaboration with third parties to develop recombinant proteins from cell lines created in mammalian cells using the Selexis expression technology,or the SelexisTechnology.The research license expired on October 9,2018,and acco
118、rdingly,we are no longer using the Selexis Technology in our research.Selexis also granted us a non-transferrable option to obtain a perpetual,non-exclusive,worldwide commercial license under the Selexis Technology tomanufacture,or have manufactured,a recombinant protein produced by a cell line deve
119、loped using the Selexis Technology for clinical testing and commercialsale.We exercised this option in April 2013 and entered into three commercial license agreements with Selexis for our ONS-3010,ONS-1045(which covers ONS-5010)and ONS-1050 product candidates.We paid an upfront licensing fee to Sele
120、xis for each commercial license and also agreed to pay a fixed milestonepayment for each licensed product.In addition,we are required to pay a single-digit royalty on a final product-by-final product and country-by-country basis,basedon worldwide net sales of such final products by us or any of our
121、affiliates or sub-licensees during the royalty term.At any time during the term,we have the rightto terminate our royalty payment obligation by providing written notice to Selexis and paying Selexis a royalty termination fee.Commercial License Agreements On April 11,2013,following the exercise of ou
122、r option to enter a commercial license under the Selexis research license,we entered into commercial licenseagreements with Selexis for each of the ONS-3010,ONS-1045 and ONS-1050(a biosimilar to Herceptin that we are no longer developing)biosimilar productcandidates that were developed under the res
123、earch license(which agreements were subsequently amended on May 21,2014).Under the terms of each commerciallicense agreement,we acquired a non-exclusive worldwide license under the Selexis Technology to use the cell lines developed under the research license andrelated materials,to manufacture and c
124、ommercialize licensed and final products,with a limited right to sublicense.7 We were required to pay an upfront licensing fee of CHF 65,000(approximately$0.1 million)to Selexis for each commercial license and also agreed to pay up toCHF 365,000(approximately$0.4 million)in milestone payments for ea
125、ch licensed product.In addition,we are required to pay a single-digit royalty on a finalproduct-by-final product and country-by-country basis,based on worldwide net sales of such final products by us or any of our affiliates or sublicensees during theroyalty term.The royalty term for each final prod
126、uct in each country is the period commencing from the first commercial sale of the applicable final product in theapplicable country and ending on the expiration of the specified patent coverage.At any time during the term,we have the right to terminate our royalty paymentobligation by providing wri
127、tten notice to Selexis and paying Selexis a royalty termination fee of CHF 1,750,000(approximately$1.8 million).The initiation of ourPhase 3 clinical program for ONS-5010 in fiscal 2019 triggered a CHF 65,000(approximately$0.1 million)milestone payment to Selexis under the commerciallicense agreemen
128、t,which we paid in November,2019.As of September 30,2019,we have paid Selexis an aggregate of approximately$0.4 million under thecommercial license agreements.Each of our commercial agreements with Selexis will expire in its entirety upon the expiration of all applicable Selexis patent rights.The li
129、censed patent rightsconsist of two patent families.The first patent family relates to methods of transferring cells,and is filed in the United States,Australia,Canada,Europe,Japan andSingapore.This patent family will begin to expire worldwide in 2022.The second patent family claims DNA compositions
130、of matter useful for having proteinproduction increasing activity.This patent family is filed in the United States,Australia,Canada,China,Europe,Hong Kong,Israel,India,Japan,South Korea,Russia,Singapore and South Africa.This patent family will begin to expire worldwide in 2025.Either party may termi
131、nate the related agreement in the event of anuncured material breach by the other party or in the event the other party becomes subject to specified bankruptcy,winding up or similar circumstances.Either party may also terminate the related agreement under designated circumstances if the Selexis Tech
132、nology infringes third-party intellectual property rights.Inaddition,we have the right to terminate each of the commercial agreements at any time for our convenience;however,with respect to the agreements relating toONS-3010 and ONS-1045,this right is subject to Liomonts consent pursuant to a corres
133、ponding letter we executed in conjunction with the standby agreemententered into between Selexis and Liomont on November 11,2014.The standby agreement permits Liomont to assume the license under the applicable commercialagreement for Mexico upon specified triggering events involving our bankruptcy,i
134、nsolvency or similar circumstances.Ex-U.S.Collaboration and License Agreements Aside from our joint participation agreement in place for ONS-3010 with Huahai,whereby we agreed to share post-Phase 1 clinical development costs,andproportionately share the revenues from commercialization of ONS-3010 in
135、 the United States,Canada,E.U.and Japan,among other markets,and under which wecould be required to form a joint venture with Huahai for ONS-3010 if so requested by Huahai,we do not have any commercial license or development agreementsfor the United States or for major ex-U.S.markets,such as the E.U.
