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1、CRISPR THERAPEUTICS CONFIDENTIAL1 2025 CRISPR Therapeutics|143rd Annual J.P.Morgan Healthcare ConferenceJanuary 14,2025CRISPR THERAPEUTICS CONFIDENTIAL2 2025 CRISPR Therapeutics|2Forward-Looking StatementsThis presentation and related materials may contain statements regarding matters that are not h

2、istorical facts are“forward-looking statements”within the meaning of the Private Securities Litigation Reform Act of 1995.Because such statements are subject to risks and uncertainties,actual results may differ materially from those expressed or implied by such forward-looking statements.Such statem

3、ents include,but are not limited to,statements regarding any or all of the following:(i)CRISPR Therapeutics preclinical studies,clinical trials and pipeline products and programs,including,without limitation,manufacturing capabilities,status of such studies and trials,potential expansion into new in

4、dications and expectations regarding data,safety and efficacy generally;(ii)CRISPR Therapeutics strategy,goals,anticipated financial performance and the sufficiency of its cash resources;(iii)regulatory submissions and authorizations,including timelines for and expectations regarding additional regu

5、latory agency decisions;(iv)the expected benefits of CRISPR Therapeutics collaborations;and(v)the therapeutic value,development,and commercial potential of CRISPR/Cas9 gene editing technologies and therapies,including as compared to other therapies.Risks that contribute to the uncertain nature of th

6、e forward-looking statements include,without limitation,the risks and uncertainties discussed under the heading“Risk Factors”in CRISPR Therapeutics most recent annual report on Form 10-K and in any other subsequent filings made by CRISPR Therapeutics with the U.S.Securities and Exchange Commission.E

7、xisting and prospective investors are cautioned not to place undue reliance on these forward-looking statements,which speak only as of the date they are made.CRISPR Therapeutics disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this presentation

8、and any related materials,other than to the extent required by law.This presentation and related materials discuss CRISPR/Cas9 gene editing investigational therapies and is not intended to convey conclusions about efficacy or safety as to those investigational therapies or uses of such investigation

9、al therapies.There is no guarantee that any investigational therapy will successfully complete clinical development or gain approval from applicable regulatory authorities.Caution should be exercised when interpreting results from separate trials involving separate product candidates.There are diffe

10、rences in the clinical trial design,patient populations,and the product candidates themselves,and the results from the clinical trials of autologous products may have no interpretative value on our existing or future results.CRISPR THERAPEUTICS standard character mark and design logo,CTX112,CTX131,C

11、TX211,CTX213,CTX310,CTX320,CTX340 and CTX450,are trademarks and registered trademarks of CRISPR Therapeutics AG.CASGEVY and the CASGEVY logo are registered trademarks of Vertex Pharmaceuticals Incorporated,and Vertex Pharmaceuticals Incorporated is the manufacturer and exclusive license holder of CA

12、SGEVY.All other trademarks and registered trademarks are the property of their respective owners.Solely for convenience,trademarks,service marks and trade names referred to in this presentation or any related material may appear without the or symbols and any such omission is not intended to indicat

13、e waiver of any such rights.CRISPR THERAPEUTICS CONFIDENTIAL3 2025 CRISPR Therapeutics|3CRISPR Therapeutics TodayCASGEVY for severe sickle cell disease and beta thalassemia enabled by Nobel-Prize winning CRISPR/Cas9 technologyExpanded portfolio into both common and rare diseases with de-risked under

14、lying biologyEstablish a sustainable industry-leading genomic medicines companyapproved therapy1clinical programs5preclinical programs10Our vision is to develop cures for people suffering from serious diseases through transformative gene-based medicinesCRISPR THERAPEUTICS CONFIDENTIAL4 2025 CRISPR T

15、herapeutics|4Executing on Our Vision Across Four Therapeutic FranchisesHemePartnered with Vertex on global launch of CASGEVY,best-in-class,commercial ex vivo CRISPR/Cas9 therapy for sickle cell disease and beta thalassemiaContinued focus on innovation to expand potential market for CASGEVYIn vivo ap

16、proaches leveraging LNP delivery CAR TBest-in-class allogeneic cell therapies with novel potency editsCTX112 shows promising efficacy/safety profile in oncologyExpanding CTX112 into autoimmune disease to significantly increase valueCTX131 and autologous anti-GPC3 in solid tumors to further diversify

