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1、Cancer has no borders.Neither do we.2022 Annual ReportUNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington,D.C.20549FORM 10-K(Mark One)ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended December 31,2022 ORTRANSITION REPORT PURSUANT TO SE
2、CTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the transition period from to Commission file number:001-37686 BEIGENE,LTD.(Exact Name of Registrant as Specified in its Charter)Cayman Islands98-1209416(State or other jurisdiction of incorporation or organization)(I.R.S.Employer Identifica
3、tion No.)c/o Mourant Governance Services(Cayman)Limited94 Solaris Avenue,Camana BayGrand CaymanCayman Islands KY1-1108(Address of principal executive offices,including zip code)+1(345)949 4123(Registrants Telephone Number,Including Area Code)Securities registered pursuant to Section 12(b)of the Act:
4、Title of each classTrading Symbol(s)Name of each exchange on which registeredAmerican Depositary Shares,each representing 13 Ordinary Shares,par value$0.0001 per shareBGNEThe NASDAQ Global Select MarketOrdinary Shares,par value$0.0001 per share*06160The Stock Exchange of Hong Kong Limited*Included i
5、n connection with the registration of the American Depositary Shares(ADSs)with the U.S.Securities and Exchange Commission.The ordinary shares are not listed for trading in the United States but are listed for trading on The Stock Exchange of Hong Kong Limited(HKEx).Securities registered pursuant to
6、Section 12(g)of the Act:The RMB shares are ordinary shares of the registrant issued to permitted investors in the Peoples Republic of China and listed and traded on the STAR Market in Renminbi.The RMB shares are not listed for trading in the United States or on the HKEx and are not fungible with the
7、 ordinary shares listed on the HKEx or the ADSs representing the ordinary shares listed on NASDAQ,and in no event will any RMB shares be able to be converted into the ordinary shares listed on the HKEx or the ADSs listed on NASDAQ,or vice versa.Indicate by check mark if the registrant is a well-know
8、n seasoned issuer,as defined in Rule 405 of the Securities Act.Yes No Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d)of the Exchange Act.Yes No Indicate by check mark whether the registrant:(1)has filed all reports required to be filed
9、 by Section 13 or 15(d)of the Securities Exchange Act of 1934 during the preceding 12 months(or for such shorter period that the registrant was required to file such reports),and(2)has been subject to such filing requirements for the past 90 days.Yes No Indicate by check mark whether the registrant
10、has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T during the preceding 12 months(or for such shorter period that the registrant was required to submit such files).Yes No Indicate by check mark whether the registrant is a large ac
11、celerated filer,an accelerated filer,a non-accelerated filer,a smaller reporting company,or an emerging growth company.See the definitions of“large accelerated filer,”“accelerated filer,”“smaller reporting company,”and“emerging growth company”in Rule 12b-2 of the Exchange Act.:Large accelerated file
12、rAccelerated filerNon-accelerated filerSmaller reporting companyEmerging growth companyIf an emerging growth company,indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant t
13、o Section 13(a)of the Exchange Act.Indicate by check mark whether the registrant has filed a report on and attestation to its managements assessment of the effectiveness of its internal control over financial reporting under Section 404(b)of the Sarbanes-Oxley Act(15 U.S.C.7262(b)by the registered p
14、ublic accounting firm that prepared or issued its audit report.If securities are registered pursuant to Section 12(b)of the Act,indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statement
15、s.Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrants executive officers during the relevant recovery period pursuant to 240.10D-1(b).Indicate by check mark whether the reg
16、istrant is a shell company(as defined in Rule 12b-2 of the Exchange Act).Yes No As of June 30,2022,the last business day of the registrants most recently completed second fiscal quarter,the aggregate market value of the ordinary shares,including in the form of ADSs,each representing 13 ordinary shar
17、es,held by non-affiliates of the registrant was approximately$16.8 billion,based upon the closing price of the registrants ADSs on the NASDAQ Global Select Market on June 30,2022.As of February 14,2023,1,356,140,180 ordinary shares,par value$0.0001 per share,were outstanding,of which 863,876,312 ord
18、inary shares were held in the form of 66,452,024 ADSs,and 115,055,260 were RMB shares.DOCUMENTS INCORPORATED BY REFERENCEThe registrant intends to file a definitive proxy statement pursuant to Regulation 14A within 120 days of the end of the fiscal year ended December 31,2022.Portions of such defini
19、tive proxy statement are incorporated by reference into Part III of this Annual Report on Form 10-K.BeiGene,Ltd.Annual Report on Form 10-KTABLE OF CONTENTS PagePART I Item 1.Business5Item 1A.Risk Factors58Item 1B.Unresolved Staff Comments113Item 2.Properties113Item 3.Legal Proceedings113Item 4.Mine
20、Safety Disclosures114 PART II Item 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purchases of Equity Securities115Item 6.Reserved118Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations119Item 7A.Quantitative and Qualitative Discl
21、osures About Market Risk133Item 8.Financial Statements and Supplementary Data134Item 9.Changes in and Disagreements With Accountants on Accounting and Financial Disclosure134Item 9A.Controls and Procedures134Item 9B.Other Information135Item 9C.Disclosure Regarding Foreign Jurisdictions that Prevent
22、Inspections135 PART III Item 10.Directors,Executive Officers and Corporate Governance137Item 11.Executive Compensation137Item 12.Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters137Item 13.Certain Relationships and Related Transactions,and Director Indepe
23、ndence137Item 14.Principal Accounting Fees and Services137 PART IV Item 15.Exhibits,Financial Statement Schedules138Item 16.Form 10-K Summary138 SIGNATURES Forward-Looking Statements and Market DataThis Annual Report on Form 10-K(the“Annual Report”)contains forward-looking statements that involve su
24、bstantial risks and uncertainties.We have based these forward-looking statements largely on our current expectations and projections about future events and trends that we believe may affect our business,financial condition,and operating results.All statements other than statements of historical fac
25、ts contained in this Annual Report,including statements regarding our strategy,future operations,future financial position,future revenue,projected costs,prospects,plans,objectives of management and expected growth,are forward-looking statements.Forward looking statements often include words such as
26、,but not limited to,“aim,”“anticipate,”“believe,”“can,”“continue,”“could,”“estimate,”“expect,”“goal,”“intend,”“may,”“ongoing,”“plan,”“potential,”“predict,”“project,”“seek,”“should,”“target,”“will,”“would”or the negative of these terms or similar expressions.These forward-looking statements include,a
27、mong other things,statements about:our ability to successfully commercialize our approved medicines and to obtain approvals in additional indications and territories for our medicines;our ability to successfully develop and commercialize our in-licensed medicines and drug candidates and any other me
28、dicines and drug candidates we may in-license;our ability to further develop sales and marketing capabilities and launch and commercialize new medicines,if approved;our ability to maintain and expand regulatory approvals for our medicines and drug candidates,if approved;the pricing and reimbursement
29、 of our medicines and drug candidates,if approved;the initiation,timing,progress and results of our preclinical studies and clinical trials and our research and development programs;our ability to advance our drug candidates into,and successfully complete,clinical trials and obtain regulatory approv
30、als;our reliance on the success of our clinical stage drug candidates;our plans,expected milestones and the timing or likelihood of regulatory filings and approvals;the implementation of our business model,strategic plans for our business,medicines,drug candidates and technology;the scope of protect
31、ion we(or our licensors)are able to establish and maintain for intellectual property rights covering our medicines,drug candidates and technology;our ability to operate our business without infringing,misappropriating or otherwise violating the intellectual property rights and proprietary technology
32、 of third parties;costs associated with enforcing or defending against intellectual property infringement,misappropriation or violation,product liability and other claims;the regulatory environment and regulatory developments in the United States,China,the United Kingdom,Switzerland,the European Uni
33、on(EU)and other jurisdictions in which we operate;the accuracy of our estimates regarding expenses,revenues,capital requirements and our need for additional financing;the potential benefits of strategic collaboration and licensing agreements and our ability to enter into and maintain strategic arran
34、gements;our plans and expectations to build significant technical operations and independent production capabilities for small molecule medicines and large molecule biologics to support the global demand for both commercial and clinical supply;our reliance on third parties to conduct drug developmen
35、t,manufacturing and other services;our ability to manufacture and supply,or have manufactured and supplied,drug candidates for clinical development and medicines for commercial sale;the rate and degree of market access and acceptance of our medicines and drug candidates,if approved;1developments rel
36、ating to our competitors and our industry,including competing therapies;the size of the potential markets for our medicines and drug candidates and our ability to serve those markets;our ability to effectively manage our growth;our ability to attract and retain qualified employees and key personnel;
37、statements regarding future revenue,hiring plans,key milestones,expenses,capital expenditures,capital requirements and share performance;the future trading price of our American Depositary Shares(ADS)listed on NASDAQ,our ordinary shares listed on HKEx,and our ordinary shares issued to permitted inve
38、stors in China and listed and traded on the STAR in Renminbi(RMB Shares),as well as the impact of securities analysts reports on these prices;andthe impact of the COVID-19 pandemic on our clinical development,regulatory,commercial,manufacturing,and other operations.These statements involve risks and
39、 uncertainties,including those that are described in Part I-Item 1A-Risk Factors of this Annual Report,that may cause actual future events or results to differ materially from those expected.Given these uncertainties,you should not place undue reliance on these forward-looking statements.We do not a
40、ssume any obligation to update any forward-looking statements whether as a result of new information,future events or otherwise,except as required by applicable law.This Annual Report includes statistical and other industry and market data that we obtained from industry publications and research,sur
41、veys and studies conducted by third parties.Industry publications and third-party research,surveys and studies generally indicate that their information has been obtained from sources believed to be reliable,although they do not guarantee the accuracy or completeness of such information.While we bel
42、ieve these industry publications and third-party research,surveys and studies are reliable,you are cautioned not to give undue weight to this information.2Summary of Risk FactorsBelow is a summary of the material factors that make an investment in our ADSs,ordinary shares or RMB Shares speculative o