136、or Japan.We currently have collaboration and license agreements for smaller ex-U.S.marketsand,collectively,such agreements have provided an aggregate of$29.0 million in payments as of September 30,2019 for our most advanced biosimilar productcandidates.Our contracts include agreements with IPCA(for
137、ONS-3010,ONS-1045 and ONS-1050 in India and other regional markets),Liomont(for ONS-3010and ONS-1045 in Mexico),Huahai(for ONS-3010 and ONS-1045 in China)and BioLexis(for ONS-3010 and ONS-1045 in emerging markets excluding China,India and Mexico).Our arrangements with these partners generally includ
138、e a strategic license for a defined territory for agreed biosimilar product candidates andmay also include agreements to assist with research and development to assist our contract counterparty in establishing their own mAb research,development andmanufacturing capabilities.Under our existing strate
139、gic licensing agreements,we generally received an upfront payment upon execution,and have the ability toearn additional regular milestone payments and the right to receive royalties(generally a mid-single digit to low-teens percentage rate)based on net sales in theagreed territory.Our existing agree
140、ments to assist with research and development also included an upfront payment upon execution,and we have the ability to earnadditional regular milestone payments,and the right to receive royalties(generally a mid-single digit to low-teens percentage rate)based on net sales in the agreedterritory.8
141、Generally,our agreements expire on a product-by-product basis on the date of the expiration of the royalty revenue term for all products in the territory.The royaltyrevenue term is 10 years from the date of first commercial sale and any renewal is subject to good faith negotiation.The license term f
142、or the agreed territory isperpetual.Either party may terminate the agreement in its entirety or with respect to a particular product if the other party materially breaches the agreement,subject to specified notice and cure periods.In addition,we have the right to terminate the agreement in connectio
143、n with any interference,opposition or challengeof our patent rights.If the agreement is terminated due to our breach,our contract counterparty is generally free to use all applicable technology and know-howthat we have provided under the agreement.As noted above,our collaboration agreements with Hua
144、hai also includes a joint participation agreement,which provides for the co-funding of development ofONS-3010 in the United States,Canada,E.U.,Japan,Australia and New Zealand and the proportionate sharing of the revenues from commercialization of ONS-3010 in the agreed countries,and also provides fo
145、r the formation of a joint venture with Huahai to further develop and commercialize ONS-3010 with Huahai inthe agreed countries,if so requested by Huahai.In the event Huahai funds its proportionate share of development costs incurred after completion of the“Phase-3 Ready Package,”Huahai would be ent
146、itled toretain its 51%value ownership,with us entitled to retain our 49%value ownership,of ONS-3010 in the agreed countries.Similarly,revenues from thecommercialization of ONS-3010 in the agreed countries(including major markets such as the United States and the E.U.,among others),would also be shar
147、edbased on such proportional ownership interests.In the event that Huahai does not fund its proportionate share of such development costs,the joint participationagreement provides for a proportionate adjustment to our respective value ownership interests based on our respective investments in such d
148、evelopment costs,which would increase our value ownership interest in ONS-3010.Throughout the term of the joint participation agreement,we and our affiliates are prohibited from,directly or indirectly,conducting or having conducted orfunding any discovery,research,development,regulatory,manufacturin
149、g or commercialization activity,alone or in collaboration with a third party,of anybiosimilar product having the same reference product as the ONS-3010 compound or corresponding products,for use in the United States,Canada,E.U.,Japan,Australia and New Zealand,other than ONS-3010 with Huahai pursuant
150、 to the joint participation agreement.Unless terminated early upon mutual agreement of the parties,or due to a material breach of either party that is uncured,the joint participation agreement willterminate upon entry into a mutually acceptable collaboration agreement between us and Huahai for ongoi
151、ng development and commercialization of ONS-3010 inthe agreed countries,or we and Huahai enter into an agreed license with a third party for such ongoing development and commercialization of ONS-3010 in theagreed countries.If the joint participation agreement is terminated for cause due to our breac
152、h,we could be required to refund Huahai any amounts funded byHuahai to develop ONS-3010,as well as pay Huahai a 6%royalty on net sales made by us or an affiliate,as well as 25%of revenues we receive from asublicensee for commercial sales of ONS-3010 until the aggregate of such payments is equal to 1
153、0 times the amount Huahai funded for the development of ONS-3010.Furthermore,if we were to file a voluntary petition in bankruptcy,or have an involuntary petition filed that we could not dismiss within 120 days,then Huahaiwould be granted an exclusive license to continue the development and commerci
154、alization of ONS-3010 in the agreed countries.As of September 30,2019,we have received an aggregate of$5.0 million of payments from IPCA under our various agreements,an aggregate of$3.0 million ofpayments from Liomont under our various agreements,an aggregate of$16.0 million of payments from Huahai
155、under our various agreements,$10.0 million ofwhich were pursuant to the joint participation agreement and an aggregate of$5.0 million from BioLexis under our joint development and licensing agreement.Competition Competition in the area of pharmaceutical research and development is intense and signif
156、icantly depends on scientific and technological factors.These factorsinclude the availability of patent and other protection for technology and products,the ability to commercialize technological developments and the ability to obtainregulatory approval for testing,manufacturing and marketing.Our co
157、mpetitors include major pharmaceutical and specialized biotechnology companies,many ofwhich have financial,technical and marketing resources significantly greater than ours.In addition,many biotechnology companies have formed collaborationswith large,established companies to support research,develop
158、ment and commercialization of products that may be competitive with ours.Academic institutions,governmental agencies and other public and private research organizations are also conducting research activities and seeking patent protection and maycommercialize products on their own or through joint v
159、entures.We are aware of certain other products manufactured or under development by competitors that areused for the treatment of the health conditions that we have targeted for product development.We can provide no assurance that developments by others will notrender our technology obsolete,noncomp
160、etitive or harm our development strategy,that we will be able to keep pace with new technological developments or thatour technology will be able to supplant established products and methodologies in the therapeutic areas that are targeted by us.The foregoing factors could have amaterial adverse eff
161、ect on our business,prospects,financial condition and results of operations.These companies,as well as academic institutions,governmentalagencies and private research organizations,also compete with us in recruiting and retaining highly qualified scientific personnel and consultants.9 We will encoun
162、ter competition from existing firms that offer competitive solutions in ocular diseases.These competitive companies could develop products thatare superior to,or have greater market acceptance,than the products being developed by us.We will have to compete against other biotechnology andpharmaceutic
163、al companies with greater market recognition and greater financial,marketing and other resources.Wet-AMD Market AMD is a medical condition that usually affects older adults and generally results in a loss of vision.AMD occurs in“dry”(non-exudative)and“wet”(exudative)forms.Wet AMD is the advanced for
