1、J.P.Morgan Healthcare ConferenceJ A N U A R Y 8,2 0 2 4This non-promotional presentation contains investigational data as well as forward-looking statements;actual results may vary materially.2Strategy&Business UpdateJ.P.M o r g a n H e a l t h c a r e C o n f e r e n c e 2 0 2 4Co-Founder,Board Co-

2、Chair,President&Chief Executive Officer3Note regarding forward-looking statementsThis presentation includes forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Regeneron Pharmaceuticals,Inc.(Regeneron or theCompany),and actual event

3、s or results may differ materially from these forward-looking statements.Words such as anticipate,expect,intend,plan,believe,seek,estimate,variations of suchwords,and similar expressions are intended to identify such forward-looking statements,although not all forward-looking statements contain thes

4、e identifying words.These statements concern,and theserisks and uncertainties include,among others,the nature,timing,and possible success and therapeutic applications of products marketed or otherwise commercialized by Regeneron and/or itscollaborators or licensees(collectively,Regenerons Products)a

5、nd product candidates being developed by Regeneron and/or its collaborators or licensees(collectively,Regenerons Product Candidates)and research and clinical programs now underway or planned,including without limitation EYLEA(aflibercept)Injection,EYLEA HD(aflibercept)Injection 8 mg,Dupixent(dupilum

6、ab)Injection,Libtayo(cemiplimab)Injection,Praluent(alirocumab)Injection,Kevzara(sarilumab)Injection,Evkeeza(evinacumab)Injection,Veopoz(pozelimab)Injection,odronextamab,itepekimab,fianlimab,garetosmab,linvoseltamab,REGN5713-5714-5715,Regenerons other oncology programs(including its costimulatory bis

7、pecific portfolio),Regenerons and its collaborators earlier-stage programs,and the use ofhuman genetics in Regenerons research programs;the likelihood and timing of achieving any of the anticipated milestones discussed or referenced in this presentation;safety issues resulting from theadministration

8、 of Regenerons Products and Regenerons Product Candidates in patients,including serious complications or side effects in connection with the use of Regenerons Products and RegeneronsProduct Candidates in clinical trials;the likelihood,timing,and scope of possible regulatory approval and commercial l

9、aunch of Regenerons late-stage product candidates and new indications forRegenerons Products,such as those listed above;the extent to which the results from the research and development programs conducted by Regeneron and/or its collaborators may be replicated in otherstudies and/or lead to advancem

10、ent of product candidates to clinical trials,therapeutic applications,or regulatory approval;ongoing regulatory obligations and oversight impacting Regenerons Products,research and clinical programs,and business,including those relating to patient privacy;determinations by regulatory and administrat

11、ive governmental authorities which may delay or restrict Regeneronsability to continue to develop or commercialize Regenerons Products and Regenerons Product Candidates;competing drugs and product candidates that may be superior to,or more cost effective than,Regenerons Products and Regenerons Produ

12、ct Candidates;uncertainty of the utilization,market acceptance,and commercial success of Regenerons Products and Regenerons Product Candidates and theimpact of studies(whether conducted by Regeneron or others and whether mandated or voluntary)or recommendations and guidelines from governmental autho

13、rities and other third parties on thecommercial success of Regenerons Products and Regenerons Product Candidates;Regenerons ability to manufacture and manage supply chains for multiple products and product candidates;the abilityof Regenerons collaborators,suppliers,or other third parties(as applicab

14、le)to perform manufacturing,filling,finishing,packaging,labeling,distribution,and other steps related to Regenerons Productsand Regenerons Product Candidates;the availability and extent of reimbursement of Regenerons Products from third-party payors,including private payor healthcare and insurance p

15、rograms,healthmaintenance organizations,pharmacy benefit management companies,and government programs such as Medicare and Medicaid;coverage and reimbursement determinations by such payors and newpolicies and procedures adopted by such payors;unanticipated expenses;the costs of developing,producing,

16、and selling products;Regenerons ability to meet any of its financial projections or guidance,including without limitation capital expenditures,and changes to the assumptions underlying those projections or guidance;the potential for any license or collaboration agreement,including Regeneronsagreemen

17、ts with Sanofi and Bayer(or their respective affiliated companies,as applicable),to be cancelled or terminated;the impact of public health outbreaks,epidemics,or pandemics(such as theCOVID-19 pandemic)on Regenerons business;and risks associated with intellectual property of other parties and pending

18、 or future litigation relating thereto(including without limitation the patentlitigation and other related proceedings relating to EYLEA),other litigation and other proceedings and government investigations relating to the Company and/or its operations(including the pending civillitigation initiated

19、 by the U.S.Attorneys Office for the District of Massachusetts),the ultimate outcome of any such proceedings and investigations,and the impact any of the foregoing may have onRegenerons business,prospects,operating results,and financial condition.A more complete description of these and other materi

20、al risks can be found in Regenerons filings with the U.S.Securities andExchange Commission.Any forward-looking statements are made based on managements current beliefs and judgment,and the reader is cautioned not to rely on any forward-looking statements made byRegeneron.Regeneron does not undertake

21、 any obligation to update(publicly or otherwise)any forward-looking statement,including without limitation any financial projection or guidance,whether as aresult of new information,future events,or otherwise.42023 achievements across key strategic priorities position Regeneron to deliver long-term

22、shareholder valueThis slide contains investigational drug candidates that have not been approved by any regulatory authority.Note:Definitions for all acronyms and abbreviations in this presentation can be found on slide 33.FDA approval and successful launch of Eylea HD positions retinal franchise fo

23、r prolonged leadershipExceptional Dupixent clinical and commercial execution;unprecedented data in eosinophilic COPD to enable potential 2024 launchSignificant immuno-oncology pipeline progress across checkpoint inhibitor,CD3 bispecific,and CD28 costimulatory bispecific platforms,including BLA submi