43、r risky.This summary does not address all of the risks that we face.Additional discussion of the risks summarized in this risk factor summary,and other risks that we face,are summarized in“Part I-Item 1A-Risk Factors”and should be carefully considered,together with other information in this Annual R
44、eport and our other filings with the SEC,before making an investment decision regarding our ADSs,ordinary shares or RMB shares.Our medicines may fail to achieve and maintain the degree of market acceptance by physicians,patients,third-party payors,and others in the medical community necessary for co
45、mmercial success.We have limited experience in launching and marketing our internally developed and in-licensed medicines.If we are unable to further develop marketing and sales capabilities or enter into agreements with third parties to market and sell our medicines,we may not be able to generate s
46、ubstantial product sales revenue.We face substantial competition,which may result in others discovering,developing,or commercializing competing medicines before or more successfully than we do.The market opportunities for our medicines may be limited to those patients who are ineligible for or have
47、failed prior treatments and may be small.If we or any third parties with which we may collaborate to market and sell our medicines are unable to achieve and maintain coverage and adequate levels of reimbursement,our commercial success and business operations could be adversely affected.We depend sub
48、stantially on the success of the clinical development of our medicines and drug candidates.If we are unable to successfully complete clinical development,obtain regulatory approvals and commercialize our medicines and drug candidates,or experience significant delays in doing so,our business will be
49、materially harmed.Clinical development involves a lengthy and expensive process with an uncertain outcome,and results of earlier studies and trials may not be predictive of future trial results.If clinical trials of our drug candidates fail to demonstrate safety and efficacy to the satisfaction of r
50、egulatory authorities or do not otherwise produce positive results,we may incur additional costs or experience delays in completing,or ultimately be unable to complete,the development and commercialization of our drug candidates.If we encounter difficulties enrolling patients in our clinical trials,
51、our clinical development activities could be delayed or otherwise adversely affected.All material aspects of the research,development,manufacturing and commercialization of pharmaceutical products are heavily regulated,and we may face difficulties in complying with or be unable to comply with such r
52、egulations,which could have a material adverse effect on our business.The approval processes of regulatory authorities in the United States,China,Europe and other comparable regulatory authorities are lengthy,time consuming,costly and inherently unpredictable.If we experience delays or are ultimatel
53、y unable to obtain regulatory approval for our drug candidates,our business will be substantially harmed.Our medicines and any future approved drug candidates will be subject to ongoing regulatory obligations and continued regulatory review,which may result in significant additional expense and we m
54、ay be subject to penalties if we fail to comply with regulatory requirements or experience unanticipated problems with our medicines and drug candidates.Even if we are able to commercialize our medicines and any approved drug candidates,the medicines may become subject to unfavorable pricing regulat
55、ions or third-party reimbursement practices or healthcare reform initiatives,which could harm our business.We have incurred significant net losses since our inception and anticipate that we will continue to incur net losses for the foreseeable future and may not become profitable.We may need to obta
56、in additional financing to fund our operations,and if we are unable to obtain such financing,we may be unable to complete the development of our drug candidates or achieve profitability.3If we are unable to obtain and maintain patent protection for our medicines and drug candidates through intellect
57、ual property rights,or if the scope of such intellectual property rights is not sufficiently broad,third parties may compete against us.We rely on third parties to manufacture some of our commercial and clinical drug supplies.Our business could be harmed if those third parties fail to provide us wit
58、h sufficient quantities of product or fail to do so at acceptable quality levels or prices.We have entered into licensing and collaboration arrangements and may enter into additional collaborations,licensing arrangements,or strategic alliances in the future,and we may not realize the benefits of suc
59、h arrangements.If we fail to maintain an effective distribution channel for our medicines,our business and sales could be adversely affected.If third-party manufacturers fail to comply with manufacturing regulations,our financial results and financial condition could be adversely affected.If we are
60、not able to successfully develop and/or commercialize Amgens oncology products,the expected benefits of the collaboration will not materialize.We have significantly increased and expect to continue to increase our research,development,manufacturing,and commercial capabilities,and we may experience d
61、ifficulties in managing our growth.Our future success depends on our ability to retain key executives and to attract,retain and motivate qualified personnel.Our business is subject to complex and evolving industry-specific laws and regulations regarding the collection and transfer of personal data.T
62、hese laws and regulations can be complex and stringent,and many are subject to change and uncertain interpretation,which could result in claims,changes to our data and other business practices,significant penalties,increased cost of operations,or otherwise adversely impact our business.We manufactur
63、e some of our medicines and intend to manufacture some of our drug candidates,if approved.Failure to comply with regulatory requirements could result in sanctions being imposed against us and delays in completing and receiving regulatory approvals for our manufacturing facilities,or damage to,destru
64、ction of or interruption of production at such facilities,could delay our development plans or commercialization efforts.Changes in the political and economic policies of the PRC government or in relations between China and the United States or other governments and the significant oversight and dis
65、cretion the PRC government has over the conduct of the business operations of our PRC subsidiaries may materially and adversely affect our business,financial condition,and results of operations and may result in our inability to sustain our growth and expansion strategies.The audit reports included
66、in our previous annual reports on Form 10-K filed with the SEC have historically been prepared by auditors who are not inspected fully by the Public Company Accounting Oversight Board,and as such,investors have previously been deprived of the benefits of such inspection.The trading prices of our ord
67、inary shares,ADSs and/or RMB Shares can be volatile,which could result in substantial losses to you.4PART IUnless the context requires otherwise,references in this report to“BeiGene,”the“Company,”“we,”“us,”and“our”refer to BeiGene,Ltd.and its subsidiaries,on a consolidated basis.Item 1.BusinessOverv
68、iewWe are a global biotechnology company that is developing and commercializing innovative and affordable oncology medicines to improve treatment outcomes and access for patients worldwide.We currently have three approved medicines that were discovered and developed in our own labs,including BRUKINS
69、A,a small molecule inhibitor of Brutons Tyrosine Kinase(BTK)for the treatment of various blood cancers;tislelizumab,an anti-PD-1 antibody immunotherapy for the treatment of various solid tumor and blood cancers;and pamiparib,a selective small molecule inhibitor of PARP1 and PARP2.We have obtained ap
70、provals to market BRUKINSA in the United States,the Peoples Republic of China(China or the PRC),the European Union(EU),the United Kingdom(UK),Canada,Australia and additional international markets,and tislelizumab and pamiparib in China.By leveraging our China commercial capabilities,we have in-licen
71、sed the rights to distribute 13 approved medicines for the China market.Supported by our global clinical development and commercial capabilities,we have entered into collaborations with world-leading biopharmaceutical companies such as Amgen Inc.(Amgen)and Novartis Pharma AG(Novartis)to develop and
72、commercialize innovative medicines.We are committed to advancing best and first-in-class clinical candidates internally or with like-minded partners to develop impactful and affordable medicines for patients across the globe.Our internal clinical development capabilities are deep,including a more th
73、an 2,700-person global clinical development and medical affairs team that is running more than 80 ongoing or planned clinical trials in over 50 medicines and drug candidates.This includes more than 30 pivotal or potentially registration-enabling trials across our portfolio,including our three intern
74、ally discovered,approved medicines.We have enrolled in our clinical trials more than 18,000 subjects,of which approximately one-half have been outside of China.We have built,and are expanding,our internal manufacturing capabilities through our state-of-the-art biologic and small molecule manufacturi
75、ng facilities in China to support current and potential future demand of our medicines,and are building a commercial-stage biologics manufacturing and clinical R&D center in New Jersey.We also work with high quality contract manufacturing organizations(CMOs)to manufacture our internally developed cl
76、inical and commercial products.Since our inception in 2010,we have become a fully integrated global organization of over 9,000 employees in 29 countries and regions,including the United States,China,Europe,and Australia.5Our Holding Company StructureWe are a holding company incorporated in the Cayma
77、n Islands with operations primarily conducted through our subsidiaries in the United States,China,United Kingdom,Switzerland and Australia.The following diagram depicts a summary of our corporate structure.Currently,our corporate structure contains no variable interest entities.Our StrategyWe were f
78、ounded with the vision to create an integrated biopharmaceutical company to transform the biotech industry,creating impactful medicines that will be affordable and accessible to far more patients around the world.We have made significant progress towards accomplishing this vision over our first 12 y
79、ears and have five strategic competitive advantages positioning us for success both near-and long-term:1.We have built one of the worlds largest,most productive and cost-effective oncology research teams with more than 950 scientists.Their efforts have been validated by commercial approvals,clinical
80、 data,and collaborations that have secured$1.4 billion in collaboration payments to the company.We have successfully developed three commercially approved medicines from our internal discovery engine,including BRUKINSA and tislelizumab.We design each research program with a differentiated biological
81、 hypothesis or a first-in-class mechanism of action.Our lead medicine,BRUKINSA,has demonstrated superiority for both progression-free survival and overall response rate versus ibrutinib in relapsed or refractory CLL.Our broad pipeline also includes internally developed products with the potential to
82、 be best-in-class or first-in-class,including our BCL-2 inhibitor,BGB-11417,our HPK1 inhibitor,BGB-15025,and BGB-16673,a BTK-targeted CDAC program that has demonstrated its potential with early data.Our pipeline also includes many early-stage assets for targets like OX40,LAG-3,and TIM-3.We have inve