17、 platformT1DUtilizing gene editing to develop an allogeneic beta-cell replacement therapy Goal to achieve insulin independence without need for constant immunosuppressive regimensDeveloping both device(CTX211)and deviceless(CTX213)approachesIn VivoEstablishing LNP-mRNA platform,initially beginning w

18、ith liverTwo Phase I programs(CTX310 and CTX320)in cardiovascular disease to de-risk platformCTX320 targeting elevated Lp(a)has potential to benefit 60M patients in the U.S.Building extrahepatic and next-generation editing capabilitiesCRISPR THERAPEUTICS CONFIDENTIAL5 2025 CRISPR Therapeutics|5Progr

19、amDiseaseResearchIND-enablingClinicalApprovedPartnerStructureHemeCASGEVY1Severe sickle cell disease(SCD)CollaborationTransfusion-dependent-thalassemia(TDT)CD117 ADC/In vivo HSC editingSCD,TDT and othersWholly owned2CAR T I/O&AutoimmuneCTX112Anti-CD19 allogeneic CAR TB-cell malignanciesWholly ownedSL

20、E,SSc,and IIMCTX131 Anti-CD70 allogeneic CAR TRenal cell carcinoma and other solid tumorsWholly ownedHematological cancersAnti-GPC3 autologous CAR THepatocellular carcinomaWholly ownedIn VivoCardiovascular&Rare DiseaseCTX310:ANGPTL3HeFH,HoFH,Mixed dyslipidemias,and sHTGWholly ownedCTX320:LPAASCVD wi

21、th elevated Lp(a)Wholly ownedCTX340:AGTRefractory hypertensionWholly ownedCTX450:ALAS1Acute hepatic porphyria(AHP)Wholly ownedT1DCTX211Type I diabetes mellitusWholly ownedCTX213Type I diabetes mellitusWholly ownedOther disclosed partneredDuchennes muscular dystrophy(DMD)License/CollaborationMyotonic

22、 dystrophy type I,Type 1 diabetes mellitus(T1D),Cystic fibrosis(CF)HeFH:Heterozygous familial hypercholesterolemia;HoFH:Homozygous familial hypercholesterolemia;sHTG Severe hypertriglyceridemia SLE:Systemic Lupus Erythematosus;SSC:Systemic Sclerosis;IIM:Idiopathic Inflammatory Myopathies 1Currently

23、approved in some countries for certain eligible patients with SCD or TDT;2Collaboration with Vertex for applications in TDT and SCDBroad and Diversified PipelineCRISPR THERAPEUTICS CONFIDENTIAL6 2025 CRISPR Therapeutics|6Established efficient operating model and strong balance sheet of$1.9 billion1

24、Inflection YearStrong launch trajectory for CASGEVY globally with favorablemarket access in SCD and TDTClinical updates acrosscore franchises including cardiovascular,immuno-oncology/autoimmune and regenerative medicineOpportunistic business development across the portfolio2025Foundational YearsRele

25、ntless focus to bring CASGEVY to global approval and launchDiversified into other therapeutic areas with multiple clinical candidatesOperationalized in-house manufacturing capabilities 2020-2024Sector-Leading BiotechCASGEVY revenue provides a path to a sustainable biotech company Clinical programs p

26、rogress into later stages of development and potential approvalPlatform engine generating 1 to 2 new IND/CTAs per year Continued business development activities based on strategic priorities2026+Entering a Critical Phase of Our Growth Journey1 Pro forma as of 12/31/2024CRISPR THERAPEUTICS CONFIDENTI

27、AL7 2025 CRISPR Therapeutics|7Q1Q2Q3Q4HemeCAR TIn vivoT1DQ4 2024 CASGEVY#sQ1 2025 CASGEVY#sQ2 2025 CASGEVY#sQ3 2025 CASGEVY#sCTX112|Broad update in oncology&AID1CTX131|UpdateCTX310&CTX320|UpdateRegenerative medicine|Update1AID:Autoimmune DiseasesAnticipated Key Milestones in 2025CRISPR THERAPEUTICS

28、CONFIDENTIAL8HemoglobinopathiesHemoglobinopathiesCRISPR THERAPEUTICS CONFIDENTIAL9 2025 CRISPR Therapeutics|9Unparalleled speed and execution to a landmark approval1As of the end of 2024,CASGEVY was approved in 8 jurisdictions,50 authorized treatment centers(ATCs)have been activated globally and 50