164、m of macular degeneration that involves the formation of abnormal and leaky blood vessels in the back of the eye behind theretina,through a process known as choroidal neovascularization.While the wet form accounts for approximately 15%of all AMD cases,according to the NationalEye Institute,it is res
165、ponsible for 90%of severe vision loss associated with AMD.The National Eye Institute also estimates that the prevalence of wet AMDamong adults 40 years or older in the United States is approximately 1.75 million people.In addition,more than 200,000 new cases are diagnosed annually inNorth America.Co
166、mpetitive Landscape in Wet-AMD Off-label use of bevacizumab(Avastin)is estimated to be at least 50%of the overall market in the United States.The current FDA approved market leaders for thetreatment of wet AMD are VEGF inhibitors,including LUCENTIS and EYLEA.Annual revenue(worldwide)was approximatel
167、y$9.0 billion in 2018 for theapproved anti-VEGF therapeutics LUCENTIS and EYLEA alone.Additionally,in 2019,BEOVU(brolucizumbab-dbll)was approved by the FDA as another anti-VEGF for the treatment of wet AMD.Bevacizumab,LUCENTIS,EYLEA and BEOVU are all administered via frequent intravitreal injections
168、 directly into theeye.We are developing ONS-5010 as an approved bevacizumab for the treatment of wet AMD,as well as DME and BRVO.In addition to the other treatments used in patients with wet AMD,there are various other companies with product candidates in Phase 1,2 and 3 clinical trials forthe treat
169、ment of wet AMD.Programs currently in Phase 2 or Phase 3 clinical trials include,but are not limited to:Abicipar Pegol,a VEGF targeting DARPin molecule being developed by Allergan plc;X-82,an oral tyrosine kinase inhibitor being developed by Tyrogenex,Inc.;ALG-1001,an integrin targeting peptide bein
170、g developed by Allegro Ophthalmics LLC;Zimura,a C-3 inhibitor being developed by Ophthotech Corporation;RG7716,a bispecific antibody to both VEGF-A and Ang2 being developed by Hoffman-La Roche AG;OPT-302,an inhibitor of VEGF-C and VEGF-D being developed by Opthea Limited;andPAN-90806,a selective inh
171、ibitor of VEGF being developed by PanOptica Inc.All of these product candidates in clinical development,with the exception of X-82 and PAN-90806,use an intravitreal route of administration much like thecurrent standards of care.We believe that ONS-5010 has potential competitive advantages through th
172、e familiarity of patients and physicians in using off-labelAvastin.We also believe we have reduced the risk in our clinical program by leveraging our prior work in developing a biosmilar drug product candidate forAvastin as a treatment for cancer.However,clinical trial data from other clinical progr
173、ams may negatively impact our ability to garner future financing or businesscollaborations,combinations or transactions with other pharmaceutical and biotechnology companies.10 Intellectual Property Our commercial success depends in part on our ability to avoid infringing the proprietary rights of t
174、hird parties,our ability to obtain and maintain proprietaryprotection for our technologies where applicable and to prevent others from infringing our proprietary rights.We seek to protect our proprietary technologies by,among other methods,evaluating relevant patents,establishing defensive positions
175、,monitoring E.U.oppositions and pending intellectual property rights,preparinglitigation strategies in view of the U.S.legislative framework and filing U.S.and international patent applications on technologies,inventions and improvementsthat are important to our business.As of September 30,2019,we o
176、wn one U.S.patent,one foreign patent,seven pending U.S.non-provisional applications,and 50pending international applications that were nationalized from eight Patent Cooperation Treaty,or PCT,applications,and one pending PCT application,whichrelate to formulations developed for ONS-3010,ONS-5010/ONS
177、-1045 and ONS-1050,methods of antibody purification,methods for purifying antibodies toseparate isoforms,methods of use,methods of reducing high molecular weight species,and modulating afucosylated species as well as efficiently determining theamino acid sequence of antibodies.Our first PCT applicat
178、ion was nationalized in April 2016 in Australia,Canada,China,Europe,Hong Kong,India,Japan,Mexico and the United States.If granted,patents issuing from these nine applications are expected to expire in 2034,absent any adjustments or extensions.Oursecond PCT application was nationalized in July 2017 i
179、n Europe and the United States.If granted,patents issuing from these two applications are expected toexpire in 2036,absent any adjustments or extensions.Our third PCT application was nationalized in June 2018 in Australia,Canada,China,Europe,India,Japan,Mexico and the United States.If granted,patent
180、s issuing from these eight applications are expected to expire in 2036,absent any adjustments or extensions.Ourfourth PCT application was nationalized in July 2018 in Australia,Canada,China,Europe,India,Japan,Mexico and the United States.If granted,patents issuingfrom these eight applications are ex
181、pected to expire in 2037,absent any adjustments or extensions.Our fifth PCT application was nationalized in July 2018 inAustralia,Canada,China,Europe,India,Japan,Mexico and the United States.If granted,patents issuing from these eight applications are expected to expire in2037,absent any adjustments
182、 or extensions.Our sixth PCT application was nationalized in July 2018 in Australia,Canada,China,Europe,India,Japan,Mexicoand the United States.If granted,patents issuing from these eight applications are expected to expire in 2037,absent any adjustments or extensions.Our seventhPCT application was
183、nationalized in August 2018 in Australia,Canada,China,Europe,India,Japan,Mexico and the United States.If granted,patents issuing fromthese eight applications are expected to expire in 2037,absent any adjustments or extensions.Our eighth PCT application was nationalized in August 2018 inAustralia,Can
184、ada,China,Europe,India,Japan,Mexico and the United States.If granted,patents issuing from these eight applications are expected to expire in2037,absent any adjustments or extensions.Any patents that may eventually issue claiming priority to our provisional patent application are expected to expire i
185、n2039.We also rely on trade secrets,know-how and continuing technological innovation to develop and maintain our proprietary position.The term of individual patents depends upon the legal term of the patents in countries in which they are obtained.In most countries,including the United States,the pa
186、tent term is generally 20 years from the earliest date of filing a non-provisional patent application in the applicable country.In the United States,a patentsterm may,in certain cases,be lengthened by patent term adjustment,which compensates a patentee for administrative delays by the United States
187、Patent andTrademark Office in examining and granting a patent or may be shortened if a patent is terminally disclaimed over a commonly owned patent or a patent naming acommon inventor and having an earlier expiration date.Regulatory Government Regulation and Product Approval The FDA and other regula
188、tory authorities at federal,state,and local levels,as well as in foreign countries,extensively regulate,among other things,the research,development,testing,manufacture,quality control,import,export,safety,effectiveness,labeling,packaging,storage,distribution,record keeping,approval,advertising,promo
189、tion,marketing,post-approval monitoring,and post-approval reporting of biologics such as those we are developing.We,along with third-partycontractors,will be required to navigate the various preclinical,clinical and commercial approval requirements of the governing regulatory agencies of thecountrie
190、s in which we wish to conduct studies or seek approval or licensure of our product candidates.The process required by the FDA before biologic product candidates may be marketed in the United States generally involves the following:completion of preclinical laboratory tests and animal studies perform
191、ed in accordance with theFDAs current Good Laboratory Practices,or GLP,regulation;submission to the FDA of an IND,which must become effective before clinical trials may begin and must be updated annually or when significantchanges are made;approval by an independent Institutional Review Board,or IRB