83、sted in technology platforms,including CDAC protein degraders,bispecific antibodies,tri-specific antibodies,ADC,CAR-NK,and mRNA.Our research and innovation capabilities will ensure we discover high-quality and impactful medicines for patients.2.We have built a substantial global clinical development
84、 team of 2,300 people on five continents,allowing us to run clinical trials predominantly without reliance on third party contract research organizations(CROs).Clinical development accounts for over 75%of the cost and most of the time to develop a medicine.We believe that by fully integrating these
85、capabilities,we can create a strategic competitive advantage.By retaining clinical development activities internally,we can decrease the costs of our trials,increase enrollment speed,and leverage technology to ensure quality and consistency across trials and clinical sites.It also allows us to becom
86、e more inclusive in the location and number of clinical sites to help improve the diversity of patients in our trials.Our demonstrated ability to complete large-scale,multi-regional clinical trials is one of our most important strategic competitive advantages and addresses an immense challenge in th
87、e pharmaceutical industry.3.We have built a strong commercial portfolio,centered around two cornerstone medicines,BRUKINSA and tislelizumab,that are becoming primary revenue sources and will support the development of our future pipeline and 6additional combination therapies.Our hematological franch
88、ise is led by BRUKINSA,which is supported by a broad clinical program with over 4,800 patients in 35 trials in 29 markets.We ran two extensive head-to-head studies versus ibrutinib with over 800 patients enrolled.We are the first and only BTK inhibitor to demonstrate superior efficacy versus ibrutin
89、ib,and the data from the head-to-head ALPINE trial were selected for the prestigious late-breaker session at the American Society of Hematology(ASH)meeting in late 2022,with simultaneous publication in The New England Journal of Medicine.Based on the pooled safety data generated from our trials,we h
90、ave shown a very favorable safety profile,especially when compared to ibrutinib in cardiovascular safety,including atrial fibrillation,ventricle arrhythmia,and hypertension.We believe BRUKINSA allows us to build a strong position in heme-oncology with our pipeline medicines,including our BCL-2 inhib
91、itor,in both monotherapy and combination settings.Our solid tumor franchise is led by our anti-PD-1 monoclonal antibody,tislelizumab,which is currently approved in China in ten indications.Tislelizumab has achieved the commercial market leader position in China in the PD-1/PDL-1 class.Outside of Chi
92、na,in conjunction with our partner Novartis,we have filed applications for approval in the U.S.and EU.With tislelizumab and the potentially best-in-class or first-in-class pipeline assets targeting OX40,TIGIT,LAG-3,and TIM-3,we are well-positioned to build our immuno-oncology business and deliver in
93、novative therapies and combinations to patients.4.We have a differentiated international commercial organization of over 3,500 people to deliver medicines to patients around the globe.In China,the commercial team is actively driving the uptake of our internally developed and partnered medicines acro
94、ss solid tumors and hematology.BRUKINSA and tislelizumab have achieved market leadership positions in China in the BTKi and PD-1/PDL-1 classes,respectively,and we have launched and sell more than 13 products from our business partners around the globe.In North America,our U.S.team has continued to g
95、row BRUKINSA sales as we launch new indications and expand to Canada.In Europe,we have built a targeted commercial team focused on medical thought leaders in blood cancer treatments.Altogether,BRUKINSA has been approved in over 65 markets,with additional filings pending or planned.Our strategy is to
96、 commercialize our medicines broadly throughout the world.Our commercial capabilities have expanded into the Asia Pacific region through our affiliates,the Latin America region,and other emerging markets through distribution partners.We have built a global commercial organization that will drive the
97、 delivery of highly effective and differentiated medicines to patients around the globe,and will collaborate with business partners to bridge health inequities.5.We have financial strength.In a time when the cost of capital has risen,we are well positioned financially.We already have substantial rev
98、enue from our cornerstone assets,which we expect to continue to grow significantly in 2023 and beyond.We expect product revenue growth to outpace our operating expense growth in the near-term,which will allow us to continue to improve our operating leverage.We will continue to be thoughtful and stra
99、tegic in how we deploy our capital,and we are committed to generating long-term value.7Our Commercial and Registration Stage ProductsThe following table summarizes the status of our commercial products and new products that are pending approval as of February 27,2023:PRODUCTLEAD INDICATIONSMECHANISM
100、 OF ACTIONREGULATORY STATUSBEIGENE COMMERCIAL RIGHTSPARTNER U.S.:CLL/SLL,R/R MCL1,WM&R/R MZL1;China:R/R MCL2,R/R CLL/SLL2&R/R WM2;EU3:WM,R/R MZL,R/R CLL/SLLBTK inhibitorApproved in more than 65 markets,incl.U.S.,China,EU and other marketsGlobalN/A1L Squamous and Non-Squamous NSCLC/2/3 L NSCLC/R/R cl
101、assical Hodgkins lymphoma2/2/3 L HCC2/R/R PD-L1+UC2,MSI-H or dMMR solid tumors,2L ESCC,1L NPC,1L GC/GEJCAnti-PD-1 antibodyApproved in China;BLA accepted in U.S.4;MAA accepted in EU4Outside North America,Japan,EU and six other European countries3L BRCA-mutated ovarian cancer2PARP inhibitorApproved in
102、 ChinaGlobalN/AGiant cell tumor of bone8/Skeletal Related Events(SREs)8Anti-RANK ligand antibodyApproved in ChinaMainland ChinaR/R Acute lymphocytic leukemia8Anti-CD19 x anti-CD3 bispecific T-cell engager(BiTE)Approved in ChinaMainland ChinaR/R Multiple myeloma8Proteasome inhibitorApproved in ChinaM
103、ainland ChinaR/R adult multiple myeloma,newly diagnosed multiple myeloma,previously treated follicular lymphomaAnti-angiogenesis,immuno-modulationApproved in ChinaMainland ChinaMyelodysplastic syndromes,acute myeloid leukemia,chronic myelomonocytic leukemiaDNA hypomethylationApproved in ChinaMainlan
104、d ChinaIdiopathic multicentric Castleman diseaseIL-6 antagonistApproved in ChinaGreater ChinaHigh-risk neuroblastoma2Anti-GD2 antibodyApproved in ChinaMainland ChinaPOBEVCY(Avastin biosimilar)Colorectal and lung cancersAnti-VEGF antibodyApproved in ChinaGreater ChinaTAFINLAR(dabrafenib)Melanoma5BRAF
105、 inhibitorApproved in ChinaChina Broad Markets7MEKINIST(trametinib)Melanoma5MEK inhibitorApproved in ChinaChina Broad Markets7VOTRIENT(pazopanib)Advance renal cell carcinomaVEGFR inhibitorApproved in ChinaChina Broad Markets7AFINITOR(everolimus)Advanced renal cell carcinoma6mTOR inhibitorApproved in
106、 ChinaChina Broad Markets7ZYKADIA(ceritinib)ALK+NSCLCALK inhibitorApproved in ChinaChina Broad Markets781.Approved under accelerated approval.Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.2.Conditionally approve
107、d.Full approval for these indications is contingent upon results from ongoing randomized,controlled confirmatory clinical trials.3.The approval is applicable to all 27 EU member states,plus Iceland,Lichtenstein and Norway.4.U.S.:For patients with unresectable recurrent locally advanced or metastatic
108、 ESCC after prior systemic therapy.EU:For patients with advanced or metastatic ESCC after prior systemic chemotherapy and for patients with NSCLC including:locally advanced or metastatic NSCLC after prior chemo,in combination with chemotherapy for 1L advanced or metastatic squamous NSCLC,and in comb
109、ination with chemotherapy for 1L locally advanced or metastatic non-squamous NSCLC with no EGFR or ALK positive mutations.5.TAFINLAR and MEKINIST are being investigated in combination by Novartis for NSCLC indications.6.Following progression on or after vascular endothelial growth factor(VEGF)-targe
110、ted therapy.7.Rights to promote and market in Chinas broad markets pursuant to a Market Development Agreement with an affiliate of Novartis Pharma AG.8.Conditionally approved.Full approval of any particular indication will depend on the results of required post-marketing study(ies)in China.Abbreviat
111、ions:ALK=anaplastic lymphoma kinase;BLA=Biologics License Application;BRAF=B-rapidly accelerated fibrosarcoma;CLL=chronic lymphocytic leukemia;EGFR=epidermal growth factor receptor;ESCC=esophageal squamous cell carcinoma;GC=gastric cancer;GEJC=gastroesophageal junction cancer;HCC=hepatocellular carc
112、inoma;MAA=marketing aothorization application;MCL=mantle cell lymphoma;MEK=mitogen-activated protein kinase(MAPK)/Extracellular-signal regulated kinase(ERK);mTOR=Mammalian target of rapamycin;MZL=marginal zone lymphoma;NPC=nasopharyngeal cancer;NSCLC=non-small cell lung cancer;R/R=relapsed/refractor
113、y;SLL=small lymphocytic lymphoma;UC=urothelial carcinoma;VEGFR=vascular endothelial growth factor receptor;WM=Waldenstrms macroglobulinemiaWe commercialize the following internally developed cancer medicines:BRUKINSABRUKINSA is a next-generation small molecule inhibitor of BTK designed to maximize B
114、TK occupancy and minimize off-target binding effects.Zanubrutinib is an orally active inhibitor that covalently binds to BTK,resulting in irreversible inactivation of the enzyme.We are marketing BRUKINSA in the United States,China,Europe,the United Kingdom,Canada,Australia and other markets.In the U
115、nited States,BRUKINSA received accelerated approval as a treatment for mantle cell lymphoma(MCL)in adult patients who have received at least one prior therapy(November 2019),and has since also been approved for patients with Waldenstrms macroglobulinemia(WM)and relapsed or refractory(R/R)marginal zo
116、ne lymphoma(MZL)who have received at least one anti-CD20-based regimen.The MCL and MZL indications were approved under accelerated approval based on overall response rate.Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmator
117、y trial.In January 2023,BRUKINSA was approved by the U.S.Food and Drug Administration(FDA)for the treatment of adult patients with CLL or small lymphocytic lymphoma(SLL).In Europe,BRUKINSA has received approval from the European Commission(EC)for the treatment of adult patients with WM who have rece
118、ived at least one prior therapy or for the first-line treatment of patients unsuitable for chemo-immunotherapy,as well as for the treatment of patients with MZL and for the treatment of patients with CLL.In China,BRUKINSA has received conditional approval for adult patients with MCL who have receive
119、d at least one prior therapy and adult patients with CLL or SLL who have received at least one prior therapy and for the treatment of patients with R/R WM.In addition,a supplemental new drug application(sNDA)has been accepted for review by the China National Medical Products Administration(NMPA)for
120、the treatment of adult patients with treatment-nave CLL or SLL and WM.In December 2021,we announced the inclusion of BRUKINSA for R/R WM in the updated National Reimbursement Drug List(NRDL)by the China National Healthcare Security Administration(NHSA).Currently,all three approved indications for BR
121、UKINSA are included in the NRDL.BRUKINSA is approved across several indications in more than 65 markets as of February 2023.Market OpportunityLymphomas are blood-borne cancers involving lymphatic cells of the immune system.They can be broadly categorized into non-Hodgkins lymphoma and Hodgkins lymph
122、oma.In 2022,estimated global revenues for BTK inhibitors were approximately$8.5 billion according to published reports.Global revenues are projected to be more than$20 billion in 2026,according to published reports.TislelizumabTislelizumab is a humanized IgG4 monoclonal antibody against the immune c
123、heckpoint receptor programmed cell death protein 1(PD-1)that we specifically designed to minimize binding to Fc receptor gamma(FcR),which is believed to play an essential role in activating phagocytosis in macrophages,to minimize its negative impact on T effector cells.9Tislelizumab is approved in C