29、patients have initiated cell collectionAddressable Market260,000Severe patients in approved territories amenable for treatment2024 Was a Foundational Year for CASGEVY1 Approved by the U.S.FDA for treatment of patients aged 12 years and older with sickle cell disease(SCD)with recurrent vaso occlusive

30、 crises(VOCs)and transfusion-dependent-thalassemia(TDT)Granted conditional marketing authorization by the UK MHRA and Bahrain NHRA for patients 12 years of age and older with SCD with recurrent VOCs or TDT for whom hematopoietic stem cell transplantation is appropriate and a human leukocyte antigen

31、matched related hematopoietic stem cell donor is not available.CASGEVY has also been approved in other countries for certain eligible patients with SCD or TDT2 Including U.S.,U.K.,E.U.,Kingdom of Saudi Arabia(KSA),Bahrain,Canada,Switzerland,and United Arab Emirates(UAE)CRISPR THERAPEUTICS CONFIDENTI

32、AL10 2025 CRISPR Therapeutics|10Investments made to meet global demand for disease-modifying therapyContinued Progress in U.S.to Serve Significant Unmet NeedNew CMMI model to improve access and health outcomes,as well as reduce expenditures($3B annual U.S.SCD cost)Growing into Untapped Middle East a

33、nd ex-U.S.MarketsFirst GCC patient reimbursed at$2M;NHS reimbursement achieved for beta-thal.Manufacturing Expansion to Support Launch1 Manufacturing agreement for global commercial supply with Lonza2025 is Focused On Execution and Expansion of OpportunityCMMI:Center for Medicare and Medicaid Innova

34、tion;GCC:Gulf Cooperation Council1 Vertex leads development,regulatory filings,manufacturing and commercializationCRISPR THERAPEUTICS CONFIDENTIAL11 2025 CRISPR Therapeutics|11Targeted ConditioningIn Vivo Editing of HSCsStudies in non-human primates(NHP)ongoingssTOXINTOXINValidated GMP toxin with HS

35、C activity and reduced hydrophobicity to limit non-target cell toxicityProprietary GMP monoclonal antibody with short half-life to enable rapid infusion of edited cellscKit(CD117)antibody-drug conjugate(ADC)for specific depletion of hematopoietic stem cells(HSCs)and no off-target/bystander toxicityD

36、ELIVERYEDITINGCreating optimized system for in vivo HSC editing with ideal characteristics,including:Core research focus in 2025 NHP studies ongoing Tolerable doses with no off-target toxicities Editing of LT-HSCs for durable effect vs.HSPCs only Potential for redosability for enhanced editing150k+a

37、ddressable patients worldwide400k+addressable patients worldwideSerial Innovation in Enabling Technologies Will Broaden Access CRISPR THERAPEUTICS CONFIDENTIAL12 2025 CRISPR Therapeutics|12CAR TCAR TCRISPR THERAPEUTICS CONFIDENTIAL13 2025 CRISPR Therapeutics|13Best-in-Class Cell Therapy Platform for

38、 the Treatment of Cancer and Autoimmune DiseaseCTX112Currently in Phase I/II trial in r/r NHL,plus Phase I trial in SLE/SSc/IIMUpdate mid-2025CTX131Currently in Phase I/II trial in RCC,plus Phase I/II trial in TCL Update in 2025Autologous GPC3Ongoing preclinical work with anti-GPC3 autologous CAR T

39、with TGFBR2 KOIND/CTA submission in 1H 2025ProgramIndication(s)ResearchIND-enablingClinicalPartnerCTX112Anti-CD19 allogeneic CAR TB cell malignanciesSLE/SSc/IIMCTX131Anti-CD70 allogeneic CAR TRenal cell carcinoma andother solid tumorsHematological cancersAnti-GPC3Autologous CAR THepatocellular carci

40、nomaSLE:Systemic Lupus Erythematosus;SSC:Systemic Sclerosis;IIM:Idiopathic Inflammatory Myopathies;TCL:T Cell lymphoma;GPC3:Glypican-3;TGFBR2:Transforming Growth Factor Beta Receptor Type 2CRISPR THERAPEUTICS CONFIDENTIAL14 2025 CRISPR Therapeutics|14Multiple scientific,manufacturing and regulatory

41、competitive advantages for CTX112Other CTX112 Competitive AdvantagesAbility to multiplex gene edits precisely and efficientlyComprehensive and FDA-validated genomic analysisScalability and low COGS to enable global expansionIn-house manufacturing enables direct control over process and timelinesMult