24、ssions for odronextamab and linvoseltamabEmerging data from hematology,genetic medicine,and obesity pipelines support advancing multiple potential first-and best-in-class opportunitiesSolid Organ Oncology Fianlimab+Libtayo:Initiate Phase 2/3 studies in 1L advanced NSCLC Initiate Phase 2 study in per

25、ioperative melanoma 2024 Initiate Phase 2 study in perioperative NSCLC 2024 Report additional data for PSMAxCD28+Libtayo 2024/2025 Report initial data across solid organ oncology,including for CD3 bispecifics and CD28 costimulatory bispecifics EC decision for Libtayo in combination with chemotherapy

26、 in 1L advanced NSCLCOdronextamab(CD20 xCD3)Initiate confirmatory studies in FL&DLBCL,including earlier lines Initiate Phase 1 study in combination with REGN5837(CD22xCD28)in aggressive DLBCL BLA and MAA acceptance in B-NHLLinvoseltamab(BCMAxCD3)Report updated pivotal Phase 2 data in R/R Multiple My

27、eloma Initiate confirmatory study in MM,including in earlier lines Initiate Phase 1 study in combination with TAAxCD28 in MM 2024 BLA submission in 3L+MM 5Delivered on key goals presented at J.P.Morgan 2023This slide contains investigational drug candidates that have not been approved by any regulat

28、ory authority.Ophthalmology FDA approval for EYLEA in ROP BLA acceptance for aflibercept 8 mg in DME and wAMD FDA approval and U.S.launch of EYLEA HD Two-year data for PHOTON(DME)and PULSAR(wAMD)studiesDupixent sBLA acceptance for CSU EC decision on pediatric AD(6mo 5yr)Report data for Phase 3 study

29、 in Type 2 COPD sBLA acceptance for pediatric EoE FDA decision on CSU received CRLVeopoz(anti-C5 antibody)FDA acceptance of CHAPLE BLA FDA decision on CHAPLE(PDUFA August 20,2023)6EYLEA HD approved by FDA for wAMD,DME,and DRhas the potential to become the next-generation standard-of-care anti-VEGF t

30、reatment4Q 2023 U.S.Net Product Sales*:$123 millionachieved in first full quarter following launchFDA approval for wAMD,DME and DR received in August 2023Early indicators suggest broad initial uptake across treatment landscapeStrong 2-year data from pivotal PULSAR and PHOTON studies presented in 2H

31、2023,supporting best-in-class efficacy,safety,and durability profile2/3 of eligible lives have coverage;vast majority of covered lives have first-line or single-step-edit access to Eylea HD100%of Medicare jurisdictions have confirmed paid claimsRemain on track for permanent J-Codeon April 1,2024*Bas

32、ed on preliminary,unaudited results.Preliminary U.S.net product sales for Eylea in 4Q 2023 were$1.34 billion.4Q 2023 combined EYLEA HD+EYLEAU.S.net product sales of$1.46 billion*7Dupixent global net product sales grew 34%and reached nearly$8.4 billion through first nine months of 2023In the third qu

33、arter of 2023,Dupixent global net sales grew 33%to$3.1 billionIncremental market penetration,new indications,and younger populations represent significant opportunity for continued growth$4.7$6.4$1.5$2.0First 9 Months of 2022First 9 Months of 2023U.S.ROW+34%$BillionsSanofi records global net product

34、 sales of DupixentThis slide contains investigational indications for dupilumab that have not been approved by any regulatory authority.Approved in FIVE indications,positive pivotal results in SEVEN Type 2 allergic diseasesNBRx#1 prescribed biologic in all 5 approved indicationsTRx#1 prescribed biol

35、ogic in 4 out of 5 approved indicationsDemonstrated clinical and real-world safety profile60 clinical trials with 10,000 patientsChronic Obstructive Pulmonary DiseaseReported positive results for pivotal BOREAS and NOTUS studiessBLA submission completed in December 2023;under review in EU750,000pati

36、ents on therapy globally8Delivering on“pipeline in a product”potentialDupixent clinical trials have demonstrated that IL-4 and IL-13 are key drivers of multiple Type 2 allergic diseasesThis slide contains investigational indications for dupilumab that have not been approved by any regulatory authori

37、ty.Under regulatoryreviewInvestigationalindicationsApproved byFDA and/or ECPotential new indications for Dupixent provide opportunity toadd up to 1 million additional eligible patients in the U.S.Atopic DermatitisInfant 6 mo-5YCOPDAdults 18+TodayEoEAdults/Adolescents 12+Prurigo NodularisAdults 18+Eo

38、EPed 1-11CSUAdults/Adol 12+BPAdults 18+CPUOAdults 18+UCAdults 18+EoGAdults/Adol 12+CSUPed 2-11AsthmaPed 2-5Prurigo NodularisPed 6m-17Atopic DermatitisAdults 18+AsthmaAdults/Adolescents 12+Atopic DermatitisAdolescent 12+CRSwNPAdults 18+Atopic DermatitisPed 6-11AsthmaPed 6-119Striving for global leade

39、rship in oncologyPotential for up to three FDA-approved products by end of 2024,spanning solid and hematological malignanciesLibtayo poised to exceed$1 billion in global net product sales in 2024;Robust oncology pipeline driven primarily by Libtayo combinations2018Libtayo FDA-approved as first treat

40、ment for advanced CSCC2023Submitted BLAs for odronextamab in B-NHL and linvoseltamab in MM,enabling potential 2024 launches2023Additional results for fianlimab+Libtayo in metastatic melanoma;began pivotal studies in melanoma&NSCLC2022Libtayo+chemotherapy FDA-approved in advanced NSCLC irrespective o

