Alnylam Presentation at JPMorgan 2023.pdf

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1、1 2023 Alnylam Pharmaceuticals,Inc.January 9,2023Yvonne Greenstreet,MBChB,MBAChief Executive Officer41stAnnual J.P.Morgan Healthcare ConferenceNathan(USA)Diagnosed with AHP2Alnylam Forward Looking StatementsThis presentation contains forward-looking statements within the meaning of Section 27A of th

2、e Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934.Allstatements other than historical statements of fact regarding Alnylams expectations,beliefs,goals,plans or prospects including,without limitation,expectations regarding Alnylamsaspiration to become a leading biotech c

3、ompany and the planned achievement of its“Alnylam P5x25”strategy,the potential for Alnylam to identify new potential drug developmentcandidates and advance its research and development programs,Alnylams ability to obtain approval for new commercial products or additional indications for its existing

4、 products,and Alnylams projected commercial and financial performance should be considered forward-looking statements.Actual results and future plans may differ materially from thoseindicated by these forward-looking statements as a result of various important risks,uncertainties and other factors,i

5、ncluding,without limitation:the direct or indirect impact of theCOVID-19 global pandemic or any future pandemic on our business,results of operations and financial condition and the effectiveness or timeliness of our efforts to mitigate the impactof the pandemic;the potential impact of the January 2

6、022 leadership transition on our ability to attract and retain talent and to successfully execute on our“Alnylam P5x25”strategy;the finalization and audit of our fourth quarter and 2022 fiscal year financial results,which could potentially result in changes or adjustments to the selected preliminary

7、 financial resultspresented herein;our ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of our product candidates;the pre-clinical and clinical results for our product candidates;actions or advice of regulatory agencie

8、s and our ability to obtain and maintain regulatory approval for our productcandidates,as well as favorable pricing and reimbursement;successfully launching,marketing and selling our approved products globally;delays,interruptions or failures in themanufacture and supply of our product candidates or

9、 our marketed products;obtaining,maintaining and protecting intellectual property;our ability to successfully expand the indicationfor ONPATTRO or AMVUTTRA in the future;our ability to manage our growth and operating expenses through disciplined investment in operations and our ability to achieve a

10、self-sustainable financial profile in the future without the need for future equity financing;our ability to maintain strategic business collaborations;our dependence on third parties for thedevelopment and commercialization of certain products,including Novartis,Sanofi,Regeneron and Vir;the outcome

11、 of litigation;the potential impact of a current governmentinvestigation and risk of future government investigations;and unexpected expenditures;as well as those risks more fully discussed in the“Risk Factors”filed with our most recentQuarterly Report on Form 10-Q filed with the SEC and in our othe

12、r SEC filings.In addition,any forward-looking statements represent our views only as of the date of this presentationand should not be relied upon as representing our views as of any subsequent date.We explicitly disclaim any obligation,except to the extent required by law,to update suchstatements.T

13、his presentation references non-GAAP financial measures.These measures are not in accordance with,or an alternative to,GAAP,and may be different from non-GAAP financialmeasures used by other companies.Percentage changes in revenue growth at Constant Exchange Rates,or CER,are non-GAAP financial measu

14、res which are presented excludingthe impact of changes in foreign currency exchange rates for investors to understand the underlying business performance.CER represents growth calculated as if the exchange rateshad remained unchanged from those used during 2021.3Alnylam Poised to Become a Top-Tier B

15、iotechPioneer in RNAi Therapeutics 5 medicines approved in 2,0502,2002,4002,5802,975Q4 2021Q1 2022Q2 2022Q3 2022Q4 2022Patients on Therapy60.1 62.3 71.1 67.2 19125.1 78.5 74.7 82.3 77.8Q4 2021Q1 2022Q2 2022Q3 2022Q4 2022Revenues($M)TTR Franchise$651M2022 revenues2,975 patientsas of December 31,2022U

16、.S.ONPATTRO ROW ONPATTROU.S.AMVUTTRAROW AMVUTTRA490560620690800Q4 2021Q1 2022Q2 2022Q3 2022Q4 2022Patients on Therapy30.2 23.7 29.7 31.2 7110.4 11.6 15.5 14.5 5.7 5.4 7.1 6.413.5 9.2 7.8 10.0 Q4 2021Q1 2022Q2 2022Q3 2022Q4 2022Revenues($M)U.S.GIVLAARIROW GIVLAARIU.S.OXLUMOROW OXLUMOUltra-Rare Diseas