42、iple scientific,manufacturing and regulatory competitive advantages for CTX112CTX112 Novel Potency Edits(TGFBR2,Regnase-1)Regnase-1 and TGFBR2 edits synergistically increase CAR T potencyAnti-CD19 CARTCRdisruptionMHC IdisruptionTGFBR2disruptionTGFBR2Regnase-12MTRACCTX112 is an Allogeneic CAR T Optim

43、ized for PotencyCRISPR THERAPEUTICS CONFIDENTIAL15 2025 CRISPR Therapeutics|15D28 assessment and follow-upOpen-label,multicenter,Phase I/II study evaluating the safety and efficacy of CTX112 in relapsed or refractory B-cell malignanciesPrimary endpoint Incidence of AEs,defined as DLTs ORR(per Lugano

44、 2014 criteria or iwCLL 2018 guidelines for CLL/SLL)Secondary endpoints CR rate Duration of response(DOR)Key eligibility criteria:Age 18 years Patient population:R/R FL grade 1-3a,MZL,MCL,DLBCL NOS,DLBCL/high-grade lymphoma with MYC and BCL-2 rearrangement,grade 3b FL,DLBCL arising from FL or MZL or

45、 LBCL with prior CAR T No prior allogeneic SCT and no history of CNS lymphoma involvement Adequate organ functionFludarabine 30 mg/m2+Cyclophosphamide 500 mg/m2 for 3 daysCTX112 infusionScreeningStandard LymphodepletionDose Level(DL),CAR+T cells;DL1=30M;DL2=100M;DL3=300M cells;DL4=600M cells(NCT0564

46、3742);AE,adverse event;BCL-2,B-cell lymphoma 2;CNS,central nervous system;DLT,dose-limiting toxicity;iwCLL,International Workshop on CLL;ORR,overall response rate;R/R,relapsed or refractory;SCT,stem cell therapy.Trial Design:Patients could receive an additional infusion of CTX112 with LD chemotherap

47、y if they achieved a partial response Progression-free survival(PFS)Overall survivalBenefits of Allogeneic CAR T:No bridging chemotherapy On-site availability of CAR T cell product Short screening timeframe No apheresisCTX112 Phase I Clinical Trial DesignCRISPR THERAPEUTICS CONFIDENTIAL16 2025 CRISP

48、R Therapeutics|16Patient-Level DataCell dose(CAR+T cells)DL130MN=3DL2100MN=3DL3300MN=3DL4600MN=3TotalN=12ORR n(%)2(67)2(67)2(67)2(67)8(67)CR n(%)1(33)2(67)1(33)2(67)6(50)PR n(%)1(33)01(33)02(17)CTX112 Initial Efficacy Data(N=12)High risk patient population(58%primary refractory;67%3 prior therapies;

49、50%with tumor SPD 4000 mm2)CTX112 demonstrated tolerability with no CRS,ICANS or infections Grade 3ORR/CR rate in line with approved autologous CAR T1 Ongoing responses in patients with poor prognostic factorsAggregated Data per Dose LevelData published at 2024 American Society of Hematology Annual

50、Meeting1 For example,Yescarta ORR/CRR 70-90%/50-60%across indications.Response rates based on modified intent to treat analyses of infused patients in the Zuma-1 and Zuma-5 trials We should take patient numbers out here add 12 pts swimlane from ASH and add asterisks on patients that didnt get additi

51、onal therapy through follow-uo Footnote what line is that data for?Initial Efficacy Data on Par with Auto CAR T CRISPR THERAPEUTICS CONFIDENTIAL17 2025 CRISPR Therapeutics|17Cell expansion comparable to autologous CAR T2CAR T Cell Expansion ComparisonCTX112 Cell Expansion DataDose dependent increase

52、s in AUC and Cmax Analysis from subsequent data cut on Dec 20,2024(N=25)CTX112(DL3/4)Autologous CAR TOtherAllogeneic CAR TMean Cmax(copies/g)45,000-70,0001Apx.6,000-30,0002Apx.500-5,00031 Mean+/-the SEM;2 Per Kymriah and Breyanzi USPI;3 Lekakis et al.ASH 2021,Hu et al.ASCO 2024071421281101001,00010,