41、f PD-L1 expression levels2022Regeneron purchases Sanofis 50%stake in Libtayo,securing global rights2021Libtayo FDA-approved as monotherapy in advanced NSCLC tumors with high(50%)PD-L1 expression2021Libtayo FDA-approved as first immunotherapy for advanced BCCODRONEXTAMAB(CD20 xCD3)LINVOSELTAMAB(BCMAX

42、CD3)This slide contains investigational drug candidates that have not been approved by any regulatory authority.10Research&Pipeline UpdateJ.P.M o r g a n H e a l t h c a r e C o n f e r e n c e 2 0 2 4Co-Founder,Board Co-Chair,President&Chief Scientific Officer11Relentless InnovationAfter 35 years,R

43、egeneron is still pushing the boundaries of science and technology2023 was another year of scientific“firsts”Collaboration with:*Sanofi;Alnylam;IntelliaDupixent in COPD*First biologic to achieve clinically meaningful reduction in COPD exacerbations and improvement in lung functionCD28 costimulatory

44、bispecificsFirst to dose patients with costimulatory bispecific in combination with a CD3 bispecific for both solid and heme tumorsReversing severe allergyPublished preclinical results on potential groundbreaking approach for reversing severe allergysiRNA in CNSFirst clinical results demonstrating s

45、ilencing of a pathological gene in human brainAntibody+siRNA targeting C5Generated first data combining antibody and siRNA therapeutic classes(for targeting C5 in PNH)CRISPR gene editingFirst to initiate a pivotal study using in vivo CRISPR gene editing cleared by U.S.FDAGene therapy for hearing los

46、sRestored hearing in profoundly deaf child with otoferlin gene therapy12Harnessing the immune system to fight cancerRegeneron has validated 3 independent classes of internally-developed immuno-oncology agents One approved medicine,two under regulatory review Robust pipeline of immuno-oncology combin

47、ationsCD28 Costimulatory Bispecifics(“Signal 2”)Odronextamab(CD20 xCD3)B-NHLLinvoseltamab(BCMAxCD3)MMREGN5678(PSMAxCD28)Prostate CancerREGN5668(MUC16xCD28)Ovarian CancerUbamatamab(MUC16xCD3)Ovarian CancerREGN7075(EGFRxCD28)Solid TumorsFianlimab(anti-LAG-3)Melanoma,NSCLC(anti-PD-1)CSCC,BCC,NSCLCREGN5

48、837(CD22xCD28)DLBCLREGN4336(PSMAxCD3)Prostate CancerCD3 Bispecifics(“Signal 1”)Checkpoint Inhibitors(anti-PD-1&anti-LAG-3)Broad pipeline of clinical-stage assets and numerous preclinical assets planned to advance to clinical studies13Unique flexibility of internally-developed pipeline drives potenti

49、al for novel and differentiated combinationsOdronextamab(CD20 xCD3)Linvoseltamab(BCMAxCD3)Ubamatamab(MUC16xCD3)PSMAxCD3(REGN4336)R/R B-NHLR/R MultipleMyelomaMetastatic prostate cancerRecurrent ovarian cancerCemiplimab(PD-1)PSMAxCD3(REGN4336)Metastatic prostate cancerCemiplimab(PD-1)Ubamatamab(MUC16x

50、CD3)Recurrent ovarian cancerCemiplimab(PD-1)EGFRxCD28(REGN7075)Cemiplimab(PD-1)MUC16xCD28(REGN5668)Cemiplimab(PD-1)PSMAxCD28(REGN5678)Solid tumorsRecurrentovarian cancerMetastaticprostate cancerFianlimab(LAG-3)Cemiplimab(PD-1)Melanoma&other advanced malignanciesHNSCCGITR(REGN6569)Cemiplimab(PD-1)CSC

51、C,MCC,BCCvidutolimod(TLR9)Cemiplimab(PD-1)METxMET(REGN5093)METxMET ADC(REGN5093-M114)MET-altered advanced NSCLCMET over-expressing advanced NSCLCUbamatamab(MUC16xCD3)MUC16xCD28(REGN5668)Recurrentovarian cancerPSMAxCD3(REGN4336)PSMAxCD28(REGN5678)Metastaticprostate cancerOdronextamab(CD20 xCD3)CD22xC

52、D28(REGN5837)R/R B-NHLPD-1 Inhibitor This slide contains investigational drug candidates that have not been approved by any regulatory authority.Bispecifics and Checkpoint Inhibitor CombosCheckpoint Inhibitor CombosPhase 1Phase 2Phase 3Melanoma1L Metastatic MelanomaAdjuvant MelanomaPerioperative Mel

53、anomaLung(NSCLC)Advanced NSCLCPerioperative NSCLCOther solid tumorsPerioperative HCCPerioperative CSCCPerioperative HNSCC14Fianlimab(anti-LAG-3)+cemiplimab(anti-PD-1):Combining two checkpoint inhibitorsResults from three independent 1L metastatic melanoma cohorts from the FIH study demonstrated stro

54、ng efficacy signal,including in patients treated with adjuvant anti-PD-1 therapy1Hamid,O.Significant durable response with fianlimab(anti-LAG-3)and cemiplimab(anti-PD-1)in advanced melanoma:post adjuvant PD-1 analysis,ASCO 2023.2Long,G.Relatlimab and nivolumab versus nivolumab in previously untreate

55、d metastatic or unresectable melanoma:Overall survival and response rates from RELATIVITY-047,ASCO Plenary Series,March 2022.This slide contains investigational drug candidates that have not been approved by any regulatory authority.There are no randomized,head-to-head clinical trials between these