124、hina in ten indications,including full approval for the first-line treatment of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma with high PD-L1 expression in combination with fluoropyrimidine and platinum chemotherapy,first-line treatment
125、 of patients with advanced squamous non-small cell lung cancer(NSCLC)in combination with chemotherapy,for first-line treatment of patients with advanced non-squamous NSCLC in combination with chemotherapy,for second-or third-line treatment of patients with locally advanced or metastatic NSCLC who pr
126、ogressed on prior platinum-based chemotherapy,for the treatment of patients with locally advanced or metastatic esophageal squamous cell carcinoma(ESCC)who have disease progression following or are intolerant to first-line standard chemotherapy,and for first-line treatment of patients with recurrent
127、 or metastatic nasopharyngeal cancer(NPC).The NMPA also granted conditional approval for the treatment of patients with classical Hodgkins lymphoma(cHL)who received at least two prior therapies,for the treatment of patients with locally advanced or metastatic urothelial carcinoma(UC)with PD-L1 high
128、expression whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy,for the treatment of patients with hepatocellular carcinoma(HCC)who have received at least one systemic therapy,for
129、patients with previously treated,locally advanced unresectable or metastatic microsatellite instability-high(MSI-H)or mismatch repair-deficient(dMMR)solid tumors.Full approval for these indications is contingent upon results from ongoing randomized,controlled,confirmatory clinical trials.Tislelizuma
130、b was included in the NRDL in 2020 for cHL and UC,in 2021 for non-squamous NSCLC,squamous NSCLC and HCC,and in 2022 for locally advanced or metastatic NSCLC,for MSI-H solid tumors,for locally advanced or metastatic ESCC following progression or intolerance to prior first-line chemotherapy,and for fi
131、rst-line recurrent or metastatic NPC.In addition,we have submitted two supplemental Biologics License Applications(sBLAs)for tislelizumab that are under review by the Center for Drug Evaluation(CDE)of the NMPA,including for patients with first-line unresectable or metastatic hepatocellular carcinoma
132、(HCC),and in combination with chemotherapy as first-line treatment in patients with unresectable locally advanced,recurrent or metastatic esophageal squamous cell carcinoma.We are evaluating tislelizumab in a broad pivotal clinical program for both solid tumor and hematological indications,both glob
133、ally and in China.We have initiated or completed 17 potentially registration-enabling clinical trials in China and globally,including 13 Phase 3 trials and four pivotal Phase 2 trials.In January 2021,we announced a collaboration and license agreement with Novartis to develop,manufacture and commerci
134、alize tislelizumab in the United States,Canada,Mexico,the EU,UK,Norway,Switzerland,Iceland,Liechtenstein,Russia and Japan(the Novartis Territory).We retained worldwide rights to commercialize outside of the Novartis Territory and with our proprietary products in combination with tislelizumab.In the
135、United States,we have filed a BLA with the FDA for tislelizumab as a treatment for patients with unresectable recurrent locally advanced or metastatic ESCC after prior systemic therapy.In addition,Novartis has disclosed plans to submit additional marketing applications in its territory.Market Opport
136、unityGlobally,the top four PD-1/PD-L1 antibody medicines had revenues of approximately$36 billion in 2022 based on public reports.The 2022 China PD-1/L1 market(net revenue)was approximately$2.2 billion.Global revenues are projected to be more than$50 billion by 2025 according to published reports,dr
137、iven by multiple factors including indication expansion,approvals and adoptions in earlier lines of therapies,further market penetration,and extension of duration of therapy.PamiparibPamiparib is a selective small molecule inhibitor of poly ADP-ribose polymerase 1(PARP1)and PARP2 enzymes.Pamiparib h
138、as demonstrated pharmacological properties such as brain penetration and PARP-DNA complex trapping in preclinical models.Pamiparib is currently in global clinical development as a monotherapy or in combination with other agents for a variety of solid tumor malignancies.To date,more than 1,300 patien
139、ts have been enrolled in clinical trials of pamiparib.In China,pamiparib received conditional approval for treatment of patients with germline BRCA(gBRCA)mutation-associated recurrent advanced ovarian,fallopian tube,or primary peritoneal cancer who have been treated with two or more lines of chemoth
140、erapy in May 2021.Full approval for this indication is contingent upon results from ongoing corroborative trials confirming the clinical benefit of pamiparib in this population.Pamiparib was included in the 2021 NRDL in its approved indication.10We are currently commercializing,or plan to commercial
141、ize,the following cancer medicines in China under an exclusive license from Amgen:XGEVAXGEVA(denosumab)is an antibody-based RANK ligand(RANKL)inhibitor that was approved globally for the prevention of skeletal-related events(SREs)in patients with bone metastases from solid tumors and in patients wit
142、h multiple myeloma,and for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone(GCTB).XGEVA is approved in over 70 countries worldwide.In China,XGEVA received conditional approval in the GCTB indication in May 2019 and received conditional approval for the SRE indi
143、cations in November 2020.We began marketing XGEVA in China in July 2020.In December 2020,we announced the inclusion of XGEVA in the NRDL for the treatment of GCTB,which was successfully renewed for inclusion in 2023.BLINCYTOBLINCYTO(blinatumomab),a bispecific CD-19 directed CD3 T-cell engager,is the
144、 first and only approved bi-specific T-cell engager(BiTE)immunotherapy.It has been approved in 60 countries for use in patients with acute lymphoblastic leukemia(ALL).In China,BLINCYTO received conditional approval as a treatment for adult patients with R/R ALL in December 2020 and was conditionally
145、 approved in April 2022 for pediatric patients with R/R B-cell precursor ALL.We began commercializing BLINCYTO in August 2021.KYPROLISKYPROLIS(carfilzomib),a proteasome inhibitor,has been approved in over 60 countries for use in patients with R/R multiple myeloma(MM).It was approved in China as a tr
146、eatment for patients with R/R MM in July 2021 and we began commercializing KYPROLIS in January 2022.KYPROLIS was included on the NRDL beginning in March 2023 for its approved indication in China.We commercialize the following cancer medicines in China under an exclusive license from BMS:REVLIMIDREVL
147、IMID(lenalidomide)is an oral immunomodulatory medicine that was approved in China in 2013 for the treatment of multiple myeloma(MM)in combination with dexamethasone in adult patients who have received at least one prior therapy.In February 2018,REVLIMID received NMPA approval of a new indication for
148、 the treatment of MM in combination with dexamethasone in adult patients with previously untreated MM who are not eligible for transplant.REVLIMID was listed on the NRDL in June 2017.In November 2019,we announced that REVLIMID received formal inclusion on the NRDL in China for R/R multiple myeloma.I
149、n November 2020 our sNDA for the use of REVLIMID in combination with rituximab in adult patients with previously treated follicular lymphoma was approved by the NMPA.VIDAZAVIDAZA(azacitidine for injection)is a pyrimidine nucleoside analog that has been shown to reverse the effects of DNA hypermethyl
150、ation and promote subsequent gene re-expression.VIDAZA was approved in China in April 2017 for the treatment of intermediate-2 and high-risk myelodysplastic syndromes(MDS),chronic myelomonocyte leukemia(CMML)and acute myeloid leukemia(AML)with 20%to 30%blasts and multi-lineage dysplasia.In January 2
151、018,VIDAZA became commercially available in China.In addition to REVLIMID and VIDAZA,we previously commercialized ABRAXANE(paclitaxel albumin-bound particles for injectable suspension),a solvent-free chemotherapy approved for use in certain patients with metastatic breast cancer,in China until March
152、 2020.On March 25,2020,the NMPA suspended the importation,sales and use of ABRAXANE in China supplied to us by BMS,and the drug was subsequently recalled by BMS and is not currently available for sale in China.This suspension was based on inspection findings at BMSs contract manufacturing facility i
153、n the United States.Additionally,in October 2021,BMS provided 180-days notice to us,which we dispute,purporting to terminate our license to market ABRAXANE in China.We have not had any sales of ABRAXANE since the suspension and do not expect future revenue from ABRAXANE.We have initiated an arbitrat
154、ion proceeding against BMS asserting that it has breached and continues to breach the terms and conditions of the license and supply agreement.For additional information,please see the section of this Annual Report titled“Legal Proceedings”.11We are commercializing or planning to commercialize the f
155、ollowing medicines in China under an exclusive license from EUSA Pharma:SYLVANTSYLVANT(siltuximab),an interleukin-6(IL-6)antagonist,was approved as a treatment for patients with idiopathic multicentric Castleman disease(iMCD)who are human immunodeficiency virus(HIV)negative and human herpesvirus-8(H
156、HV-8)negative.SYLVANT was approved in China in December 2021 for the treatment of adult patients with multicentric Castleman disease(MCD)who are human immunodeficiency virus(HIV)negative and human herpes virus-8(HHV-8)negative,also known as idiopathic MCD(iMCD).QARZIBAQARZIBA(dinutuximab beta),a mou
157、se-human chimeric monoclonal GD2 antibody,was granted conditional approval by the NMPA for the treatment of high-risk neuroblastoma in patients aged 12 months and above who have previously received induction chemotherapy and achieved at least a partial response,followed by myeloablative therapy and
158、stem cell transplantation,as well as patients with a history of relapsed or refractory(R/R)neuroblastoma with or without residual disease.We began commercializing QARZIBA in December 2021.We commercialize the following product in China under an exclusive license from Bio-Thera:POBEVCY(BAT1706)POBEVC
159、Y is a biosimilar to Avastin(bevacizumab)developed by Bio-Thera Solutions,Ltd.,a commercial-stage biopharmaceutical company located in Guangzhou,China.In China,Avastin is approved for the treatment of patients with metastatic colorectal cancer,liver cancer and NSCLC.POBEVCY was approved by the NMPA
160、in China in November 2021 and launched in late 2021 for the treatment of patients with advanced,metastatic or recurrent NSCLC and metastatic colorectal cancer.We have acquired the right to develop,manufacture and commercialize POBEVCY in China,including Hong Kong,Macau,and Taiwan.Bio-Thera submitted
161、 a marketing application to the EMA and a BLA to the FDA in November 2020.Reimbursement and Market AccessOur sales are largely dependent on the availability and extent of coverage and reimbursement by third party payors.In many markets these third parties are government health systems and in some ma
162、rkets such as the United States there are also private payors such as private health insurers and health systems.In 2022,we commercialized our products in 60 markets.In China,there is one main payor,the governments national health care coverage system,which provides Basic Medical Insurance to the ma
163、jority(greater than 95%)of Chinas approximately 1.4 billion people.There are three types of coverage plans in China at the national level that depend on if a resident lives in an urban or rural setting and if they are employed.The different plans have different characteristics in terms of how the pl