53、000100,000Timepoint(Day)CAR(Copies/g)LLOQLODDL3/4DL1/2New CTX112 Data Shows PK in Line with Auto CAR TCRISPR THERAPEUTICS CONFIDENTIAL18 2025 CRISPR Therapeutics|18TCE:T cell engager;FL:follicular lymphoma;LBCL:Large B-cell lymphoma Histology#Prior LinesPrior Bispecific T Cell Engager(TCE)TCE Best O

54、verall ResponseCTX112Best Overall ResponseDose level 3FL75L:MosunetuzumabPRPRLBCL22L:R-ICE&EpcoritamabPDPRLBCL105L:MosunetuzumabUNKPR6L:Tafasitamab&Rituximab&LenalidomidePDDose Level 4LBCL44L:Epcoritamab&GemOxCRCRFL87L:Imvotamab(IGM-2323)PDCRFL53L:Glofitamab&RG6333(CD19/CD28)PRCR100%overall response

55、 rate(ORR)for 6 patients receiving CTX112 post-TCE therapy 100%ORR for 3 LBCL patients at higher dose levelsNew CTX112 Data Demonstrates Efficacy in Post-TCE SubsetAnalysis from subsequent data cut on Dec 20,2024CRISPR THERAPEUTICS CONFIDENTIAL19 2025 CRISPR Therapeutics|19CTX112 vs.Autologous CAR T

56、 Safety benefits are critical in context of larger patient populations and in community hospital settings Improved patient experience with no apheresis;enables fast enrollment to dosing without the need to pause immunosuppressants Significantly lower COGS and scalability are critical for expanding a

57、ddressable populationCTX112 vs.TCE Initial clinical results with CAR Ts show deep B-cell depletion in tissues,likely critical for immune reset Long term data in oncology supports more durable clinical responses with CAR T therapy vs.TCEs Initial CTX112 data shows promising efficacy in post-TCE patie

58、nts(i.e.,100%OR rate)CTX112 vs.Other Allogeneic CAR T/NK Case studies from other allogeneic CAR T therapies in AID provides derisking for CTX112 CTX112 is potentially superior with potency edits that lead to significantly higher CAR T cell expansion and functional persistenceBroad CTX112 update acro

59、ss oncology and autoimmune disease expected in mid-2025CTX112 Is Positively Differentiated from Other CD19 TherapiesCRISPR THERAPEUTICS CONFIDENTIAL20 2025 CRISPR Therapeutics|20CTX131 next-generation CAR T chassis:Most sophisticated allogeneic CAR T candidate in the clinicRegnase-1 and TGFBR2 edits

60、 synergistically increase CAR T potencyAnti-CD70 CARTCRdisruptionMHC IdisruptionCD70disruptionTGFBR2disruptionTGFBR2Regnase-1CD70ProgramIndicationsAnti-GPC3 autologous CAR T with TGFBR2 KOCTX131 Anti-CD70 allogeneic CAR TPhase I trial in RCC and other solid tumors ongoing;Phase I trial in hematologi

61、c malignancies,including T cell lymphomas(TCL)dose escalation ongoingUpdate in 2025IND/CTA submission for Phase I trial in HCC in 1H 2025TGFB edit prevents exhaustion;with validating data from clinical trials in ChinaRoswell Park conducts manufacturing and clinical trial;CRISPR has commercial rights

62、Solid Tumor CAR T pipeline2MTRACNext-Generation CAR T for Solid TumorsRCC:renal cell carcinoma;HCC:Hepatocellular carcinoma carcinomaCRISPR THERAPEUTICS CONFIDENTIAL21In VivoIn VivoCRISPR THERAPEUTICS CONFIDENTIAL22 2025 CRISPR Therapeutics|221Heterozygous familial hypercholesterolemia;2Homozygous f

63、amilial hypercholesterolemia;3Severe hypertriglyceridemiaCTX320CTX340 /CTX450CTX310 Additional preclinical programs targeting AGT and ALAS1 respectivelyProgressing to IND/CTA ANGPTL3 targeted asset with potential across multiple indicationsUpdate in 1H 2025Potential to address large patient populati

64、ons with elevated Lp(a)Update in 1H 2025ProgramIndication(s)ResearchIND-enablingClinicalCTX310:ANGPTL3HeFH1,HoFH2,Mixed dyslipidemias,and SHTG3CTX320:Lp(a)ASCVD with elevated Lp(a)CTX340:AGTRefractory hypertensionCTX450:ALAS1Acute hepatic porphyriaPlug-and-Play LNP/mRNA Platform for Gene DisruptionC