56、products.Study data being provided for descriptive purposes only.Caution is advised when drawing conclusions based on cross-trial comparisons.Potentially pivotal data expected 2H24Initiating 1H24Initiating 1H24EnrollingEnrollingSafety profile of fianlimab+cemiplimab combination similar to anti-PD-1

57、monotherapyResults in 1L Metastatic Melanomafianlimab+cemiplimabFIH POC study1ORRDCRmPFS(KM-estimate)Cohort MM1(n=40)Initial63%80%24 moCohort MM2(n=40)Confirmatory63%80%15 moCohort MM3(n=18)PD-1 in adjuvant setting56%67%12 moCombined(n=98)61%78%15 moRELATIVITY-047 Phase 32nivolumab(n=359)33%51%4.6 m

58、onivolumab+relatlimab(n=355)43%63%10.2 moInitial data expected 2H24Initiating 2024EnrollingInitiating 2024Regenerons leading CD3 bispecifics Our blood cancer research is focused on bispecific antibodies that are being investigated both as monotherapies and in combination with each other and emerging

59、 therapeutic modalitiesBLA submitted in December 2023 for R/R multiple myeloma,pending FDA acceptanceEU submission planned for 1Q 2024BLA accepted by FDA for R/R FL&DLBCL(PDUFA March 31,2024)EU submission completed;decision expected 2H 202415Linvoseltamab(BCMAxCD3)MM Linvoseltamab has the potential

60、to be the best-in-class BCMAxCD3 bispecific with its clinical profile,dosing,and administrationConfirmatory Phase 3 study underway;expanding into early stages of diseaseOdronextamab(CD20 xCD3)NHL Odronextamab can treat both indolent and aggressive lymphomas with potential best-in-class efficacy in F

61、L and a competitive profile in DLBCL,including patients previously treated with CAR-T therapy Confirmatory Phase 3 OLYMPIA program underway and enrolling patients in earlier lines of therapyT Cell Receptor/CD3Tumor-specific target*Data source:Regeneron press release from Dec 7,2023.Per Protocol.30-m

62、in as long as patient tolerability allows;discretion at Day 8.Teclistamab-FDA Approved(per U.S.FDA Prescribing Information*)Elranatamab-FDA approved(per U.S.FDA Prescribing Information*)Linvoseltamab*(per LINKER-MM1 primary analysis*)Follow-up 7.4-months among respondersFollow-up 11.1-months among r

63、espondersFollow-up 11.0-months all patients CRS median time to onset:2 daysmedian duration:2 days CRS median time to onset:2 daysmedian duration:2 daysCRS median time to onset:1 daymedian duration:within 1 day3 X 48-hr hospitalizationrequirements during step-up dosing(over initial 9 days)Subcutaneou

64、s(by HCP only)1 X 48-hr+1 X 24-hr hospitalization requirements during step-up dosing(over initial 5 days)Subcutaneous(by HCP only)1 X 24-hrs in W1+1 x 24-hrs in W2;Hospitalized for 1 day during step-up dosing on Day 1&Day 8Intravenous(Week 3+=30-min)44%14%0.5%3%G1G2G3+ICANS50%21%0.6%6%G1G2G3+ICANS16

65、Within the BCMA bispecific class,linvoseltamab has differentiated and compelling clinical profile in r/r multiple myelomaCRSSafety Hospitalization,Administration&Dosing scheduleEfficacyWeek 25+for responders Weeks 1-24Q2WQWQ4WWeek 24+if VGPR+Weeks 1-14Weeks 15-23QWQ2WQWCRS62%28%ORRsCR+CR200mg dose35

66、%10%1.0%8%G1G2G3+ICANSCRS200mg dose58%26%ORRsCR+CR71%46%ORRsCR+CRx 6 daysx 3 daysx 2 days Not full safety profile.Please refer to U.S.FDA prescriber information and Regenerons disclosures for further detailsThis slide contains investigational drug candidates that have not been approved by any regula

67、tory authority.There are no randomized,head-to-head clinical trials between these products.Study data being provided for descriptive purposes only.Caution is advised when drawing conclusions based on cross-trial comparisons.Dose EscalationProof-of-MechanismDose ExpansionStatus/Next StepsCombined wit

68、h:PSMAxCD28Prostate CancerEnrolling monotherapy cohort;combo with PSMAxCD3 to start 1H24EGFRxCD28Solid TumorsExpansion cohorts with cemiplimab to initiate in 1H24 in multiple tumorsMUC16xCD28Ovarian CancerPresented initial dose escalation results with cemiplimab;expansion cohorts expected to initiat

69、e in 2024;enrolling dose escalation with ubamatamabCD22xCD28DLBCLEnrolling dose escalation cohortsCD38xCD28MMInitiating Phase 1 study in 202417Progressing CD28 costimulatory bispecificsAdditional costimulatory bispecifics expected to enter the clinic in 2024 and beyondCemiplimabPSMAxCD3CemiplimabCem

70、iplimabUbamatamab(MUC16xCD3)Odronextamab(CD20 xCD3)Linvoseltamab(BCMAxCD3)18Potential to change the COPD treatment paradigmwith Dupixent and itepekimab(anti-IL4/13)Demonstrated 42%reduction in exacerbations in former smokers vs.placebo in Phase 2 study RGC-generated human genetics data support ratio

71、nale for IL-33 blockade to treat COPD Pivotal results from both AERIFY studies expected in 2025Positive results in Phase 3 BOREAS and NOTUS studies in eosinophilic COPD reported during 2023sBLA submission completed in December 2023Lung function benefit vs.placebo observed at Week 12 sustained at Wee

72、k 52Safety findings generally consistent with known safety profile of DupixentThis slide contains investigational drug candidates that have not been approved by any regulatory authority.BOREASNOTUSPrimary endpoint:Significant reduction in moderate or severe COPD exacerbations over 52 weeks compared