192、,or ethics committee at each clinical site before the trial is commenced;11 performance of adequate and well-controlled human clinical trials to establish the safety,purity and potency of the proposed biologic product candidatefor its intended purpose;preparation of and submission to the FDA of a BL
193、A after completion of all pivotal clinical trials;satisfactory completion of an FDA Advisory Committee review,if applicable;a determination by the FDA within 60 days of its receipt of a BLA to file the application for review;satisfactory completion of an FDA pre-approval inspection of the manufactur
194、ing facility or facilities at which the proposed product is produced toassess compliance with cGMP and to assure that the facilities,methods and controls are adequate to preserve the biological products continued safety,purity and potency,and of selected clinical investigation sites to assess compli
195、ance with Good Clinical Practices,or GCP;andFDA review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the United States.Preclinical and Clinical Development Prior to beginning the first clinical trial with a product candidate in the United
196、 States,we must submit an IND to the FDA.An IND is a request for authorizationfrom the FDA to administer an investigational new drug product to humans.The central focus of an IND submission is on the general investigational plan and theprotocol(s)for clinical studies.The IND also includes results of
197、 animal and in vitro studies assessing the toxicology,pharmacokinetics,pharmacology,andpharmacodynamic characteristics of the product;chemistry,manufacturing,and controls information;and any available human data or literature to support the useof the investigational product.An IND must become effect
198、ive before human clinical trials may begin.The IND automatically becomes effective 30 days afterreceipt by the FDA,unless the FDA,within the 30-day time period,raises safety concerns or questions about the proposed clinical trial.In such a case,the INDmay be placed on clinical hold and the IND spons
199、or and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.Submissionof an IND therefore may or may not result in FDA authorization to begin a clinical trial.Clinical trials involve the administration of the investigational product to human subjects under t
200、he supervision of qualified investigators in accordance with GCPs,which include the requirement that all research subjects provide their informed consent for their participation in any clinical study.Clinical trials are conductedunder protocols detailing,among other things,the objectives of the stud
201、y,the parameters to be used in monitoring safety and the effectiveness criteria to beevaluated.A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequentprotocol amendments.Furthermore,an independent IRB for e
202、ach site proposing to conduct the clinical trial must review and approve the plan for any clinical trialand its informed consent form before the clinical trial begins at that site and must monitor the study until completed.Regulatory authorities,the IRB or the sponsormay suspend a clinical trial at
203、any time on various grounds,including a finding that the subjects are being exposed to an unacceptable health risk or that the trial isunlikely to meet its stated objectives.Some studies also include oversight by an independent group of qualified experts organized by the clinical study sponsor,known
204、 as a data safety monitoring board,which provides authorization for whether or not a study may move forward at designated check points based on access tocertain data from the study and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other ground
205、s,such as nodemonstration of efficacy.There are also requirements governing the reporting of ongoing clinical studies and clinical study results to public registries.For purposes of BLA approval,human clinical trials are typically conducted in three sequential phases that may overlap.Phase 1 The inv
206、estigational product is initially introduced into healthy human subjects or patients with the target disease or condition.These studiesare designed to test the safety,dosage tolerance,absorption,metabolism and distribution of the investigational product in humans,the side effectsassociated with incr
207、easing doses,and,if possible,to gain early evidence on effectiveness.Phase 2 The investigational product is administered to a limited patient population with a specified disease or condition to evaluate the preliminaryefficacy,optimal dosages and dosing schedule and to identify possible adverse side
208、 effects and safety risks.Multiple Phase 2 clinical trials may beconducted to obtain information prior to beginning larger and more expensive Phase 3 clinical trials.Phase 3 The investigational product is administered to an expanded patient population to further evaluate dosage,to provide statistica
209、lly significantevidence of clinical efficacy and to further test for safety,generally at multiple geographically dispersed clinical trial sites.These clinical trials areintended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product ap
210、proval.12 In some cases,the FDA may require,or companies may voluntarily pursue,additional clinical trials after a product is approved to gain more information about theproduct.These so-called Phase 4 studies may be made a condition to approval of the BLA.Concurrent with clinical trials,companies ma
211、y complete additionalanimal studies and develop additional information about the biological characteristics of the product candidate and must finalize a process for manufacturing theproduct in commercial quantities in accordance with cGMP requirements.The manufacturing process must be capable of con
212、sistently producing quality batches ofthe product candidate and,among other things,must develop methods for testing the identity,strength,quality and purity of the final product,or for biologics,thesafety,purity and potency.Additionally,appropriate packaging must be selected and tested,and stability
213、 studies must be conducted to demonstrate that theproduct candidate does not undergo unacceptable deterioration over its shelf life.BLA Submission and Review Assuming successful completion of all required testing in accordance with all applicable regulatory requirements,the results of product develo
214、pment,nonclinicalstudies and clinical trials are submitted to the FDA as part of a BLA requesting approval to market the product for one or more indications.The BLA must includeall relevant data available from pertinent preclinical and clinical studies,including negative or ambiguous results as well
215、 as positive findings,together with detailedinformation relating to the products chemistry,manufacturing,controls,and proposed labeling,among other things.The submission of a BLA requires payment ofa substantial application user fee to FDA,unless a waiver or exemption applies.Once a BLA has been sub
216、mitted,the FDAs goal is to review standard applications within ten months after it accepts the application for filing,or,if the applicationqualifies for priority review,six months after the FDA accepts the application for filing.In both standard and priority reviews,the review process is oftensignif
217、icantly extended by FDA requests for additional information or clarification.The FDA reviews a BLA to determine,among other things,whether a product issafe,pure and potent and the facility in which it is manufactured,processed,packed,or held meets standards designed to assure the products continued
218、safety,purity and potency.The FDA may convene an advisory committee to provide clinical insight on application review questions.Before approving a BLA,the FDAwill typically inspect the facility or facilities where the product is manufactured.The FDA will not approve an application unless it determin
219、es that themanufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within requiredspecifications.Additionally,before approving a BLA,the FDA will typically inspect one or more clinical sites to assure compliance with
220、 GCP.If the FDAdetermines that the application,manufacturing process or manufacturing facilities are not acceptable,it will outline the deficiencies in the submission and often willrequest additional testing or information.Notwithstanding the submission of any requested additional information,the FD
221、A ultimately may decide that theapplication does not satisfy the regulatory criteria for approval.After the FDA evaluates a BLA and conducts inspections of manufacturing facilities where the investigational product and/or its drug substance will be produced,the FDA may issue an approval letter or a