164、an is paid for and what it covers.Coverage and reimbursement of pharmaceuticals in China comes under the purview of the NHSA,which oversees the NRDL.The NRDL is composed of three lists.The A and B list are commonly referred to as the regular lists.The A list generally includes older,off-patent medic
165、ines,while the B list generally includes newer medicines,some with remaining patent protection,which are reimbursed at a lower rate compared to the A list.In 2017,a third list was added to the system,often referred to as the C list or the negotiation list.This list generally includes newer innovativ
166、e medicines which are accepted on the list after successful negotiation between the NHSA and the company.Typically,inclusion on the C list is accompanied by a discount to the prevailing list price in China for the medicine at the time of inclusion.The NRDL price for a medicine is its prevailing pric
167、e in China,but the actual reimbursement rate that is used can be modified at the provincial level.Innovatively,in the 2022 NRDL,a price bidding process for non-exclusive drugs was undertaken on the C list to set the national reimbursement price benchmark.Several of our medicines are listed on the NR
168、DL.In the most recent NRDL list announced in January 2023,the following medicines were included in the NRDL,effective March 1,2023:Tislelizumab in nine of its eligible approved indications:For the treatment of adult patients with locally advanced or metastatic non-squamous non-small cell lung cancer
169、(NSCLC)who are negative for epidermal growth factor receptor(EGFR)and anaplastic mesenchymal lymphoma kinase(ALK)mutations and have progressed after or are intolerant of prior chemotherapy with platinum-containing regimens;and adult patients with locally advanced or metastatic squamous NSCLC who are
170、 negative 12or unknown for EGFR and ALK mutations and have progressed after or are intolerant of prior chemotherapy with platinum-containing regimens(approved in January 2022 and included in the NRDL in 2023);For the treatment of adult patients with advanced unresectable or metastatic microsatellite
171、 instability-high(MSI-H)or mismatch repair deficient(dMMR)solid tumors:patients with advanced colorectal cancer with disease progression after prior treatment with fluoropyrimidines,oxaliplatin and irinotecan;patients with other advanced solid tumors with disease progression after prior treatment an
172、d no satisfactory alternative treatment options(approved in March 2022 and included in the NRDL in 2023);For the treatment of patients with locally advanced or metastatic esophageal squamous cell carcinoma who have progressed after or are intolerant of prior first-line standard chemotherapy(approved
173、 in April 2022 and included in the NRDL in 2023);As a first-line treatment for patients with recurrent or metastatic nasopharyngeal cancer(approved in June 2022 and included in the NRDL in 2023);For use in combination with pemetrexed and platinum chemotherapy as a first-line treatment in patients wi
174、th unresectable,locally advanced or metastatic non-squamous non-small cell lung cancer(NSCLC),with EGFR genomic tumor aberrations negative and ALK genomic tumor negative(approved in June 2021 and included in the NRDL in 2021);For the treatment of patients with hepatocellular carcinoma(HCC)who have b
175、een previously treated with at least one systemic therapy(conditionally approved in June 2021 and included in the NRDL in 2021);For use in combination with paclitaxel and carboplatin as a first-line treatment in patients with unresectable,locally advanced or metastatic squamous NSCLC(approved in Jan
176、uary 2021 and included in the NRDL in 2021);For the treatment of patients with locally advanced or metastatic urothelial carcinoma(UC)with PD-L1 high expression whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with
177、 platinum-containing chemotherapy(conditionally approved in April 2020 and included in NRDL in 2020);andFor the treatment of patients with classical Hodgkins lymphoma(cHL)who have received at least two prior therapies(conditionally approved in December 2019 and included in the NRDL in 2020).BRUKINSA
178、 in all three of its approved indications:For the treatment of adult patients with Waldenstrms macroglobulinemia(WM)who have received at least one prior therapy(conditionally approved in June 2021 and included in the NRDL in 2021);For the treatment of adult patients with MCL who have received at lea
179、st one prior therapy(conditionally approved in June 2020 and included in the NRDL in 2020);andFor the treatment of adult patients with chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma(SLL)who have received at least one prior therapy(conditionally approved in June 2020 and included in the
180、 NRDL in 2020).Pamiparib in its approved indication:For the treatment of patients with germline BRCA(gBRCA)mutation-associated recurrent advanced ovarian,fallopian tube,or primary peritoneal cancer who have been treated with two or more lines of chemotherapy(conditionally approved in May 2021 and in
181、cluded in the NRDL in 2021).KYPROLIS in its approved indication as of March 1,2023:For the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least two prior therapies,including a proteasome inhibitor and an immunomodulatory agent.XGEVA was successfully ren
182、ewed in NRDL as of March 2023 in its approved indication:For the treatment of patients with giant cell tumor of the bone(GCTB)that is unresectable or where surgical resection is likely to result in severe morbidity(first included in NRDL in 2020).13Additionally,two of our medicines were listed in pa
183、st NRDLs:REVLIMID was included in the 2017 NRDL negotiation list and later received formal inclusion in the 2019 B list,while VIDAZA was listed in the 2018 NRDL negotiation list and later received formal inclusion to the 2020 B list.In 2018,China started a new program to centrally purchase non-exclu
184、sive medicines for the nations health care system called volume-based procurement,or group purchasing organization or 4+7 when the program was first piloted in 11 major cities.After the 2018 pilot program,it was implemented nationally in 2019.It is a tender-based system that provides guaranteed volu
185、me for lowered pricing.Participation in the program requires a product to have passed a generic quality consistency evaluation,which in turn requires passing a bioequivalence comparison to the reference listed drug(RLD).The system offers a major portion of a markets volume to winning bidders.More th
186、an one company can win a given tender,and more guaranteed volume is awarded as more bidders win.The system is still evolving and,as such,the exact terms of how many bidders win and what amount of volume are won and at what price is also evolving.It is common in China for pharmaceutical companies to
187、employ patient assistance programs to help patients afford their innovative medicines.Usually these programs have been offered to patients who are self-paying.A typical program provides a certain number of free doses to patients after a certain number of doses have been paid for.Usually these progra
188、ms end when a medicine is included in the NRDL.We offer these types of patient assistance programs to our patients.In the United States,most health insurance coverage is provided by private insurers,often accessed via employer-sponsored plans,and the two main public insurance programs,Medicare and M
189、edicaid.All three types of programs usually have some type of coverage for pharmaceutical products.Often this is through a pharmacy benefit manager(PBM).The structure of the pharmacy benefit can be quite different for different beneficiaries depending on the negotiations between plan sponsors and pl
190、an purchasers.There is no central list of covered pharmaceuticals in the United States,as there is no single payer system.As such,the prices paid for pharmaceuticals in the United States can vary.We offer patient assistance programs in the United States under our myBeiGene program.This program seeks
191、 to enhance access to BRUKINSA by assisting with obtaining reimbursement,co-pay assistance when allowed,temporary supply of free product for insurance delays,and free product assistance for some uninsured and underinsured patients.The programs also seek to support patients and caregivers by providin
192、g education and information about BRUKINSA and its approved indications,nurse advocates,and connecting patients to sources of support such as support groups and transportation/lodging assistance.14Our Pipeline ProductsThe following table summarizes the status of our internally-discovered drug candid
193、ates as of February 27,2023:ASSETPROGRAMPHASE 1PHASE 2PHASE 3ZanubrutinibmonotherapyR/R CLL/SLL+rituximabTN MCL and R/R MZL+/-venetoclaxTN CLL/SLL+obinutuzumabR/R FLTislelizumabmonotherapy2L advanced ESCC,1L HCC,2L/3L NSCLCPreviously treated HCC,R/R cHL+chemotherapy1L advanced ESCC,1L GC/GEJC,1L NPC
194、+zanidatamab+chemotherapy1L GEA+sitravatinib2L NSCLCSolid tumors+fruquintinibSolid tumorsOciperlimab+tislelizumab1L PD-L1 high NSCLC2L PD-L1+ESCC,2/3 L cervical cancerSolid tumors+tislelizumab+chemotherapy1L NSCLC+tislelzumab+concurrent chemoradiotherapyLA NSCLC(PD-L!+)1L LS-SCLCSurzebiclimab+tislel
195、izumab+/-LBL-007Solid tumorsBGB-A445+tislelizumabSolid tumorsBGB-10188+tislelizumabSolid tumors+/-zanubrutinibB-cell lymphoid malignancies+/-tislelizumabB-cell malignanciesBGB-15025+tislelizumabSolid tumorsPamiparibmonotherapy1L maintenance platinum-sensitive GC+temozolomideSolid tumorsBGB-3245monot
196、herapySolid tumors with BRAF mutationsLifirafenib+mirdametinibSolid tumorsBGB-11417monotherapyR/R MCL,R/R CLL/SLL+/-zanubrutinibMature B-cell malignancies+azacitidine+/-posaconazoleMyeloid malignancies+dexamethasone+/-carfilzomibR/R multiple myelome with t(11;14)BGB-16673monotherapyB-cell malignanci
197、esBGB-23339monotherapyInflammation and immunologyBGB-24714+/-chemotherapySolid tumorsBGB-B167+/-tislelizumabSolid tumorsAbbreviations:cHL=classical Hodgkin lymphoma;CLL=chronic lymphocytic leukemia;ESCC=esophageal squamous-cell carcinoma;FL=follicular lymphoma;GC=gastric cancer;GEA=gastroesophageal
198、adenocarcinoma;GEJC=gastroesophaegeal junction cancer;HCC=hepatocellular carcinoma;MCL=mantle cell lymphoma;MZL=marginal zone lymphoma;NPC=nasopharyngeal carcinoma;NSCLC=non-small cell lung cancer;R/R=relapsed/refractory;SCLC=small cell lung cancer;SLL=small lymphocytic lymphoma;TN=treatment treatme
199、nt-nave15The following table summarizes the status of our in-licensed drug candidates as of February 27,2023:PartnerMolecule/AssetIndicationsPhaseCommercial RightsSotorasibSolid tumors,CRC,NSCLCPhase 3 Chinatarlatamab SCLCPhase 2 Chinaacapatamab Prostate cancer,NSCLCPhase 1 ChinaAMG 176Hematologic m
200、alignanciesPhase 1 ChinaAMG 427 AMLPhase 1 ChinaAMG 509Prostate cancerPhase 1 ChinaAMG 199 GC/GEJCPhase 1 ChinaAMG 650Solid tumorsPhase 1 ChinaAMG 256Solid tumorsPhase 1 ChinaSitravatinib +TislelizumabNSCLCPhase 3 Asia,Australia,New ZealandSitravatinib +TislelizumabHCC,GC/GEJCPhase 2 Asia,Australia,
201、New ZealandSitravatinib +TislelizumabSolid tumorsPhase 1 Asia,Australia,New ZealandZanidatamab+chemo+Tislelizumab GEAPhase 3 Asia,Australia,New ZealandZanidatamab(monotherapy)BTCPhase 2 Asia,Australia,New ZealandZanidatamabBC,GC,GEAPhase 2 Asia,Australia,New ZealandZW49HER2 expressing cancersPhase 1
202、 Asia,Australia,New ZealandBGB-32451Solid tumorsPhase 1 AsiaSEA-CD70MDS,AMLPhase 1 Asia,Australia,New ZealandDKN-01+Tislelizumab+ChemoGC/GEJCPhase 2 Asia,Australia,New ZealandLBL-007+TislelizumabAdvanced solid tumorsPhase 2 Ex-ChinaABI-H3733Chronic hepatitis B virusPhase 1 China BiTE molecule;Half-l
203、ife extended BiTE;XmAb is a registered trademark of Xencor,Inc.Mirati is also conducting its own clinical studies with sitravatinib,including the Phas3 SAPPHIRE trial in non Sq NSCLC;ZW25;1 By MapKure,a JV with SpringWorksAbbreviations:AML=acute myelogenous leukemia;BC=breast cancer;BTC=biliary trac
204、t cancers;CRC=colorectal cancer;GC=gastric cancer;GEA=gastroesophageal adenocarcinoma;GEJC=gastroesophaegeal junction cancer;HCC=hepatocellular carcinoma;MDS=myelodysplastic syndromes;NSCLC=non-small cell lung cancer;SCLC=small cell lung cancerOur Commercial-and Clinical-Stage Drug CandidatesA descr