73、to placebo30%(p=0.0005)34%(p=0.0002)Key secondary endpoint:Significant improvement in lung function at week 12 compared to placebo*+83 mL(p0.0001)+82 mL(p=0.0001)*Results shown are placebo-adjusted improvements in pre-bronchodilator forced expiratory volume(FEV1).Positive data in former smokers in P

74、hase 2 COPD study informed Phase 3 trial designPhase 3 AERIFY studies passed interim futility analysis in 2023Itepekimab(anti-IL-33)Phase 2 COPD TrialItepekimab led to 42%reduction in exacerbations in former smokers42%reduction1.550.89ITEPEKIMABPLACEBO21.51.5019Novel treatment approach for reversing

75、 severe allergy:Linvoseltamab(BCMAxCD3)plus Dupixent(anti-IL4R)This slide contains investigational drug candidates that have not been approved by any regulatory authority.Clinical trial with the two-drug regimen in patients with severe food allergies to begin in 20241Adapted from Limnander et al,Sci

76、.Transl.Med.2023.2Asrat et al,Sci.Immunol.2020.*Pooled data from n=12 multiple myeloma patients from the LINKER-MM1 Phase 1 study,treated with six different dose levels of linvoseltamabLinvoseltamab and Dupixent regimen could eliminate IgE:potential groundbreaking approach for controlling severe all

77、ergy Immunoglobulin E(IgE)is the key driver of allergic reactions,such as food allergies;long-lived plasma cells consistently produce IgE2 In atopic patients,transient linvoseltamabtreatment with Dupixent maintenance has the potential of permanently eliminating IgE and durably reversing severe aller

78、gies,while allowing the restoration of other immunoglobulinsMyeloma patients treated with linvoseltamab rapidly reduce IgE levels1Linvoseltamab effectively eliminates BCMA-expressing cells,including long-lived plasma cellsIgE reduction seen in myeloma patients supports the two-drug regimen for sever

79、e food allergiesMedian concentrations of serum IgE over time in MM patients(n=12)receiving QW linvoseltamab*Transient plasma cell depletion with BCMAxCD3 plus sustained IL-4R blockade durably eliminates IgE production in cynomolgus monkeys1Controlbispecific(single dose)BCMAxCD3bispecific(single dose

80、)+IL-4R antibody(QW)BCMAxCD3bispecific(single dose)BCMAxCD3transiently reduces serum IgEReconstitution of IgEBCMAxCD3 combined with anti-IL-4R results in persistent reduction of serum IgE20Regenerons approach to obesity:combinations with leading medicines aim to improve quality of weight lossIncreti

81、n-based therapies,such as semaglutide(sema)and tirzepatide,are emerging as standards of care for weight loss;however,up to 40%of this weight loss is due to decreases in lean muscle mass1Novel approaches for obesityRationaleProgram statusGLP1RImproving upon once weekly standard of care in obesity/T2D

82、MNHP studies underway for our antibody-tethered GLP-1 ligand+-MSTN+-ACT-AImproving quality of weight loss by preserving lean muscle during weight lossMid-2024:Start Phase 2 study of semaglutide with trevogrumab(anti-myostatin)garetosmab(anti-activin A)GPR75GPR75 gene mutations are associated with pr

83、otection against obesitysiRNA,small molecule,and antibody candidate identification and screening underway1Wilding,Diabetes Obes Metab,2022;PMID:35441470,2from Mastaitis J,et al.Manuscript in preparation and ADA 2023 presentation,n=10 per arm;DXA:dual-energy X-ray absorptiometry measurement Adding my

84、ostatin blockade to semaglutide leads to greater fat loss and less lean mass loss compared to semaglutide monotherapy in obese non-human primates2This slide contains investigational drug candidates that have not been approved by any regulatory authority.Incretin-based therapyChange in Body Weight th

85、rough 20 WeeksAverage change from baseline(g)VehicleSemaSema+-MSTNSema+-MSTN+-ACT-A Change in Body Composition at Week 20 measured by DXASema+-MSTN+-ACT-ASema+-MSTNSemaVehicleLean mass loss/gainFat mass loss/gain1000-10000More fat mass lostLess lean mass lost21Obesity clinical program to start in mi

86、d-2024Phase 2 study to investigate if addition of trevogrumab(anti-myostatin)to semaglutide with and without garetosmab(anti-activin A)improves the quality of weight loss and/or improves maintenance of weight loss post semaglutide discontinuationPhase 2 General Obesity Trial DesignRandomized(1:1:1:1

87、:1:1:1:1)double-blind,active controlled trialPERIOD 1(weight loss phase)PERIOD 2(weight maintenance phase)FOLLOW UP-2 WEEKDAY 1WEEK 26WEEK 52Primary EndpointsSecondary EndpointsA0A1B0B1C0C1D0D1PBO RUN-IN SEMA SC+PLACEBO SC+PBO IVPBO SC-MSTN HIGH DOSE SCPBO RUN-IN SEMA SC+-MSTN LOW DOSE SC+PBO IVPBO

88、SC-MSTN HIGH DOSE SCPBO RUN-IN SEMA SC+-MSTN HIGH DOSE SC+PBO IVPBO SC-MSTN HIGH DOSE SCPBO RUN-IN SEMA SC+-MSTN HIGH DOSE SC+-ACT-A IVPBO SC-MSTN HIGH DOSE SCA0A1B0B1C0C1D0D1 Obese patient enrollment starting mid-2024,pending safety and tolerability trial of high dose trevogrumab in healthy volunte

89、ersThis slide contains investigational drug candidates that have not been approved by any regulatory authority.22Leveraging Regenerons novel genetics discovery GPR75 as a target for obesityExome sequencing of 640,000 individuals revealed that gene variants in GPR75 are associated with reduced risk o