222、Complete Response letter.An approval letter authorizes commercial marketing of the product with specific prescribinginformation for specific indications.A Complete Response letter will describe all of the deficiencies that the FDA has identified in the BLA,except that where theFDA determines that th
223、e data supporting the application are inadequate to support approval,the FDA may issue the Complete Response letter without firstconducting required inspections,testing submitted product lots,and/or reviewing proposed labeling.In issuing the Complete Response letter,the FDA mayrecommend actions that
224、 the applicant might take to place the BLA in condition for approval,including requests for additional information or clarification.TheFDA may delay or refuse approval of a BLA if applicable regulatory criteria are not satisfied,require additional testing or information and/or require post-marketing
225、 testing and surveillance to monitor safety or efficacy of a product.13 If regulatory approval of a product is granted,such approval will be granted for particular indications and may entail limitations on the indicated uses for whichsuch product may be marketed.For example,the FDA may approve the B
226、LA with a Risk Evaluation and Mitigation Strategy,or REMS,to ensure the benefits ofthe product outweigh its risks.A REMS is a safety strategy to manage a known or potential serious risk associated with a product and to enable patients to havecontinued access to such medicines by managing their safe
227、use,and could include medication guides,physician communication plans,or elements to assure safeuse,such as restricted distribution methods,patient registries and other risk minimization tools.The FDA also may condition approval on,among other things,changes to proposed labeling or the development o
228、f adequate controls and specifications.Once approved,the FDA may withdraw the product approval ifcompliance with pre-and post-marketing requirements is not maintained or if problems occur after the product reaches the marketplace.The FDA may require oneor more Phase 4 post-market trials and surveill
229、ance to further assess and monitor the products safety and effectiveness after commercialization and may limitfurther marketing of the product based on the results of these post-marketing studies.Post-Approval Requirements Any products manufactured or distributed by us pursuant to FDA approvals are
230、subject to pervasive and continuing regulation by the FDA,including,among otherthings,requirements relating to record-keeping,reporting of adverse experiences,periodic reporting,product sampling and distribution,and advertising andpromotion of the product.After approval,most changes to the approved
231、product,such as adding new indications or other labeling claims,are subject to prior FDAreview and approval.There also are continuing user fee requirements,under which FDA assesses an annual program fee for each product identified in an approvedBLA.Biologic manufacturers and their subcontractors are
232、 required to register their establishments with the FDA and certain state agencies and are subject toperiodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP,which impose certain procedural and documentationrequirements upon us and our third-party manufacturers
233、.Changes to the manufacturing process are strictly regulated,and,depending on the significance of thechange,may require prior FDA approval before being implemented.FDA regulations also require investigation and correction of any deviations from cGMP andimpose reporting requirements upon us and any t
234、hird-party manufacturers that we may decide to use.Accordingly,manufacturers must continue to expend time,money and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance.The FDA may withdraw approval if compliance with regula
235、tory requirements and standards is not maintained or if problems occur after the product reaches themarket.Later discovery of previously unknown problems with a product,including adverse events of unanticipated severity or frequency,or with manufacturingprocesses,or failure to comply with regulatory
236、 requirements,may result in revisions to the approved labeling to add new safety information;imposition of post-market studies or clinical studies to assess new safety risks;or imposition of distribution restrictions or other restrictions under a REMS program.Other potentialconsequences include,amon
237、g other things:restrictions on the marketing or manufacturing of a product,complete withdrawal of the product from the market or product recalls;fines,warning letters or holds on post-approval clinical studies;refusal of the FDA to approve pending applications or supplements to approved applications
238、,or suspension or revocation of existing product approvals;product seizure or detention,or refusal of the FDA to permit the import or export of products;orinjunctions or the imposition of civil or criminal penalties.The FDA closely regulates the marketing,labeling,advertising and promotion of biolog
239、ics.A company can make only those claims relating to safety and efficacy,purity and potency that are approved by the FDA and in accordance with the provisions of the approved label.The FDA and other agencies actively enforce thelaws and regulations prohibiting the promotion of off-label uses.Failure
240、 to comply with these requirements can result in,among other things,adverse publicity,warning letters,corrective advertising and potential civil and criminal penalties.Physicians may prescribe legally available products for uses that are not describedin the products labeling and that differ from tho
241、se tested by us and approved by the FDA.Such off-label uses are common across medical specialties.Physiciansmay believe that such off-label uses are the best treatment for many patients in varied circumstances.The FDA does not regulate the behavior of physicians in theirchoice of treatments.The FDA
242、does,however,restrict manufacturers communications on the subject of off-label use of their products.14 Biosimilars and Reference Product Exclusivity The Patient Protection and Affordable Care Act,as amended by the Health Care and Education Reconciliation Act,or collectively,the ACA,signed into law
243、in2010,includes a subtitle called the Biologics Price Competition and Innovation Act of 2009,or BPCIA,which created an abbreviated approval pathway forbiological products that are biosimilar to or interchangeable with an FDA-approved reference biological product.To date,a number of biosimilars have
244、beenlicensed under the BPCIA,and numerous biosimilars have been approved in Europe.The FDA has issued several guidance documents outlining an approach toreview and approval of biosimilars.Biosimilarity,which requires that there be no clinically meaningful differences between the biological product a
245、nd the reference product in terms of safety,purity,and potency,can be shown through analytical studies,animal studies,and a clinical study or studies.Interchangeability requires that a product is biosimilar to thereference product and the product must demonstrate that it can be expected to produce t
246、he same clinical results as the reference product in any given patient and,for products that are administered multiple times to an individual,the biologic and the reference biologic may be alternated or switched after one has beenpreviously administered without increasing safety risks or risks of di
247、minished efficacy relative to exclusive use of the reference biologic.Complexities associatedwith the larger,and often more complex,structures of biological products,as well as the processes by which such products are manufactured,pose significanthurdles to implementation of the abbreviated approval
248、 pathway that are still being worked out by the FDA.Under the BPCIA,an application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was firstlicensed by the FDA.In addition,the approval of a biosimilar product may not be made eff
249、ective by the FDA until 12 years from the date on which the referenceproduct was first licensed.During this 12-year period of exclusivity,another company may still market a competing version of the reference product if the FDAapproves a full BLA for the competing product containing that applicants o
250、wn preclinical data and data from adequate and well-controlled clinical trials todemonstrate the safety,purity and potency of its product.The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products.Other U.S.Healthcare Laws and Compliance Requirements Alth