205、iption of our commercial-and clinical-stage drug candidates and clinical data from selected clinical trials is set forth below.Historically,we have made available,and we intend to continue to make available,clinical data and/or topline results from clinical trials of our drug candidates in our press
206、 releases and/or filings with the U.S.Securities and Exchange Commission(SEC),the Stock Exchange of Hong Kong Limited(HKEx),and the Shanghai Stock Exchange(SSE),copies of which are available on the Investors section of our website.Commercial-StageBRUKINSA(zanubrutinib),a BTK InhibitorWe are currentl
207、y evaluating zanubrutinib in a broad pivotal clinical program globally to treat a number of B-cell malignancies.Zanubrutinib has demonstrated sustained 24-hour BTK occupancy in both the peripheral blood and lymph node compartments in patients.Zanubrutinib is the only BTK inhibitor to demonstrate sup
208、erior progression-free survival versus IMBRUVICA(ibrutinib),an approved BTK inhibitor.16Overview of Clinical Development Program and Regulatory StatusWe have announced BRUKINSA approvals around the world,including in the United States,China,the EU,the U.K.,Canada,Australia,South Korea and Switzerlan
209、d.As of December 2022,26 additional marketing authorization applications for BRUKINSA have been submitted and are under review,including by BeiGene and with support from our five distribution partners:Adium Pharma in Latin America and the Caribbean,NewBridge Pharmaceuticals in the Middle East and No
210、rth Africa,Erkim in Turkey,Nanolek in Russia,and Medison in Israel.Based on the clinical data to date,we believe that BRUKINSA has a best-in-class profile,and we are running a broad global pivotal program in multiple indications,including 10 registration or registration-enabling clinical trials.Five
211、 of the 10 trials are Phase 3 and five are designed to be registration-enabling Phase 2 trials.We have reported results from the monotherapy head-to-head Phase 3 trial versus ibrutinib in WM(ASPEN,NCT03053440),which has been included in several filings globally.We have also reported results from the
212、 Phase 3 trial comparing BRUKINSA to bendamustine and rituximab in patients with treatment-nave(TN)CLL/SLL(SEQUOIA,NCT03336333)and the head-to-head Phase 3 trial in R/R CLL/SLL versus ibrutinib(ALPINE,NCT03734016).Both trials are the basis for our approvals in CLL in the U.S.and EU.Our fourth Phase
213、3 trial is an ongoing Phase 3 confirmatory trial in patients with TN MCL(NCT04002297).Our fifth Phase 3 trial is an ongoing Phase 3 confirmatory trial in patients with R/R follicular lymphoma(FL)or R/R MZL(NCT05100862).Additionally,we have five filed or ongoing Phase 2 trials that are designed to be
214、 registration-enabling,including four monotherapy studies in R/R MCL,R/R WM,R/R CLL/SLL(NCT03206970,NCT03332173,NCT03206918),and R/R MZL(MAGNOLIA,NCT03846427)and an ongoing pivotal Phase 2 trial in combination with GAZYVA(obinutuzumab)in patients with R/R FL(ROSEWOOD,NCT03332017).Data from the ROSEW
215、OOD trial were presented at the European Hematology Association(EHA)2022,meeting its primary endpoint.Finally,we are also investigating zanubrutinib in several combination studies in MCL,MZL and CLL/SLL,including a Phase 3 trial in combination with venetoclax in front-line CLL/SLL.We continue to pur
216、sue regulatory approvals for BRUKINSA globally.Besides our recent approvals in CLL/SLL in the United States(January 2023)and EU(November 2022)we expect continued regulatory decisions for some of our global filings this year,including potential additional approvals in more than 10 markets.Tislelizuma
217、b,an anti-PD-1 AntibodyTislelizumab is a humanized monoclonal antibody against the immune checkpoint receptor PD-1 that is currently being evaluated in pivotal clinical trials globally and for which we plan to commence additional pivotal trials as a monotherapy and in combination with standard of ca
218、re to treat various solid and hematological cancers.Overview of Clinical Development Program and Regulatory StatusBeiGene has initiated or completed 21 potentially registration-enabling clinical trials in China and globally,including 13 Phase 3 trials and four pivotal Phase 2 trials intended to supp
219、ort regulatory submissions globally and in China.Our trials in lung cancer include:A global Phase 3 trial evaluating tislelizumab as a second-or third-line treatment compared to docetaxel in patients with locally advanced or metastatic NSCLC(NCT03358875);Two Phase 3 trials in China evaluating tislel
220、izumab plus chemotherapy versus chemotherapy in squamous and non-squamous NSCLC(NCT03594747 and NCT03663205,respectively);A Phase 3 trial in China in 1L SCLC evaluating tislelizumab plus chemotherapy versus chemotherapy(NCT04005716);andA Phase 3 trial in China of tislelizumab in combination with pla
221、tinum-based doublet chemotherapy as neoadjuvant treatment for patients with NSCLC(NCT04379635).Our trials in liver cancer include:A global Phase 3 trial comparing tislelizumab with sorafenib as first-line treatment for patients with HCC(NCT03412773);andA global single-arm pivotal Phase 2 trial in se
222、cond or third line unresectable HCC(NCT03419897).17Our trials in gastric cancer include:A global Phase 3 trial of tislelizumab combined with chemotherapy versus placebo combined with chemotherapy as first-line treatment for patients with gastric cancer(NCT03777657).Our trials in lymphoma include:A P
223、hase 3 trial in China comparing tislelizumab to salvage chemotherapy in patients with relapsed or refractory classical Hodgkin Lymphoma(cHL;NCT04486391);andA Phase 2 trial in China in patients with relapsed or refractory cHL(NCT03209973).Our trials in urothelial carcinoma include:A Phase 3 trial in
224、China in patients with locally advanced or metastatic urothelial carcinoma(NCT03967977);andPhase 2 trial in China in patients with locally advanced or metastatic urothelial bladder cancer(NCT04004221).Our trials in ESCC include:A global Phase 3 trial comparing tislelizumab with chemotherapy as secon
225、d-line treatment for patients with advanced ESCC(NCT03430843);A global Phase 3 trial of tislelizumab in combination with chemotherapy as first-line treatment for patients with ESCC(NCT03783442);andA Phase 3 trial in China of tislelizumab versus placebo in combination with chemoradiotherapy in patien
226、ts with localized ESCC(NCT03957590).Finally,our trials in solid tumors and nasopharyngeal cancer include:A Phase 2 trial in China in patients with MSI-H/dMMR solid tumors(NCT03736889);andA Phase 3 trial in China and Thailand of tislelizumab combined with chemotherapy versus placebo combined with che
227、motherapy as first-line treatment in patients with nasopharyngeal cancer(NCT03924986).As of December 2022,we had enrolled over 11,000 subjects in clinical trials of tislelizumab in 31 geographies,including more than 4,000 subjects outside of China.These studies include 11 multi-regional registration
228、al trials that are designed for global regulatory approvals.Data from our trials thus far suggested that tislelizumab was generally well-tolerated and exhibited anti-tumor activity in a variety of tumor types.Pamiparib,a PARP1 and PARP2 InhibitorPamiparib is a selective small molecule inhibitor of p
229、oly ADP-ribose polymerase 1(PARP1)and PARP2 enzymes that is being evaluated as a potential monotherapy and in combinations for the treatment of various solid tumors.We believe that pamiparib has the potential to be differentiated from other PARP inhibitors because of its brain penetration,greater se
230、lectivity,strong DNA-trapping activity,and good oral bioavailability demonstrated in preclinical models.Overview of Clinical Development Program and Regulatory StatusIn China,pamiparib received conditional approval in May 2021 for treatment of patients with germline BRCA(gBRCA)mutation-associated re
231、current advanced ovarian,fallopian tube,or primary peritoneal cancer who have been treated with two or more lines of chemotherapy.Full approval for this indication is contingent upon results from ongoing corroborative trials confirming the clinical benefit of pamiparib in this population.In addition
232、,our clinical development program includes a Phase 3 trial as a maintenance therapy in patients with platinum-sensitive recurrent OC(NCT03519230),a Phase 2 trial in first-line platinum-sensitive GC maintenance(NCT03427814),and a Phase 1b trial in combination with temozolomide in solid tumors(NCT0315
233、0810).18Clinical-StageOciperlimab(BGB-A1217),a TIGIT InhibitorOciperlimab(BGB-A1217)is an investigational humanized IgG1-variant monoclonal antibody directed against TIGIT.An immune checkpoint molecule,ociperlimab is currently being investigated in two global Phase 3 clinical trials,the AdvanTIG-301
234、(NCT04866017)and AdvanTIG-302(NCT04746924)trials,in combination with tislelizumab in NSCLC.As of December 2022,more than 1,600 subjects have been enrolled across the ociperlimab development program,which includes eight global trials in patients with lung cancers,esophageal squamous cell carcinoma,an
235、d cervical cancer.In December 2021 we announced an option,collaboration and license agreement with Novartis to develop,manufacture and commercialize ociperlimab in North America,Europe,and Japan,as discussed further below under Novartis Collaboration Option Collaboration and License Agreement for Oc
236、iperlimab.We have completed patient enrollment in the AdvanTIG-202 trial(NCT04693234)in patients with previously treated recurrent or metastatic cervical cancer.We expect to initiate additional pivotal clinical trials and announce data from Phase 2 trial expansion cohorts in 2023 to inform our subse
237、quent development for ociperlimab.Lifirafenib(BGB-283)and BGB-3245,Inhibitors of RAFLifirafenib is an investigational novel small molecule inhibitor with RAF monomer and dimer inhibition activities.Lifirafenib has shown antitumor activities in preclinical models and in cancer patients with tumors ha
238、rboring BRAF V600E mutations,non-V600E BRAF mutations or KRAS/NRAS mutations.We have been developing lifirafenib for the treatment of cancers with aberrations in the mitogen-activated protein kinase(MAPK),pathway,including BRAF gene mutations and KRAS/NRAS gene mutations where first generation BRAF
239、inhibitors are not effective.We believe that lifirafenib as monotherapy or in combination with other agents may have potential for treating various malignancies such as melanoma,NSCLC,and endometrial cancer.BeiGene is working together with SpringWorks Therapeutics,Inc.(SpringWorks)in a global clinic
240、al collaboration and has initiated a Phase 1b clinical trial(NCT03905148)to evaluate the safety,tolerability,and preliminary efficacy of lifirafenib in combination with SpringWorks investigational MEK inhibitor,mirdametinib(PD-0325901),in patients with advanced solid tumors.In addition to the collab
241、oration,BeiGene and SpringWorks formed a separate company,MapKure,LLC,to develop BGB-3245,an investigational,selective next-generation RAF kinase inhibitor discovered by BeiGene scientists.MapKure has an ongoing Phase 1 clinical trial of BGB-3245(NCT04249843)in patients with advanced or refractory t
242、umors harboring specific v-RAF murine sarcoma viral oncogene homolog B(B-RAF)genetic mutations.Sitravatinib,a Multi-Kinase InhibitorIn January 2018,we entered into an exclusive license agreement with Mirati Therapeutics,Inc.(Mirati)for the development,manufacturing and commercialization of Miratis s
243、itravatinib in Asia(excluding Japan and certain other countries),Australia and New Zealand.Sitravatinib is an investigational spectrum-selective kinase inhibitor,which potently inhibits receptor tyrosine kinases,including RET,TAM family receptors(TYRO3,Axl,MER),and split family receptors(VEGFR2,KIT)
244、.Sitravatinib is being evaluated by Mirati in multiple clinical trials to treat patients who are refractory to prior immune checkpoint inhibitor therapy,including a Phase 3 SAPPHIRE trial of sitravatinib in NSCLC initiated in 2019.In 2022,as part of our collaboration with Mirati,we initiated patient