90、f obesity;Individuals with at least one inactive copy of the GPR75 gene had lower BMI and,on average,tended to weigh about 12 pounds less1GPR75:a novel target for obesity1Akbari,Science,2021;PMID:34210852,2unpublished data for humanized GPR75 mice,n=20-21 per arm,3unpublished data for Gpr75 knockout

91、 mice versus wild-type mice,4unpublished self-reported data(via the International Physical Activity Questionnaire IPAQ)for a small number of heterozygous GPR75 pLOF carriers versus non-carriers;pLOF predicted Loss Of Function GPR75 siRNA treatment halts weight gain and fat mass gainwithout lean mass

92、 loss in high fat diet fed obese mice2This slide contains investigational drug candidates that have not been approved by any regulatory authority.Change in Body Weight through 3 WeeksVehicleGPR75 siRNAChange in Fat Massthrough 3 WeeksChange in Lean Massthrough 3 WeeksRegeneron is pursuing three moda

93、lities to target GPR75:siRNA collaboration with AlnylamSmall molecule collaboration with AstraZenecaAntibody approachGpr75knockout micePeople with an inactive copy of GPR75 geneBody WeightPhysical Activity3423Regeneron Genetic Medicines:multiple investigational approaches for treatment of genetic di

94、seasesEstablished clinical proof-of-principle across several diseases with novel genetic medicine technologiessiRNA Gene Silencing(alone and antibody combos)First clinical results demonstrating silencing of a pathological gene in human brain(APP)*Pioneers in siRNA+antibody combo(C5)AAV Gene Therapy

95、Local delivery:restored hearing in first treated patient(OTOF)Antibody-targeted delivery:proof-of-concept in non-human primates;clinical approach in development(muscle disorders)CRISPR Knockout and Insertion Genome Editing Gene knockout:first clinical results demonstrating genome editing in humans;P

96、hase 3 started(TTR)Gene insertion:clinical program to start in 2024,pending regulatory approval(Factor 9)This slide contains investigational drug candidates that have not been approved by any regulatory authority.Collaboration with:*Alnylam;Intellia.24Regeneron Genetic Medicines pipelinePhase 3Phase

97、 2Phase 1Select Pre-IND CandidatesCIDEB*CIDEB siRNANASHHTT*HTT siRNAHuntingtons DiseaseFactor 9F9 CRISPR+AAVHemophilia BGAAGAA CRISPR+AAVPompe DiseaseGJB2/DB-103GJB2 AAVGJB2-related Hearing LossDB-OTO|OTOF AAV Dual Vector Gene TherapyOTOF-related Hearing Loss ANL-PNP*PNPLA3 siRNANASHALN-APP*APP siRN

98、AEarly-onset Alzheimers Disease and Cerebral Amyloid AngiopathyALN-HSDHSD17B13 siRNANASHPozelimab+CemdisiranC5 Antibody+C5 siRNAMyasthenia gravis and Paroxysmal Nocturnal Hemoglobinuria;Geographic atrophy initiating in 2H 2024NTLA-2001CRISPR/Cas9Transthyretin Amyloidosis(ATTR)with cardiomyopathyThis

99、 slide contains investigational drug candidates that have not been approved by any regulatory authority.SOD1*SOD1 siRNA SOD1 ALSCollaboration with:*Alnylam;Intellia.25Regeneron pioneers first combination of siRNA+antibody therapeutic classes OverviewStatusPNHPhase 3 ACCESS-1Complement inhibitor-nave

100、 patients Cohort A:Interim results recently reported Cohort B:Enrolling,data expected in 2024/2025gMGPhase 3 NIMBLEPatients with symptomatic generalized myasthenia gravis Study enrolling Data expected in 2025GAPatients with geographic atrophy secondary to age-related macular degenerationSystemic adm

101、inistration-Single subcutaneous injection to treat bilateral disease Phase 3 pivotal program initiating in 2H 20240.50.60.70.80.911.11.21.31.41.5BLwk 2wk 4wk 8wk 10wk 12wk 16wk 18wk 20wk 24wk 26LDH to ULNTimeLDH to ULN at wk 26:0.8 combo Baseline LDH/ULN:6.6 combo&5.9 ravu22,2419,20 19,2019,1718,171

102、6,1415,1313,1312,1111,1122,24nLDH to ULN at wk 26:1.2 ravuupper limit of normalpozelimab+cemdisiran comboSC Q4WravulizumabIV Q8WPrimary Endpoint:the percent change in lactate dehydrogenase(LDH)from baseline to week 26.LDH is a well-accepted biomarker of hemolysis with adequate control and normalizat

103、ion defined as 1.5 and 1.0 times the upper limit of normal(ULN),respectively.Only patients that completed 26 weeks of the study were evaluated for efficacy at the time of the data cut.This slide contains investigational drug candidates that have not been approved by any regulatory authority.Our anti

104、body+siRNA combination has the potential to improve on current standards of care across many diseases including complement mediated disorders:Complete and sustained C5 inhibition at a lower dose Reduced dosing frequency Convenient subcutaneous formulationPNH:Phase 3 ACCESS-1Exploratory Cohort A Pool

105、ed Patient DataPozelimab+cemdisiran reduces LDH levels in almost all patients Prior to this combination,no treatment has reduced and sustained average LDH to normal levels in PNH patientssiRNA reduces target load so that antibody can completely block target for extended periodPrior to this combinati

106、on,no treatment has reduced and sustained average LDH to normal levels in PNH patientsCurrent Geographic Atrophy LandscapeRegeneron Opportunity(Pozelimab+Cemdisiran Combo)MarketOpportunity 1M diagnosed in U.S.Increasing diagnosis and drug-treatment rates 2 approved agents,many more in development Le