251、ough we currently do not have any products on the market,our current and future arrangements with healthcare professionals,principal investigators,consultants,customers and third-party payors expose us to broadly applicable healthcare regulation and enforcement by the federal government and the stat
252、es andforeign governments in which we conduct our business.These laws include,without limitation,state and federal anti-kickback,fraud and abuse,false claims,privacy and security and physician sunshine laws and regulations.The federal Anti-Kickback Statute prohibits,among other things,any person or
253、entity from knowingly and willfully offering,soliciting,receiving or providingremuneration,directly or indirectly,in cash or in kind,either to induce or award the referral of an individual,for an item or service or the purchasing,recommending or ordering of a good or service,for which payment may be
254、 made under federal healthcare programs such as the Medicare and Medicaid programs.The federal Anti-Kickback Statute is subject to evolving interpretations.In the past,the government has enforced the federal Anti-Kickback Statute to reach largesettlements with healthcare companies based on,in certai
255、n cases,sham consulting and other financial arrangements with physicians.Further,the Patient Protectionand Affordable Care Act,as amended by the Health Care and Education Reconciliation Act,or collectively,the Affordable Care Act,among other things,amendsthe intent requirement of the federal Anti-Ki
256、ckback Statute and the criminal statutes governing healthcare fraud.A person or entity no longer needs to have actualknowledge of these statutes or specific intent to violate them in order to commit a violation.In addition,the Affordable Care Act provides that the government mayassert that a claim i
257、ncluding items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes ofthe civil False Claims Act or federal civil monetary penalties statute.Additionally,the federal false claims and civil monetary penalties laws,including t
258、he civil False Claims Act prohibit,among other things,knowingly presenting orcausing the presentation of a false,fictitious or fraudulent claim for payment to the U.S.government,or making a false statement to avoid,decrease,or conceal anobligation to pay money to the federal government.Actions under
259、 the civil False Claims Act may be brought by the Attorney General or as a qui tam action by aprivate individual in the name of the government.The federal government has used the civil False Claims Act,and the accompanying threat of significant liability,in its investigation and prosecution of pharm
260、aceutical and biotechnology companies throughout the country,for example,in connection with the promotion ofproducts for unapproved uses and other illegal sales and marketing practices.15 The federal Health Insurance Portability and Accountability Act of 1996,or HIPAA,created additional federal crim
261、inal statutes that prohibit,among other actions,knowingly and willfully executing,or attempting to execute,a scheme to defraud any healthcare benefit program,including private third-party payors,knowinglyand willfully embezzling or stealing from a healthcare benefit program,willfully obstructing a c
262、riminal investigation of a healthcare offense,and knowingly andwillfully falsifying,concealing or covering up a material fact or making any materially false,fictitious or fraudulent statement in connection with the delivery of orpayment for healthcare benefits,items or services.HIPAA,as amended by t
263、he Health Information Technology for Economic and Clinical Health Act,or HITECH,and their implementing regulations,imposesrequirements regarding the privacy and security of individually identifiable health information,including mandatory contractual terms,for covered entities,orcertain healthcare pr
264、oviders,health plans,and healthcare clearinghouses,and their business associates that provide services to the covered entity that involveindividually identifiable health information.HITECH also increased the civil and criminal penalties that may be imposed against covered entities and businessassoci
265、ates and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce HIPAA.In addition,there has been a recent trend of increased federal and state regulation of payments made to physicians and other healthcare providers.The AffordableCare
266、 Act,among other things,via the Physician Payments Sunshine Act,imposes annual reporting requirements on certain manufacturers of drugs,devices,biologics,and medical supplies for which payment is available under Medicare,Medicaid,or the Childrens Health Insurance Program,with specific exceptions,for
267、 payments made by them to physicians and teaching hospitals,as well as ownership and investment interests held by physicians and their immediate familymembers.Certain states also impose restrictions on pharmaceutical manufacturer marketing practices and/or require the tracking and reporting of gifts
268、,compensation andother remuneration to physicians.Certain states and local governments require the registration of pharmaceutical sales representatives.Additionally,analogousstate and foreign laws and regulations,such as state anti-kickback and false claims laws,may apply to sales or marketing arran
269、gements and claims involvinghealthcare items or services reimbursed by non-governmental third party payors,including private insurers.State laws may also apply that require pharmaceuticalcompanies to comply with the pharmaceutical industrys voluntary compliance guidelines and the relevant compliance
270、 guidance promulgated by the federalgovernment or otherwise restrict payments that may be made to healthcare providers or other potential referral sources.In addition,certain states require drugmanufacturers to report information related to payments and other transfers of value to physicians and oth
271、er healthcare providers or marketing expenditures or drugpricing.In addition,state and local laws may require the registration of pharmaceutical sales representatives.We may also be subject to,and foreign lawsgoverning the privacy and security of health information in certain circumstances,many of w
272、hich differ from each other in significant ways and often are notpreempted by HIPAA,thus complicating compliance efforts.The shifting commercial compliance environment and the need to build and maintain robust systems to comply with different compliance and/or reportingrequirements in multiple juris
273、dictions increase the possibility that a healthcare company may violate one or more of the requirements.If our operations are foundto be in violation of any of such laws or any other governmental regulations that apply to us,we may be subject to significant penalties,including,withoutlimitation,civi
274、l,criminal and administrative penalties,damages,fines,disgorgement,additional reporting requirements and oversight if we become subject to acorporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws,the curtailment or restructuring of our operations,e
275、xclusion from participation in federal and state healthcare programs and individual imprisonment,any of which could adversely affect our ability to operate ourbusiness and our financial results.16 Healthcare Reform The Affordable Care Act has had,and is expected to continue to have,a significant imp
276、act on the healthcare industry.The Affordable Care Act was designed toexpand coverage for the uninsured while at the same time containing overall healthcare costs.With regard to pharmaceutical products,among other things,theAffordable Care Act expanded and increased industry rebates for drugs covere
277、d under Medicaid programs and made changes to the coverage requirements underthe Medicare prescription drug benefit.There have been judicial,Congressional and executive branch challenges to certain aspects of the Affordable Care Act,andwe expect there will be additional challenges and amendments to
278、the Affordable Care Act in the future.While Congress has not passed comprehensive repeallegislation,it has enacted laws that modify certain provisions of the Affordable Care Act such as removing or delaying penalties,starting January 1,2019,for notcomplying with the Affordable Care Acts individual m
279、andate to carry health insurance,delaying the implementation of certain Affordable Care Act-mandatedfees,and increasing the point-of-sale discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D.Additionally,on December 15,2018,a Texas U.S.District Court Judge ruled t