65、RISPR THERAPEUTICS CONFIDENTIAL23 2025 CRISPR Therapeutics|231Cegla et al.2019;2:2Gurdasani et al.2012;3Laschkolnig et al.2014;4Nordestgaard et al.2010 Comparison of atherogenicity of Lp(a)and LDLLp(a)is 6x more atherogenic than LDL on a per-particle basis4,highlighting its significance as a critica

66、l target for drug-based interventionsLp(a):lipoprotein(a);1 Enas et al.2019;2 Gurdasani et al.2012;3 Laschkolnig et al.2014;4 Bjrnson et al.2024 Lp(a):An independent risk factor of atherosclerotic cardiovascular disease(ASCVD)Lp(a)is an LDL-like lipoprotein synthesized and secreted by hepatocytesEpi

67、demiologic,Mendelian randomization,and genome-wide association studies have shown that elevated Lp(a)levels increase ASCVD risk1,2,3The genetic risk of elevated Lp(a)is cumulative throughout a persons lifetime and cannot be sufficiently reduced by lifestyle changes or currently approved therapiesLp(

68、a)is Emerging as a Key Target to Potentially Reduce CV EventsLp(a)contains a single apo(a)molecule covalently bound by a disulfide bridge to ApoBApo(a)is encoded by the LPA gene and determines plasma Lp(a)levelsCRISPR THERAPEUTICS CONFIDENTIAL24 2025 CRISPR Therapeutics|24Single dose of CTX320(2 mg/

69、kg)administered to NHPs(N=4)on Day 1;Editing data presented at the American Heart Association Scientific Sessions.11 Nov 2023;Editing rate reflects whole liver editing1 LPA gene encodes apolipoprotein(a),a key component of lipoprotein(a)95%reduction in plasma Lp(a)sustained at 2 years70%editing of L

70、PA1 at 1 year081624324048566472808896104-100-80-60-40-200Study WeekChange from Baseline(%)1020406080Liver Editing(%)2 mg/kgUpdated NHP data shows continued durability of CTX320 out to 2 yearsSingle CTX320 Dose Resulted in Durable Lp(a)Reduction(NHP)CRISPR THERAPEUTICS CONFIDENTIAL25 2025 CRISPR Ther

71、apeutics|25Phase I:Single ascending dose escalation to identify optimal biological dose Phase II Patients with elevated levels of Lp(a)Phase II dose informed by Phase IDose level 4Dose level 3Dose level 2Dose level 1Day 30Acute toxicity monitoringDay 112-month total follow-upCTX320 infusionScreening

72、Long-term follow-upKey eligibility criteriaAge 18-65 yearsElevated levels of Lp(a)and CVDAdequate renal,liver,cardiac,and pulmonary organ functionNo significant co-morbiditiesEndpointsIncidence of adverse events,defined as DLTsChange in Lp(a)compared to baselinePharmacokineticsCTX320 update in 1H 20

73、25Phase I Study Evaluating the Safety and Efficacy of CTX320CRISPR THERAPEUTICS CONFIDENTIAL26 2025 CRISPR Therapeutics|2610Elevated Lp(a)is considered the most common genetically inherited risk factor for cardiovascular disease(CVD)1A one-time durable reduction in Lp(a)has the potential to transfor

74、m the current treatment paradigm in cardiovascular disease(compliance with small molecules and mAbs remains key issue)siRNA cardiovascular outcomes trials in 2025/2026 has potential to significantly de-risk Lp(a)CTX320 has potential to benefit 60M U.S.patients with elevated Lp(a)Approximately one-fi

75、fth of the global population have elevated Lp(a)levels 3x greater lifetime risk for most elevated Lp(a)populationDistribution of Lp(a)levels in general population2Population Lp(a)level based on male distribution;similar distribution seen across women1Madsen et al.2020;2Nordestgaard et al.2010;3Krone

76、nberg et al.2022350 nmol/L230 nmol/L175 nmol/L115 nmol/L70 nmol/L16 nmol/LLifetime risk of major cardiovascular events with increasing Lp(a)levels3(Population median)mg/dL050100150200nmol/L0115230350460Age(years)4050607080010203040Fraction of populationCTX320 Has Potential to Address Population with