107、adership in ophthalmology Differentiated MOARoute of Administration Q4W/Q8W intravitreal injections Bilateral disease requires injections in each eye Less invasive treatment option Systemic administration enables treatment of bilateral disease Q4W systemic treatmentOcularSafety Reported cases of occ

108、lusive retinal vasculitis along with other ocular safety events Systemic administration potentially reduces risk of ocular safety eventsEfficacy Approved agents lack evidence of maintenance of visual function Opportunity to demonstrate greater reduction in lesion growth rate along with preservation

109、of visual functionOfficeVisits Administered in office by retinal specialist Potential for self-administration(subcutaneous coformulation)26Geographic atrophy(in dry AMD):Extending our C5 siRNA+antibody approach to ophthalmologyPivotal Phase 3 program to initiate in 2H 2024Program Overview(Trials to

110、initiate in 2H 2024)Two Phase 3 pivotal trials(multi-center,randomized,double-masked)in geographic atrophy secondary to age-related macular degenerationThis slide contains investigational drug candidates that have not been approved by any regulatory authority.Regeneron restores hearing in a profound

111、ly deaf child27Gene therapy for genetic hearing lossPotentially first-in-class,one-time treatment to rescue hearing in infants born with profound deafness due to biallelic OTOF mutations DB-OTO is a surgically delivered AAV-based dual-vector gene therapy that selectively expresses functional OTOF in

112、 the inner ear hair cells of patients,enabling the ear to transmit sound to the brain Preliminary,positive safety and efficacy results from the first patient(2 years old)continue to show improvements in auditory responses,now through week 12,compared to baseline Paves the way for next gene therapy f

113、or genetic hearing loss GJB2 Currently in IND-enabling studiesDB-OTO AAV-based dual-vector gene therapy delivered to the inner ear to rescue hearing in infantsPreliminary results for first patient dosed:Profoundly deaf child at baseline,demonstrates markedly improved hearing at 12 weeks post-treatme

114、ntIntensity/volume(dB HL)Frequency/Pitch(Hz)Behavioral pure tone audiogram a plot of softest sounds a patient can hear in an individual ear*Arrows indicate no response at maximum level testedLower volume threshold for normal hearingProfound hearing impairment treated by cochlear implantModerate hear

115、ing loss treatable with a hearing aid125 25050010002000 4000 8000007080900Treated ear at week 12:moderate hearing lossTreated ear at week 4:responds to multiple pitchesTreated ear at baseline*This slide contains investigational drug candidates that have not been approved by any

116、 regulatory authority.28Optimizing genetic medicines with antibody-targeted deliveryTargeting of vector delivery with the skeletal muscle cell-specific protein(“M”)and blood-brain barrier endothelial cell-specific protein(“B”)“M”-and“B”-mediated AAV9 delivery results in enhanced targeting to skeleta

117、l muscles and the central nervous system,respectively,as well as de-targeting other organs like the liver and heartSkeletal Muscle Targeting PlatformBlood-Brain Barrier Crossing PlatformThis slide contains investigational drug candidates that have not been approved by any regulatory authority.292024

118、 key upcoming milestonesOphthalmology EU decision for aflibercept 8 mg in wAMD and DME Now Approved Japan decision for aflibercept 8 mg in wAMD and DME(1H)Initiate pivotal RVO study of Eylea HD to enable FDA filing(mid)Obtain permanent J-code for EYLEA HD(2Q)Initiate pivotal studies of pozelimab+cem

119、disiran combination in geographic atrophy(2H)Dupixent/I&I Regulatory decisions for pediatric(1-11 yrs)eosinophilic esophagitis(U.S.Q1,EU 2H)sBLA acceptance for COPD with a Type 2 inflammatory phenotype(Q1);potential FDA approval(mid/2H)Report results from ongoing Phase 3 study in CSU(4Q)Initiate Pha

120、se 1 study in severe food allergy following transient linvoseltamab treatment Complete enrollment of Phase 3 studies of itepekimab in COPD(2H)Obesity Initiate Phase 2 proof-of-concept study of combination of semaglutide and trevogrumab(anti-myostatin)with and without garetosmab(anti-Activin A)(mid)S

121、olid Organ Oncology Report potentially pivotal interim analysis of Libtayo in Adjuvant CSCC(mid)Report potentially pivotal results from Phase 2/3 study of fianlimab+cemiplimab in 1L metastatic melanoma(2H);initial data in 1L advanced NSCLC(2H)Initiate potentially pivotal Phase 2 studies for fianlima

122、b+cemiplimab in perioperative melanoma(1H)and perioperative NSCLC(1H)Initiate dose-expansion cohorts of EGFRxCD28+cemiplimab in EGFR-high tumors(1H)Initiate cohorts combining PSMAxCD28+PSMAxCD3 in mCRPC as well as PSMAxCD28 monotherapy in RCC(1H)Hematology FDA decision on odronextamab in R/R FL and

123、R/R DLBCL(1Q);EU decision(2H)BLA acceptance for linvoseltamab in R/R multiple myeloma(1Q);potential FDA approval(2H);EU submission(1Q)Initiate Phase 1 study of linvoseltamab in combination with CD38xCD28 costimulatory bispecific in multiple myeloma Report Phase 2 proof-of-concept results for Factor

124、XI antibody(2H)Genetic Medicines Initiate Phase 1 study of Factor 9 gene insertion in hemophilia(mid)Report additional proof-of-concept data for DB-OTO Initiate proof-of-concept study of SOD1 siRNA in ALSThis slide contains investigational drug candidates that have not been approved by any regulator