280、hat the Affordable Care Act is unconstitutional in its entirety because the individual mandate was repealed byCongress.While the Texas U.S.District Court Judge,as well as the current presidential administration and the Centers for Medicare&Medicaid Services,orCMS,have stated that the ruling will hav
281、e no immediate effect pending appeal of the decision.We continue to evaluate the effect that the Affordable Care Act hason our business.Other legislative changes have been proposed and adopted in the United States since the Affordable Care Act was enacted.For example,throughthe process created by th
282、e Budget Control Act of 2011,there are automatic reductions of Medicare payments to providers up to 2%per fiscal year,which went intoeffect in April 2013 and,due to subsequent legislative amendments,will remain in effect through 2029 unless additional Congressional action is taken.In January2013,Pre
283、sident Obama signed into law the American Taxpayer Relief Act of 2012,which,among other things,further reduced Medicare payments to severalproviders.In addition,there has been heightened governmental scrutiny recently over the manner in which drug manufacturers set prices for their marketedproducts,
284、which have resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to,among other things,bringmore transparency to product pricing,review the relationship between pricing and manufacturer patient programs,and reform government program reimbursement
285、methodologies for drug products.At the federal level,the Trump administrations budget proposals for fiscal years 2019 and 2020 contain further drug pricecontrol measures that could be enacted during the budget process or in other future legislation.In addition,the current presidential administration
286、 released a“Blueprint”to lower drug prices and reduce out of pocket costs of drugs that contains additional proposals to increase manufacturer competition,increase thenegotiating power of certain federal healthcare programs,incentivize manufacturers to lower the list price of their products and redu
287、ce the out of pocket costs ofdrug products paid by consumers.The Department of Health and Human Services,or HHS,has started soliciting feedback on some of these measures and,at thesame,is implementing others under its existing authority.While some of these measures may require additional authorizati
288、on to become effective,U.S.Congressand the Trump administration have indicated that they will continue to seek new legislative and/or administrative measures to control drug costs.Although anumber of these,and other measures may require authorization to become effective,Congress and the executive br
289、anch have each indicated that it will continue toseek new legislative and/or administrative measures to control drug costs.In the coming years,additional legislative and regulatory changes could be made togovernmental health programs that could significantly impact pharmaceutical companies and the s
290、uccess of our product candidates.At the state level,legislatureshave increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing,including price or patientreimbursement constraints,discounts,restrictions on certain product access and
291、marketing cost disclosure and transparency measures,and,in some cases,designedto encourage importation from other countries and bulk purchasing.The Affordable Care Act,as well as other federal,state and foreign healthcare reformmeasures that have been and may be adopted in the future,could harm our
292、future revenues.International Regulation In addition to regulations in the United States,foreign regulations also govern clinical trials,commercial sales and distribution of product candidates within theirjurisdiction.The regulatory approval process varies from country to country and the time to app
293、roval may be longer or shorter than that required for FDA approval.In the European Union,the approval of a biosimilar for marketing is based on an opinion issued by the European Medicines Agency and a decision issued by theEuropean Commission.However,substitution of a biosimilar for the innovator is
294、 a decision that is made at the local(national)level on a country-by-country basis.Additionally,a number of European countries do not permit the automatic substitution of biosimilars for the reference product.Many countries also have publishedtheir own legislation outlining a regulatory pathway for
295、the development and approval of biosimilars.In some cases,countries have either adopted Europeanguidance or are following guidance issued by the World Health Organization.Although similarities are apparent across these various regulatory guidance,there isalso the potential for additional country-spe
296、cific requirements.17 Pharmaceutical Coverage,Pricing and Reimbursement In the United States and other countries,sales of any products for which we receive regulatory approval for commercial sale will depend in part on the availabilityof coverage and the adequacy of reimbursement from third-party pa
297、yors,including government health administrative authorities,managed care organizations,private health insurers and other organizations.Third-party payors are increasingly examining the medical necessity and cost effectiveness of drug products andservices in addition to safety and efficacy and,accord
298、ingly,significant uncertainty exists as to the reimbursement status of newly drug products.A payors decisionto provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved.Further,there is no uniform policy for coverage andreimbursement in the United States
299、.Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursementrates,but also have their own methods and approval process apart from Medicare determinations.As such,one payors determination to provide coverage for adrug product does not assure
300、that other payors will also provide coverage for the drug product.Adequate third-party reimbursement may not be available to enableus to realize an appropriate return on our investment in product development.Obtaining and maintaining adequate reimbursement for our product candidates,onceapproved,may
301、 be difficult.We may be required to conduct expensive pharmacoeconomic studies to justify coverage and reimbursement or the level ofreimbursement compared to existing approved biologics and other therapies.There may be significant delays in obtaining coverage and reimbursement for newlyapproved drug
302、s in the United States,and coverage may be more limited than the indications for which the product is approved by the FDA or similar regulatoryauthorities outside the United States.In addition,the U.S.government,state legislatures and foreign governments have continued implementing cost-containmentp
303、rograms,including price controls,restrictions on coverage and reimbursement and requirements for substitution of generic products.Adoption of price controlsand cost-containment measures and adoption of more restrictive policies in jurisdictions with existing controls and measures could further limit
304、 our net revenueand results.Decreases in third-party reimbursement for our product candidates or a decision by a third-party payor to not cover our product candidates couldreduce physician utilization of our products and have a material adverse effect on our sales,results of operations and financial
305、 condition.Employees As of September 30,2019,we had 14 full-time employees,two of whom were primarily engaged in research and development activities and two of whom have aPh.D.degree.We also have two full-time consultants,who act as executive officers.None of our employees are represented by a labor
306、 union or covered by acollective bargaining agreement.Facilities We occupy approximately 66,000 square feet of office,manufacturing and laboratory space in Cranbury,New Jersey,under a lease,as amended,that expires inFebruary 2028.Most of this space is no longer being used by us and we are in the pro
307、cess of attempting to sublease all or part of the facility to reduce expenses.Corporate Information We initially incorporated in January 2010 in New Jersey as Oncobiologics,Inc.,and in October 2015,we reincorporated in Delaware by merging with and into aDelaware corporation.In November 2018,we chang
308、ed our name to Outlook Therapeutics,Inc.Our headquarters are located at 7 Clarke Drive,Cranbury,NewJersey,08512,and our telephone number at that location is(609)619-3990.Our website address is .The information contained on,or that can be accessed through,our website is not part of,and is not incorpo