245、 enrollment for a Phase 2 clinical trial of sitravatinib in combination with tislelizumab in locally advanced unresectable or metastatic ESCC that progressed on or after anti-PD-L1 antibody therapy(NCT05461794).We are evaluating sitravatinib in multiple clinical trials including a Phase 3 trial comb
246、ined with tislelizumab in NSCLC(NCT04921358).BGB-11417,a Small Molecule Bcl-2 InhibitorBGB-11417 is an investigational small molecule Bcl-2 inhibitor.We have completed preclinical and investigational new drug(IND)-enabling studies of BGB-11417,which demonstrated potent activity and high selectivity
247、against the pro-apoptotic protein Bcl-2.The molecule appears to be more potent than venetoclax and shows the potential to overcome resistance to venetoclax.Further,it is more selective than venetoclax for Bcl-2 relative to Bcl-xL.Finally,we believe that it is well-positioned to be combined with BRUK
248、INSA.Phase 1 clinical data for non-Hodgkins lymphoma,CLL,acute myeloid leukemia(AML)and multiple myeloma(MM)(NCT04883957,NCT04277637,NCT04771130,and NCT04973605)were presented at ASH 2022.We initiated patient dosing in a Phase 2 study to evaluate BCL-2 inhibitor BGB-11417 in patients with relapsed o
249、r 19refractory mantle cell lymphoma(NCT05471843)and relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma(NCT05479994)in 2022 and expect data readouts from ongoing studies in 2023.BGB-A445,an OX40 Agonist AntibodyBGB-A445 is an investigational agonistic antibody directed
250、to the OX40 antigen.BGB-A445 is a non-ligand competing antibody that does not disrupt OX40 to OX40 ligand engagement.Preclinical experiments showed that BGB-A445 has increasing effectiveness at higher doses versus an antibody that was ligand-competing,which showed falling effectiveness at higher dos
251、es.BGB-A445 has also showed in preclinical tests the potential to be combined with several agents,such as tislelizumab,as well as a TLR9 agonist,a PI3K inhibitor,sitravatinib,and chemotherapy.We have an ongoing Phase 1 trial(NCT04215978)of BGB-A445 in combination with tislelizumab in patients with a
252、dvanced solid tumors and initiated tumor-specific dose expansion cohorts in a Phase 1 monotherapy trial(NCT04215978)in patients with solid tumors in 2022.We initiated patient dosing in a Phase 2 basket trial in melanoma,renal cell cancer and bladder cancer(NCT05661955).ZW25(Zanidatamab),a bispecific
253、 HER2-targeted antibodyZanidatamab,a novel investigational Azymetric bispecific antibody targeting HER2,is currently in late-stage clinical development with Zymeworks Inc.BeiGene has development and commercial rights to zanidatamab in Asia(excluding Japan),Australia,and New Zealand.We are participat
254、ing in three ongoing clinical studies with zanidatamab.The first is a Phase 1/2 study(NCT04215978)in HER2-positive breast and gastric cancer.The breast cancer arm combines zanidatamab with docetaxel,and the gastric cancer arm combines zanidatamab with our PD-1 inhibitor tislelizumab and chemotherapy
255、.The second study HERIZON-BTC-01(NCT04466891)is a Phase 2b study in patients with advanced or metastatic HER2-amplified biliary tract cancers(BTC)in which zanidatamab is being used as monotherapy.Positive topline results from this trial were announced in 2022.We initiated a global Phase 3 clinical t
256、rial(NCT05152147)examining zanidatamab in combination with chemotherapy with and without tislelizumab in HER2-positive gastroesophageal cancer in late 2021.We completed enrollment in 2L biliary tract cancer in 2022.Surzebiclimab(BGB-A425),a TIM-3 InhibitorSurzebiclimab(BGB-A425)is an investigational
257、 humanized IgG1-variant monoclonal antibody against T-cell immunoglobulin and mucin-domain containing-3(TIM-3).We have an ongoing Phase 1/2 trial(NCT03744468)of surzebiclimab in combination with tislelizumab in various solid tumors.BGB-15025,a Small Molecule HPK1 InhibitorBGB-15025 is an investigati
258、onal small molecule inhibitor of HPK1,which is a key negative feedback regulator of TCR signaling.Inhibition of HPK1 leads to enhanced T-cell activation pre-clinically.In addition,preclinical studies showed that BGB-15025 exhibits combination activity with tislelizumab and has a wide therapeutic win
259、dow.We initiated a Phase 1 trial(NCT04649385)of BGB-15025 alone and in combination with tislelizumab in patients with advanced solid tumors in 2021.This trial is being conducted in multiple countries globally.We expect to initiate dose-expansion for BGB-15025 in 2023.BGB-16673,a BTK-targeted CDACBGB
260、-16733 is an investigational BTK-targeting chimeric degradation activation compound(CDAC)active against both wild-type and mutant BTK.BGB-16673 has demonstrated preclinical antitumor activity in models with wild-type BTK and models with BTK inhibitorresistant mutations commonly observed in patients
261、who have progressed on prior BTK inhibitor treatment.A Phase 1 open-label,dose-escalation,and dose-expansion trial(NCT05006716)in adult patients with relapsed/refractory(R/R)B-cell malignancies is currently enrolling.BGB-23339,a TYK2 inhibitorBGB-23339 is a potent,highly selective,allosteric,investi
262、gational tyrosine kinase 2(TYK2)inhibitor discovered and being developed by BeiGene.TYK2 is a member of the JAK family and functions as a critical mediator in cytokine signaling pathways implicated in multiple immune-mediated disorders.Designed to target the regulatory pseudokinase(JH2)domain on TYK
263、2,BGB-23339 has demonstrated strong selectivity in preclinical studies with potent inhibition of interleukin(IL)-12,IL-23,and Type 1 interferons(IFNs)pro-inflammatory cytokines that play a determinant role in the induction of inflammation.BGB-23339 is currently being evaluated in a Phase 1 clinical
264、study(NCT05093270).BGB-24714,a SMAC mimeticBGB-24714 is an investigational Second Mitochondrial-derived Activator of Caspase(SMAC)mimetic currently enrolling in a Phase 1 clinical trial(NCT05381909)as monotherapy or in combination with paclitaxel in advanced solid tumors.20BGB-B167,a CEA x 4-1BB bis
265、pecificBGB-B167 is an investigational first-in-class CEA x 4-1BB bispecific antibody.It is currently enrolling in a Phase 1 clinical trial(NCT05494762)as a monotherapy and in combination with tislelizumab in patients with selected CEA-expressing advanced or metastatic solid tumors,including colorect
266、al cancer(CRC).BGB-10188(PI3K inhibitor)BGB-10188 is an investigational PI3K inhibitor being evaluated in a Phase 1 clinical trial(NCT04282018)as monotherapy or in combination with BRUKINSA in hematology malignancies,or in combination with tislelizumab in solid tumors.Our Preclinical ProgramsWe have
267、 a proprietary biology research platform that has allowed us to research and develop both small molecules and biologic molecules.In the last decade,this platform has generated more than 10 clinical stage assets,including three internally-developed molecules that have been approved by regulatory bodi
268、es in the United States,China,EU and other markets,with other filings pending globally and planned to be submitted.The platform is a full-process technology system spanning from early discovery to commercialization of oncology medicines based on multiple drug technology platforms that can be applied
269、 to oncology and other fields.We have core technology platforms for the development of small molecule and antibody medicines and the manufacturing of our own and potentially other medicines.Currently,we have over 60 pre-clinical programs and we believe the majority have best-in-class or first-in-cla
270、ss potential.We anticipate advancing multiple our preclinical drug candidates into the clinic in the next 12 months.We believe that we have the opportunity to combine tislelizumab with our preclinical candidates to target multiple points in the cancer immunity cycle.We also may seek to develop compa
271、nion diagnostics that will help identify patients who are most likely to benefit from the use of our medicines and drug candidates.Manufacturing and SupplyWe manufacture our medicines and drug candidates internally and in some cases with the help of third-party CMOs.The manufacturing of our medicine
272、s and drug candidates is subject to extensive regulations that impose various procedural and documentation requirements governing recordkeeping,manufacturing processes and controls,personnel,quality control,and quality assurance,among others.Our manufacturing facilities and the facilities of the CMO
273、s we use to manufacture our medicines and drug candidates operate under current good manufacturing practice regulations(cGMP)conditions.cGMP regulations are requirements for the production of pharmaceuticals that will be used in humans.Our Manufacturing FacilitiesWe have manufacturing facilities for
274、 small molecule drugs and large molecule biologics in Suzhou and Guangzhou,China,respectively,to support the commercialization and potential future demand of our internally developed or in-licensed products.Our manufacturing facility in Suzhou is over 13,000 square meters and consists of a manufactu
275、ring base for small molecule drug products with an annual production capacity of about 100 million tablets and capsules and a biologics clinical development production facility with 2 x 500 liters capacity to produce biologics candidates for clinical supply.The facility meets or exceeds design crite
276、ria of the United States,EU,and China regulatory requirements.The facility has received a manufacturing license to produce commercial volumes of BRUKINSA and pamiparib for the China market.As a result of our growing commercial and clinical demands,we have broken ground on a new small molecule manufa
277、cturing facility nearby in Suzhou that will have the capability to produce up to 600 million solid oral dosages annually.This approximately 50,000 square meter facility is expected to replace our current Suzhou site and support our growing pipeline of small molecule medicines and drug candidates.We
278、continue to invest in our state-of-the-art commercial-scale manufacturing facility in Guangzhou of approximately 100,000 square meters for the manufacturing of large molecule biologics.Phases 1 and 2 of the facility were completed in September 2019 and December 2020,respectively,with 24,000 liters o
279、f single use disposable capacity.Additionally,total capacity has been increased to 54,000 liters,with an additional expansion of 10,000 liters expected in the second quarter of 2023,which will bring the final capacity to 64,000.Phase 1 is currently approved for the end-to-end commercial production o
280、f tislelizumab for the China market.We have purchased an adjacent tract of land to the south of the current site and initiated the next phase of expansion to support our growing pipeline of large molecule medicines and drug candidates.We have also commenced construction on our commercial-stage manuf
281、acturing and clinical R&D campus at the 42-acre site at the Princeton West Innovation Park in Hopewell,New Jersey.The property,located strategically in the Interstate 95 21corridor of New Jersey,with a deep and rich talent pool,has more than one million square feet of developable real estate for pot
282、ential future expansion to cover our existing medicines and pipeline.Contract Manufacturing OrganizationsWe currently rely on,and expect to continue to rely on,a limited number of third-party CMOs and CROs for the production of some drug products and drug substances and the supply of raw materials t
283、o meet the commercial,clinical,and preclinical needs of our medicines and drug candidates.We have adopted procedures to ensure that the production qualifications,facilities,and processes of the third-party suppliers engaged by us comply with relevant regulatory requirements and our internal quality
284、and operational guidelines.We select our third-party suppliers carefully by considering a number of factors,including their qualifications,relevant expertise,production capacity,geographic proximity,reputation,track record,product quality,reliability in meeting delivery schedules,and business terms.