17、e PortfolioGLOBALGLOBAL$243M2022 revenues800 patientsas of December 31,20226Alnylam Clinical Development Pipeline1Includes marketing application submissions;2Novartis has obtained global rights to develop,manufacture and commercialize inclisiran;50%of inclisiran royalty revenue from Novartis will be

18、 payable to Blackstone by Alnylam;3Alnylam and Regeneron are evaluating potential combinations of the investigational therapeutics cemdisiran and pozelimab;4Dicerna is leading and funding development of belcesiran;5Vir is leading and funding development of ALN-HBV02;6Regeneron is leading and funding

19、 development of ALN-HSD;*Not approved for any indication and conclusions regarding the safety or efficacy of the drug have not been established;*U.S.sNDA has been filed.As of January 2023EARLY/MID-STAGE(IND/CTA Filed-Phase 2)LATE STAGE(Phase 2-Phase 3)REGISTRATION/COMMERCIAL1COMMERCIAL RIGHTShATTR A

20、myloidosis with PNGlobalhATTR Amyloidosis with PNGlobalAcute Hepatic PorphyriaGlobalPrimary Hyperoxaluria Type 1GlobalHypercholesterolemiaMilestones&up to 20%Royalties2Patisiran*ATTR Amyloidosis with CMGlobalVutrisiranATTR Amyloidosis with CMGlobalFitusiran*Hemophilia15-30%RoyaltiesCemdisiran(+/-Poz

21、elimab)3*Complement-Mediated DiseasesGlobal;Milestone/RoyaltyALN-TTRsc04*ATTR AmyloidosisGlobalBelcesiran4*Alpha-1 Liver DiseaseEx-U.S.option post-Phase 3ALN-HBV02(VIR-2218)5*Hepatitis B Virus Infection50-50 option post-Phase 2Zilebesiran*HypertensionGlobalALN-HSD6*NASHRoyaltyALN-APP*Alzheimers Dise

22、ase;Cerebral Amyloid Angiopathy50-50ALN-PNP*NASH50-50ALN-KHK*Type 2 DiabetesGlobalFocused in 4 Strategic Therapeutic Areas(STArs):Genetic MedicinesCardio-Metabolic DiseasesInfectious DiseasesCNS/Ocular Diseases7High-Yield Productivity of Alnylam RNAi Therapeutics Platform Comparison of Historical Me

23、trics to Alnylam Portfolio over Past Decade11Analysis of Alnylam programs from January 2012 through December 2022;Past rates of Alnylam and industry respectively may not be predictive of the future 2Alnylam programs biomarker-driven at all stages of development(100%);figures include Alnylam-originat

24、ed molecules now being developed by partners3Wong et al.,Biostatistics(2019)20,2,pp.273286Probability of Success(POS)by Phase Transition86.781.887.562.044.538.663.710.335.227.469.25.70102030405060708090100%POS,Phase 1 to 2%POS,Phase 2 to 3%POS,Phase 3%POS,CumulativePercent POSAlnylam2Industry(biomar

25、ker-driven programs)3Industry(overall)38Patients:Over 0.5 million on Alnylam RNAi therapeutics globallyProducts:6+marketed products in rare and prevalent diseasesPipeline:Over 20 clinical programs,with 10+in late stages and 4+INDs per yearPerformance:40%revenue CAGR through YE 2025Profitability:Achi

26、eve sustainable non-GAAP profitability within periodAmbitious Five-Year Strategy to Drive Growth9Multiple Drivers of Future GrowthTTR Franchise LeadershipExpansion Beyond Rare DiseasesEngine for Sustainable Innovation10Multiple Drivers of Future GrowthTTR Franchise LeadershipExpansion Beyond Rare Di

27、seasesEngine for Sustainable InnovationLiana(Brazil)Diagnosed with hATTR amyloidosis11ATTR AmyloidosisRare,Progressively Debilitating,and Fatal Disease1Coelho T,et al.N Engl J Med.2013;369(9):819-8292Ando,et al.Orphanet J Rare Dis,2013;Ruberg,et al.Circulation,2012(includes hATTR amyloidosis patient

28、s with polyneuropathy and cardiomyopathy);Gertz,et al.Am J Manag Care.2017;23:S107-S1123Information based on Alnylam modeling dataDescriptionCaused by a misfolded TTR protein that accumulates as amyloid deposits in multiple tissues including heart,nerves,and GI tract1GU:ProteinuriaKidney failureUTII