309、rated by reference into this Annual Report on Form 10-K.18 Item 1A.Risk Factors You should consider carefully the risks and uncertainties described below,together with all of the other information in this Annual Report on Form 10-K.If any ofthe following risks are realized,our business,financial con
310、dition,results of operations and prospects could be adversely affected.The risks described below arenot the only risks facing our company.Risks and uncertainties not currently known to us or that we currently deem to be immaterial also may adversely affect ourbusiness,financial condition,results of
311、operations and/or prospects.Risks Related to Our Financial Condition and Capital Requirements We have incurred significant losses and negative cash flows from operations since our inception and expect to continue to incur significant losses and negativecash flows from operations for at least the nex
312、t 12 months.We are a late clinical-stage biopharmaceutical company and we have incurred net losses in each year since our inception in January 5,2010,including net losses of$34.5 million and$30.1 million for the years ended September 30,2019 and 2018,respectively.We have devoted substantially all of
313、 our financial resources to identify,develop and manufacture our product candidates,including conducting,among otherthings,analytical characterization,process development and manufacture,formulation and clinical trials,regulatory filing and communication activities andproviding general and administr
314、ative support for these operations.To date,none of our product candidates have been approved for sale and we have financed ouroperations primarily through the sale of equity securities and debt financings,as well as to a limited degree,payments under our co-development and licenseagreements with Zhe
315、jiang Huahai Pharmaceutical Co.,Ltd.,or Huahai,Laboratorios Liomont,S.A.de C.V.,or Liomont,IPCA Laboratories Limited,or IPCA,andBioLexis Pte.Ltd.,or BioLexis.The amount of our future net losses will depend,in part,on our ability to generate revenue from product sales,the rate of ourfuture expenditur
316、es and our ability to obtain funding through equity or debt financing or strategic licensing or co-development collaborations.We expect to continue to incur significant expenses and operating losses for at least the next 12 months.We anticipate that our expenses may increase substantiallyif and as w
317、e:continue the clinical development of our lead product candidate,ONS-5010;advance ONS-5010 into additional clinical trials;change or add contract manufacturing providers,clinical research service providers,testing laboratories,device suppliers,legal service providers or othervendors or suppliers;se
318、ek regulatory and marketing approvals for ONS-5010 in the United States and other markets if we successfully complete clinical trials;establish a sales,marketing and distribution infrastructure to commercialize any products for which we may obtain marketing approval;seek to identify,assess,acquire o
319、r develop other product candidates that may be complementary to ONS-5010;make upfront,milestone,royalty or other payments under any license agreements;seek to create,maintain,protect and expand our intellectual property portfolio;engage in litigation,including patent litigation,with respect to our p
320、roduct candidates;seek to attract and retain skilled personnel;create additional infrastructure to support our operations as a public company and any future commercialization efforts;andexperience any delays or encounter issues with any of the above,including but not limited to failed clinical trial
321、s,conflicting results,safety issues orregulatory challenges that may require longer follow-up of existing studies,additional major studies or additional supportive studies in order to pursuemarketing approval.Our failure to become and remain profitable would decrease our value and could impair our a
322、bility to raise capital,maintain our research and development efforts,expand our business or continue our operations.A decline in our value could also cause you to lose all or part of your investment.19 Our independent registered public accounting firm has expressed substantial doubt about our abili
323、ty to continue as a going concern.As described in their audit report,our auditors have included an explanatory paragraph that states that we have incurred recurring losses and negative cash flowsfrom operations and have a stockholders deficit at September 30,2019 of$16.1 million,$6.7 million of conv
324、ertible senior secured notes that become due onDecember 22,2019,$3.6 million unsecured indebtedness due on demand,and$1.0 million of unsecured notes also due on demand,but subject to a forbearanceagreement through March 2020.These matters raise substantial doubt about our ability to continue as a go
325、ing concern.Our consolidated financial statements donot include any adjustments that might result from the outcome of this uncertainty.If we cannot continue as a viable entity,our securityholders may lose some orall of their investment in our company.We have never generated any revenue from product
326、sales and may never be profitable.Although we have received upfront and milestone payments from our license and collaboration agreements,we have no products approved for commercializationand have never generated any revenue from product sales.Our ability to generate revenue and achieve profitability
327、 depends on our ability,alone or with strategiccollaboration partners,to successfully complete the development of,and obtain the regulatory and marketing approvals necessary to commercialize,ONS-5010 forthe treatment of wet age related macular degeneration,or wet AMD,and our other targeted indicatio
328、ns,and as appropriate,any of our other product candidates.We cannot predict when we will begin generating revenue from product sales,as this depends heavily on our success in many areas,including but not limited to:completing clinical development of ONS-5010 for the treatment of wet AMD and the othe
329、r targeted indications,and any other product candidates we maydevelop in the future;obtaining regulatory and marketing approvals for ONS-5010 and any other product candidates for which we or our partners complete clinical trials;securing a manufacturing partner for ONS-5010 and any approved product
330、candidates to support clinical development,regulatory requirements and themarket demand for any such approved product candidates;launching and commercializing ONS-5010 and any other product candidates for which we or our partners obtain regulatory and marketing approval;obtaining third-party coverag
331、e and adequate reimbursements for our products;obtaining market acceptance of ONS-5010 and any other product candidates for which we obtain regulatory and marketing approval as viable treatmentoptions;negotiating favorable terms in any collaboration,licensing or other arrangements into which we may
332、enter;maintaining,protecting and expanding our portfolio of intellectual property rights,including patents,trade secrets and know-how;andattracting,hiring and retaining qualified personnel.Even if ONS-5010 or one or more of our other product candidates is approved for commercialization,we anticipate
333、 incurring significant costs to commercializeany such product.Our expenses could increase beyond our expectations if we are required by the U.S.Food and Drug Administration,or the FDA,the EuropeanMedicines Agency,or the EMA,other regulatory agencies,domestic or foreign,or by any unfavorable outcomes in intellectual property litigation filed against us,to change our manufacturing processes or assay
0731-84720580
sgpjbg002
工作日 9:30 - 18:00
研報
新質生產力
DeepSeek?
低空經濟
大模型
AI Agent
AI Infra
具身智能
自動駕駛
寵物
銀發經濟
人形機器人
企業出海
算力
微短劇
薪酬
白皮書
創新藥
人工智能
AI產業
信息科技
互聯網
消費經濟
汽車交通
電商零售
傳媒娛樂
醫藥健康
投資金融
能源環境
地產建筑
傳統產業
英文報告
其它
最新報告
中英對照
全文搜索
報告精選
PDF上傳翻譯
多格式文檔互轉
入駐&報告售賣
會員權益
機構報告
券商研報
財報庫
專題合集
英文報告
數據圖表
會議報告
其他資源
行業聚焦
芯片產業
熱點概念
全球咨詢智庫
人工智能
500強
新質生產力
會議峰會
新能源汽車
企業年報
互聯網
公司研究
行業綜觀
消費教育
科技通信
醫藥健康
人力資源
投資金融
汽車產業
物流地產
電子商務
傳統產業
傳媒營銷
其它
2025低空經濟/低空產業報告合集（共49套打包）
2025年智算中心/AIDC/AI數據中心研究報告合集（共37套打包）
AI、科技與通信
廣告、傳媒與營銷
消費、零售與支付
HR、文化與旅游
金融、保險與投資
能源、環境與工業
醫療制藥與大健康
物流、地產與建筑
其他行業
AI ? 科技 ? 通信
數字化
金融財經
智能制造
電商傳媒
地產建筑
醫療醫學
能源化工
其他行業
收藏
下載
2025-05-20
AI查數
行業數據
政策法規
商業模式
產業鏈
競爭格局
市場規模
產業概述
其它
2025年
AI讀財報
年報
一季報
半年報
三季報
IPO招股書
社會責任報告
A股
IPO申報
港股
美股&全球
新三板
掃碼登錄
手機快捷登錄
賬號登錄