125、y authority.Three responsibility focus areas all reflect our“doing well by doing good”ethos30Improve the lives of people with serious diseasesFoster a culture of integrity and excellenceBuild sustainable communities Product quality and safety Diverse,healthy and engaged workforce Ethics and integrit

126、y STEM education-sponsorship of top science competitions:Regeneron Science Talent Search Regeneron InternationalScience and Engineering Fair Environmental sustainability Pipeline innovation Access to medicine and fair pricing Patient advocacyOur mission:Use the power of science to repeatedly bring n

127、ew medicines to people with serious diseasesCo-Founder,Board Co-Chair,President&Chief Executive OfficerEVP,Head of CommercialCo-Founder,Board Co-Chair,President&Chief Scientific OfficerQ&A3132Regeneron-discovered,approved and investigational medicines across a diverse set of diseasesREGN4336(PSMAxCD

128、3)REGN5093(METxMET)REGN5093-M114(METxMET ADC)REGN5668(MUC16xCD28)REGN5678(PSMAxCD28)REGN6569(GITR)REGN7075(EGFRxCD28)REGN5459(BCMAxCD3)REGN5837(CD22xCD28)REGN7257(IL-2R)REGN7508(Factor XI)REGN7999(TMPRSS6)ALN-APP (APP)ALN-PNP (PNPLA3)DB-OTO(AAV Gene Therapy)REGN7544(NPR1 antagonist)vidutolimod(TLR9)

129、ubamatamab(MUC16xCD3)REGN9933(Factor XI)mibavademab(LEPR)REGN5381/REGN9035(NPR1)HSD siRNA(HSD17B13)sarilumab*(IL-6R)Over 30 product candidatesCollaboration with:*Sanofi;Alnylam;#Intellia;Bayer,*Ultragenyx Kiniksa is solely responsible for development and commercialization of ARCALYST Sanofi is solel

130、y responsible for development and commercialization of ZALTRAPPhase 1Phase 2Phase 3ApprovedAs of December 2023.This slide contains investigational drug candidates that have not been approved by any regulatory authority.aflibercept 8 mg(VEGF)dupilumab*(IL-4R)itepekimab*(IL-33)REGN5713-5714-5715(Bet v

131、 1)cemiplimab(PD-1)fianlimab(LAG-3)pozelimab+cemdisiran(anti-C5+C5 siRNA)odronextamab(CD20 xCD3)linvoseltamab(BCMAxCD3)NTLA-2001#(TTR)alirocumab(PCSK9)garetosmab (Activin A)SOLID ORGAN ONCOLOGYHEMATOLOGYINTERNAL/GENETIC MEDICINESI&IOPHTHALMOLOGY*33Abbreviations and DefinitionsAbbreviationDefinition1

132、LFirst lineAAVAdeno-associated virusALSAmyotrophic lateral sclerosisAPPAmyloid precursor proteinBCCBasal cell carcinomaBCMAB-cell maturation antigenBLABiologics license applicationB-NHLB-cell non-Hodgkins lymphomaBPBullous pemphigoidCAR-TChimeric antigen receptor T-cellCIndU-COLDChronic inducible ur

133、ticaria coldCNSCentral nervous systemCOPDChronic obstructive pulmonary diseaseCPUOChronic pruritis of unknown originCRComplete responseCRSCytokine release syndromeCRSwNPChronic sinusitis with nasal polyposisCSCCCutaneous squamous cell carcinomaCSUChronic spontaneous urticariadB HLDecibel hearing los

134、sDCRDuration of complete responseDLBCLDiffuse large B-cell lymphomaDMEDiabetic macular edemaDRDiabetic retinopathy DXADual-energy X-ray absorptiometryECEuropean CommissionEGFREpidermal growth factor receptorEoEEosinophilic esophagitisEoGEosinophilic gastroenteritis AbbreviationDefinitionFIHFirst in

135、humanFLFollicular lymphomaGAGeographic atrophyGAAAlpha glucosidaseGITRGlucocorticoid-induced TNFR-related proteinGLP-1Glucagon-like peptide 1GLP-1RGlucagon-like peptide 1 receptorgMGGeneralized myasthenia gravisHCCHepatocellular carcinomaHCPHealthcare Provider HNSCCHead and neck squamous cell carcin

136、omaHzHertzICANSImmune effector cell-associatedneurotoxicity syndromeINDInitial new drug applicationIVIntravenous KMKaplan-Meier curveLAG-3Lymphocyte-activation gene 3 LDHLactate dehydrogenase LEPRLeptin receptor MAAMarketing authorization applicationMCCMerkel cell carcinomamCRPCMetastatic castration

137、-resistant prostate cancerMMMultiple myelomaMOAMechanism of actionmPFSMedian progression-free survivalMUC16Mucin 16NASHNon-alcoholic steatohepatitisNBRxNew to Brand PrescriptionsNHPNon-human primateAbbreviationDefinitionNSCLCNon-small cell lung cancerORROverall Response RateOTOFOtoferlinPBOPlaceboPD

138、-1/PD-(L)1Programmed cell death protein/(ligand)1PDUFAPrescription Drug User Fee ActPNHParoxysmal nocturnal hemoglobinuriaPOCProof-of-conceptPSMAProstate-specific membrane antigenR/RRelapsed/Refractory RCCRenal cell carcinomaRGCRegeneron Genetics CenterROWRest of worldRVORetinal vein occlusion sBLAS

139、upplemental biologics license applicationSCSubcutaneous sCRStringent complete responsesiRNASmall interfering RNAT2DMType 2 diabetes mellitusTAATumor-associated antigenTRxTotal prescriptionsTTRTransthyretin proteinUCUlcerative colitisULNUpper limit of normalVEGFVascular endothelial growth factorwAMDWet age-related macular degeneration