29、ncontinenceImpotenceCARDIAC:Heart failureArrhythmiaGI:DiarrheaNauseaVomitingPERIPHERAL:Numbness/tinglingPainWeaknessImpaired walkingAUTONOMIC:FallsLightheadednessWeight lossHereditary ATTR(hATTR)Amyloidosis50,000patients worldwide2Wild-Type ATTR(wtATTR)Amyloidosis200,000 300,000patients worldwide312

30、hATTR Amyloidosis with PN&Mixed*ATTR Amyloidosis with CM(incl.WT)PatisiranOcular&CNS hATTR AmyloidosisNovel siRNA ConjugatesATTR Amyloidosis with CM(incl.WT)VutrisiranATTR AmyloidosisALN-TTRsc04Stargardt DiseaseTBD1Phase 3hATTR Amyloidosis with PN&MixedhATTR Amyloidosis with PN&MixedATTR Amyloidosis

31、 with CM(incl.WT)hATTR Amyloidosis with PN&MixedVutrisiranBiannual Dosing Regimen hATTR Amyloidosis with PN&Mixed*Building a Leading TTR FranchisePotential to Expand Benefit to Patients Globally for Many Years to Come*ONPATTRO is approved in the U.S.and Canada for the treatment of the PN of hATTR am

32、yloidosis in adults,and in the EU,Japan and other countries for the treatment of hATTR amyloidosis in adults with stage 1 or 2 PN;ONPATTRO and AMVUTTRA have not been approved by the FDA,EMA,or any other regulatory agency for cardiac manifestations of amyloidosis.No conclusions can or should be drawn

33、 regarding its safety or effectiveness in this populationAMVUTTRA is approved in the U.S.for the treatment of the PN of hATTR amyloidosis in adults and in the EU and Japan for the treatment of hereditary transthyretin-mediated amyloidosis(hATTR amyloidosis)in adult patients with stage 1 or stage 2 p

34、olyneuropathy;Novel siRNA conjugate development candidates for ocular or CNS hATTR amyloidosis not yet selected;1The Company is considering options for the best path forward to bring an RNAi therapeutic to patients with Stargardt Disease.2024&Beyond2018 2022hATTR Amyloidosis with PN&Mixed*2022 2024P

35、atisiran13Patisiran sNDA Submitted with Positive Study ResultsIf Approved,Broadens Commercial Opportunity to Full Spectrum of ATTR Amyloidosis PatientsaPrimary endpoint analysis based on the stratified Wilcoxon Rank Sum test.Median(95%CI)change from baseline values were based on the observed 6-MWT d

36、ata and the imputed values;for each patient,the change from baseline was averaged across 100 complete datasets.Missing Month 12 values due to non-COVID-19 death or inability to walk due to progression of ATTR amyloidosis were imputed as the worst 10th percentile change observed across all patients i

37、n the double-blind period,capped by the worst possible change for the patient(i.e.,0 minus the patients baseline 6-MWT).Missing Month 12 data due to other reasons were multiply imputed(assuming data were missing at random)to create 100 complete datasets.At baseline,the median(range)6-MWT was 358.000

38、(155.70,808.00)in the patisiran group and 367.740(130.00,740.00)in the placebo group.Abbreviations:6-MWT,6-minute walk test;ATTR,transthyretin-mediated;CI,confidence interval;HL,HodgesLehmann;m,meters.bMMRM model.Missing data not explicitly imputed and assumed to be missing at random.At baseline,the

39、 mean(SD)KCCQ-OS was 69.836(21.178)in the patisiran group and 70.330(20.709)in the placebo group.Abbreviations:KCCQ-OS,Kansas City Cardiomyopathy Questionnaire Overall Summary;LS,least squared;MMRM,mixed model repeated measures;SD,standard deviation;SEM,standard error of mean.Change from Baseline in

40、 6-MWTaChange From Baseline in KCCQ-OS using MMRMbWorseBetterHL estimate of median difference(95%CI):14.693(0.693,28.692)p=0.0162Median(95%CI)change from baseline(m)-40-30-20-1001006912PlaceboPatisiran-9.83(-16.50,0.85)-0.81(-8.80,8.00)-8.15(-16.42,1.50)-6.75(-13.90,1.50)-13.20(-19.65,-1.15)-21.35(-