285、We have commercial supply and related agreements with most of our manufacturing service providers.For example,we entered into a commercial supply agreement with Catalent Pharma Solutions,LLC(Catalent)to produce BRUKINSA at Catalents Kansas City,Missouri site for clinical and commercial use in the Un
286、ited States and other countries outside of China.We currently source the active pharmaceutical ingredient for BRUKINSA from a supplier in China and are in the process of bringing online an additional source of supply outside of China.In addition,we entered into a commercial supply agreement with Boe
287、hringer Ingelheim Biopharmaceuticals(China)Ltd.(Boehringer Ingelheim)for tislelizumab,which is being manufactured at Boehringer Ingelheims facility in Shanghai,China.Additionally,our collaboration agreements with Novartis include the right for Novartis to manufacture tislelizumab and ociperlimab for
288、 its territory,to be managed by Novartis following tech transfer,and our right to conduct a specified percentage of production at our planned U.S.manufacturing site,subject to the terms of the agreements.For our commercial and clinical stage products in-licensed from Amgen,BMS and others,we rely on
289、the licensors and their manufacturing facilities or their CMOs for the supply of those medicines and drug candidates.Our agreements with the outsourced suppliers engaged by us generally set out terms,including product quality or service details,technical standards or methods,delivery terms,agreed pr
290、ice and payment,and product inspection and acceptance criteria.We are generally allowed to return any products that fail to meet specified quality standards.Our outsourced suppliers procure raw materials themselves.Typically,outsourced suppliers request settlement of payment within 30 days from the
291、date of invoice.Either party may terminate the agreements by serving notice to the other party under certain circumstances.We generally obtain raw materials for our manufacturing activities from various suppliers who we believe have sufficient capacity to meet our demands.Raw materials and starting
292、materials used at our facilities in Beijing and Suzhou include active pharmaceutical ingredients custom-made by our third-party CROs and excipients,which are commercially available from well-known vendors that meet the requirements of the relevant regulatory agencies.The core raw materials used in m
293、anufacturing at our Guangzhou facility are genetically modified cell lines that we have co-developed and licensed from Boehringer Ingelheim and other third parties.We typically order raw materials on a purchase order basis and do not enter into long-term,dedicated capacity or minimum supply arrangem
294、ents.We pay for our purchases of raw materials on credit.Credit periods granted to us by our suppliers generally range from 30 to 60 days.Our suppliers are generally not responsible for any defects in our finished products.Amgen CollaborationCollaboration AgreementOn October 31,2019,our wholly-owned
295、 subsidiary,BeiGene Switzerland GmbH(BeiGene Switzerland),entered into a Collaboration Agreement with Amgen,which became effective on January 2,2020(as amended,the Amgen Collaboration Agreement).Pursuant to the terms of the Amgen Collaboration Agreement,we are responsible for commercializing Amgens
296、oncology products XGEVA,BLINCYTO and KYPROLIS in China(excluding Hong Kong,Macao and Taiwan)for a period of five or seven years following each products regulatory approval in China,as specified in the Amgen Collaboration Agreement,with the commercialization period for XGEVA commencing following the
297、transition of operational responsibilities for the product.In addition,as specified in the agreement,we have the option to retain one of the three products to commercialize for as long as the product is sold in China.The parties have agreed to equally share profits and losses for the products in Chi
298、na during each products commercialization period.After expiration of the commercialization period for each product,the products not retained will be transitioned back to Amgen and we will be eligible to receive tiered mid-single to low-double digit royalties on net sales in China of each product for
299、 an additional five years.Additionally,pursuant to the terms of the Amgen Collaboration Agreement,we and Amgen have agreed to collaborate on the global clinical development and commercialization of a portfolio of Amgen clinical-and late-preclinical-stage oncology 22pipeline products.Starting from th
300、e commencement of the Amgen Collaboration Agreement,we and Amgen will co-fund global development costs,with BeiGene contributing up to$1.25 billion worth of development services and cash over the term of the collaboration.We will be eligible to receive tiered mid-single digit royalties on net sales
301、of each product globally outside of China,other than LUMAKRAS(sotorasib)(AMG 510),on a product-by-product and country-by-country basis,until the latest of the expiration of the last valid patent claim,the expiration of regulatory exclusivity,or the earlier of eight years after the first commercial s
302、ale of such product in the country of sale and 20 years from the date of first commercial sale of such product anywhere in the world.For each pipeline product that is approved in China,we will have the right to commercialize the product for seven years,with the parties sharing profits and losses for
303、 the product in China equally.In addition,we will have the right to retain approximately one of every three approved products,up to a total of six,other than AMG 510,to commercialize for as long as each such product is sold in China.After the expiration of the seven-year commercialization period,eac
304、h product will be transitioned back to Amgen and we will be eligible to received tiered mid-single to low-double digit royalties on net sales in China for an additional five years.The parties are subject to specified exclusivity requirements in China and the rest of the world.Recently,in connection
305、with our ongoing assessment of the Collaboration Agreement cost-share contributions,we determined that our further investment in the development of AMG 510 was no longer commercially viable for BeiGene.As a result,in February 2023,we entered into an amendment to the Collaboration Agreement to(i)stop
306、 sharing costs with Amgen for the further development of AMG 510 during the period starting January 1,2023 and ending August 31,2023;and(ii)cooperate in good faith to prepare a transition plan with the anticipated termination of AMG 510 from the Collaboration Agreement.BeiGene,Ltd.has guaranteed cer
307、tain obligations of BeiGene Switzerland under the Amgen Collaboration Agreement pursuant to the terms of a separate Guarantee Agreement.The Amgen Collaboration Agreement contains customary representations,warranties and covenants by the parties.The agreement will continue in effect on a product-by-p
308、roduct basis unless terminated by either party pursuant to its terms.The agreement may be terminated by mutual written consent of the parties,or by either party upon the other partys uncured material breach,insolvency,failure to comply with specified compliance provisions,or subject to a specified n
309、egotiation mechanism,certain adverse economic impacts or the failure to meet commercial objectives.In addition,Amgen may terminate the agreement with respect to a pipeline product in the event it suspends development of such pipeline product on specified terms,subject to the parties determining whet
310、her to continue development of the pipeline product in China.Share Purchase AgreementIn connection with the Amgen Collaboration Agreement,pursuant to a share purchase agreement dated October 31,2019,as amended,by and between BeiGene,Ltd.and Amgen(as amended,the“Share Purchase Agreement”),we issued t
311、o Amgen 206,635,013 ordinary shares in the form of 15,895,001 American Depositary Shares(ADSs)of BeiGene,Ltd.on January 2,2020,representing approximately 20.5%of our then outstanding shares,for an aggregate purchase price of$2.78 billion,or$13.45 per ordinary share,or$174.85 per ADS.Pursuant to the
312、Share Purchase Agreement,Amgen has agreed to(i)a lock-up on sales of its shares until the earliest of(a)the fourth anniversary of the closing,(b)the expiration or termination of the Collaboration Agreement and(c)a change of control of BeiGene,Ltd.,(ii)a standstill until the date on which it holds le
313、ss than 5%of our then outstanding shares,and(iii)a voting agreement to vote its shares on certain matters presented for shareholder approval until the later of(a)the fifth anniversary of the closing and(b)the expiration of the standstill period,all under specified circumstances and as set forth in t
314、he agreement.Following the later of(i)the expiration of the lock-up period and(ii)the expiration of the standstill period,Amgen has agreed not to sell shares representing more than 5%of our then outstanding shares in any rolling 12-month period.Under the terms of the Share Purchase Agreement,Amgen w
315、ill also have specified registration rights upon expiration of the lock-up.Additionally,we have agreed to use reasonable best efforts to provide Amgen with an opportunity to participate in subsequent new securities offerings upon the same terms and conditions as other purchasers in the offering in a
316、n amount needed to allow Amgen to hold up to 20.6%of our shares,subject to applicable law and HKEx rules and other specified conditions.On March 17,2020,BeiGene,Ltd.and Amgen entered into an Amendment No.2(the“Second Amendment”)to the Share Purchase Agreement in order to account for periodic dilutio
317、n from the issuance of shares by us,which agreement was restated in its entirety on September 24,2020(the“Restated Second Amendment”).Pursuant to the Restated Second Amendment,Amgen has an option(the“Direct Purchase Option”)to subscribe for additional ADSs in an amount necessary to enable it to incr
318、ease(and subsequently maintain)its ownership at approximately 20.6%of our outstanding shares.The Direct Purchase Option is exercisable on a monthly basis,but only if Amgens interest in our outstanding shares at the monthly reference date is less than 20.4%.The Direct Purchase Option(i)is exercisable
319、 by Amgen solely as a result of dilution arising from issuance of 23new shares by us under our equity incentive plans from time to time,and(ii)is subject to annual approval by our independent shareholders each year during the term of the Restated Second Amendment.The exercise period of the Direct Pu
320、rchase Option commenced on December 1,2020 and will terminate on the earliest of:(a)the date on which Amgen and its affiliates collectively own less than 20%of the outstanding share capital of the Company as a result of Amgens sale of shares;(b)at least 60-day advance written notice from either Amge
321、n or the Company that such party wishes to terminate the Direct Purchase Option;or(c)December 1,2023.The Direct Purchase Option has no vesting period.Novartis CollaborationCollaboration and License Agreement for TislelizumabOn January 11,2021,our wholly-owned subsidiary,BeiGene Switzerland GmbH,ente
322、red into a Collaboration and License Agreement,which became effective on February 26,2021(the“Novartis Collaboration and License Agreement”)with Novartis,pursuant to which Novartis will have the right to develop,manufacture and commercialize tislelizumab in the United States,Canada,Mexico,member cou
323、ntries of the European Union,United Kingdom,Norway,Switzerland,Iceland,Liechtenstein,Russia,and Japan(the“Licensed Territory”).Under the Novartis Collaboration and License Agreement,we received an upfront cash payment of$650 million from Novartis.Additionally,we are eligible to receive up to$1.3 bil
324、lion upon the achievement of regulatory milestones,$250 million upon the achievement of sales milestones,and tiered royalties based on percentages of annual net sales of tislelizumab in the Licensed Territory ranging from the high-teens to high-twenties,with customary reductions in specified circums
325、tances.Royalties are payable on a country-by-country basis from the time of the first commercial sale until the latest of the expiration of the last valid patent claim,the expiration of regulatory exclusivity,or 10 years after the first commercial sale of tislelizumab in the country of sale.Under th
326、e Novartis Collaboration and License Agreement,we and Novartis have agreed to jointly develop tislelizumab in the Licensed Territory,with Novartis responsible for regulatory submissions after a transition period and for commercialization upon regulatory approvals.In addition,both companies may condu
327、ct clinical trials to explore potential combinations of tislelizumab with other cancer treatments.We will be responsible for funding the ongoing clinical trials of tislelizumab,and Novartis has agreed to fund any new registrational,bridging,or post-marketing studies in the Licensed Territory.Subject
328、 to specified conditions,both parties have agreed to jointly fund other new clinical trials in the Licensed Territory agreed by the parties,provided that each party will be responsible for funding clinical trials evaluating tislelizumab in combination with its own-or third-party cancer treatments.We
329、 will initially be responsible for supplying tislelizumab to Novartis,with Novartis having the right to conduct manufacturing for its use in the Licensed Territory after successful transfer of the manufacturing process.In addition,we have an option to co-detail the product in the United States,Canad
330、a and Mexico,on an indication-by-indication basis,funded in part by Novartis.Each party retains the worldwide right to commercialize its propriety products in combination with tislelizumab.We retain the rights to manufacture and supply a specified percentage of commercial supply of tislelizumab from
331、 our planned U.S.manufacturing facility to be built in Hopewell,New Jersey,subject to the terms of the agreement.The Novartis Collaboration and License Agreement contains customary representations,warranties and covenants by the parties.Unless earlier terminated,the agreement will expire on a countr
332、y-by-country basis upon expiration of the royalty term in such country and in its entirety upon the expiration of all applicable royalty terms in all countries in the Licensed Territory.We may terminate the agreement in its entirety upon written notice(i)if Novartis challenges the licensed BeiGene p
333、atents,or(ii)if Novartis files a biologics license application for its anti-PD-1 antibody,spartalizumab,in the Licensed Territory,and we do not elect to include spartalizumab as a licensed product under the agreement or Novartis does not divest the product candidate,in which case Novartis would pay us a specified termination fee.The agreement may be terminated by Novartis upon 120 days prior writt