77、 Elevated Lp(a)CRISPR THERAPEUTICS CONFIDENTIAL27 2025 CRISPR Therapeutics|27Presented at the American Heart Association Scientific Sessions.11 Nov 2023A single dose of CTX310 durably reduced ANGPTL3 and triglycerides in NHPs out to 1 year70%editing of ANGPTL3Sustained reduction in plasma ANGPTL3 in

78、 NHPsSustained reduction in TG2 mg/kg020406080Liver Editing(%)0481216202428323640444852-100-80-60-40-200Study WeekChange from Baseline(%)3 months12 months-100-80-60-40-200Change from Baseline(%)Single dose of CTX310(2 mg/kg)administered to non-human primates(NHPs)(N=8)on Day 1;study ongoing;Editing

79、rate reflects whole liver editing;HoFH;Homozygous familial hypercholesterolemia;sHTG;Severe hypertriglyceridemia1 Minicocci et al.2012;2 DErasmo et al.2023Natural loss-of-function mutations in ANGPTL3 are associated with reduced LDL-C,triglycerides(TG),and ASCVD risk without any negative impact on o

80、verall health1,2Phase I trial in HoFH,sHTG and Mixed dyslipidemias;10M addressable U.S.patients CTX310 update in1H2025 CTX310 Targeting ANGPTL3 for Cardiovascular DiseaseCRISPR THERAPEUTICS CONFIDENTIAL28 2025 CRISPR Therapeutics|28CTX450 Targeting ALAS1 for AHPsCTX340 Targeting AGT For Refractory H

81、ypertensionDose-dependent reduction in MAP PBS 0.5 mpk1 mpk2 mpk80100120140160180mmHgNormal02040608010071Liver Editing(%)Dose-dependent,durable reduction in blood pressure in SHR model70%editing of ALAS1 Leading to reduction of ALA and PBG biomarkers in PB challenge modelEditing rates reflect whole

82、liver editing;MAP:mean arterial pressure;SHR:spontaneous hypertensive rat;ALA:Aminolevulinic acid;PBG:porphobilinogen;PB:phenobarbital(PB)1 Zhou et al.2021;2 Danaei et al.2009;3 Anderson et al.2001;4 Chan et al.2015N=8 per group;mean SEMHypertension is the leading cause of cardiovascular morbidity a

83、nd mortality worldwide1,2By going upstream of typical therapeutic approaches by targeting AGT,we can significantly impact hypertension and reduce dependence on other antihypertensivesALAS1 editingALAS1 editingAcute hepatic porphyrias(AHP)are caused by deficiencies of specific enzymes in the heme bio

84、synthesis pathway leading to the build-up of toxic metabolites3,4By targeting the upstream enzyme ALAS1 we can significantly reduce the production of these metabolites(e.g.,ALA,PBG)N=5 per group;mean SEM0.5mpkTwo Additional Programs Advancing Toward ClinicControlPBCTX450+PB0100200300200040006000ng/m

85、LALAPBGCRISPR THERAPEUTICS CONFIDENTIAL29 2025 CRISPR Therapeutics|29Gene-editing is key to achieving the goal of developing a beta-cell replacement product to treat diabetes without requiring long-term immunosuppressionCTX211First-in-class edited beta-cell replacement therapy Encapsulated pancreati

86、c progenitor cells derived from pluripotent stem cells with gene-edits for immune evasion and cell survival Phase I clinical trial1CTX213Deviceless,iPS-derived,edited beta-cell replacement therapyPancreatic progenitor cells derived from edited pluripotent stem cells directly infused vs.delivered via

87、 deviceAdvancing into IND-enabling phase2Non-exclusive license with VertexCovers Vertexs gene-edited hypoimmune programs for T1DUp to$160M in additional research and development milestones,plus royalties on future products3$170M in upfront and milestone payments to CRISPR in 2023T1D update in 2025Th

88、ree Parallel Efforts in Type 1 Diabetes(T1D)CRISPR THERAPEUTICS CONFIDENTIAL30 2025 CRISPR Therapeutics|302025 Could be a Year of Significant Value CreationOngoing launch of CASGEVY;investments driven by strong patient demandCatalyst-rich year with several data readouts expected across our pipeline

89、candidates:-Quarterly updates for CASGEVY launch progress-CTX310 and CTX320 update in cardiovascular indications in the first half of 2025-CTX112 update in oncology and autoimmune disease in mid-2025-Additional updates across our pipeline including CTX131 and T1D in 2025Strong balance sheet with clear path to a sustainable biotechnology company Potential for additional business development across our portfolio