41、34.05,-7.52)Time(months)PlaceboPatisiranN evaluable178181178181178181178181LS mean(SEM)difference:3.709(1.796)p=0.0397Median(95%CI)change from baseline(m)-5-4-3-2-101206912PlaceboPatisiran0.113(1.110)0.738(1.184)0.300(1.263)-1.087(1.108)-2.706(1.191)-3.408(1.277)Time(months)PlaceboPatisiranN evaluab

42、le178181170169167170164170Patisiran demonstrated statistically significant and clinically meaningful improvements in functional capacity,health status and quality of life compared to placebo at month 1214Safety and Exploratory Endpoints Support Patisirans Therapeutic PotentialaGarcia-Pavia P,et al.E

43、ur J Heart Fail.2021 Jun;23(6):895905;bPatients who are missing Month 12 due to COVID-19 are excluded from analysis.Odds ratio and 95%CI from CochranMantelHaenszel test stratified by baseline tafamidis use;cFor the composite parameter,the summary presents the odds ratio(95%CI)of no progression on an

44、y component(ie,30%increase or change 300 ng/L in NT-proBNP AND 30%increase in troponin I AND no increase in ATTR disease stage);dFor each component,the summary presents the odds ratio(95%CI)of no progression on the specified component(ie,30%increase or change 300 ng/L for NT-proBNP,10%,excluding pat

45、ients with history of stroke and women of child-bearing potential;2.Estimated from multiple sources and internal estimates:Dorans et al.J Am Heart Assoc 2018;7:e008888;Al Kibria et al.Hypertens Res.2019;42:163143;CDC Hypertension Cascade.2019;High CV risk:ASCVD risk score 20%and/or history of CVD;3.

46、Excluding stroke and WOCBP;4.U.S.Department of Health and Human Services.The Surgeon Generals Call to Action to Control Hypertension.Washington,DC:U.S.Department of Health and Human Services,Office of the Surgeon General,2020.Primary Hypertension1in 7 Major Markets,2020219MMHigh CV Risk with Hyperte

47、nsion2in 7 Major Markets,2020377MM70%UNCONTROLLED HYPERTENSION(130/80 mmHg despite treatment)4StrokeHeart AttackArteriosclerosisKidney FailurePotential complications of uncontrolled hypertensionHypertension risk further exacerbated by variability in BP control,lack of nighttime dipping,and poor medi

48、cation adherenceTogether,contribute to substantial risk of CV morbidity and mortality20Zilebesiran:Potential Novel Treatment for Patients with HypertensionCompelling Phase 1 Data Support Transformative Product Profile*After single dose of zilebesiran 800mgMonotherapy Phase 2 Study(N=394)Exploring mu

49、ltiple doses and dosing regimens Enrollment completed December 2022 Topline results expected mid-2023Combination Phase 2 Study(N 630)Background treatment standardized with ARB,calcium channel blocker or diuretic Enrollment completion expected early 2023 Topline results expected at or around year-end

50、 202390%mean serum AGT reduction for 6 months*Serum AGT Lowering40200204060801000122420 mmHgSBP reduction at 6 months*Blood Pressure ReductionMean+/-SEM Change from Baseline in 24-hour ABPM,mmHg-0.7-15.0-13.3-16.9-30-25-20-15-10-50Placebo(n=10)200 mg(n=2)400 mg(n=8)800 mg(n=8)Week 12-12.5-9.3-22.5-3

51、0-25-20-15-10-50200 mg(n=6)400 mg(n=8)800 mg(n=8)Week 24Tonic BP controldemonstrated over 24hr*Consistent BP ReductionNightDay1101201301401501609 10 11 12 13 14 15 16 17 18 19 20 21 22 23 012345678Change in RAAS BiomarkersDurable reductionin Ang II&aldosterone*21Additional Growth Opportunities via P

52、artnered ProgramsALN-HBV02(VIR-2218)Hepatitis B/D Virus InfectionPotential for functional cure of chronic HBV infectionAdditional Phase 2 HBV readouts expected in 2023Phase 2 HDV study ongoing;data expected in 2023Alnylam opt-in right to VIR-2218 prior to Phase 3CEMDISIRAN/POZELIMABComplement-Mediat

53、ed DiseasesNovel approach providing potent C5 inhibitionPhase 3 Myasthenia Gravis study ongoingPhase 2 and 3 Paroxysmal Nocturnal Hemoglobinuria studies ongoingFITUSIRANHemophiliaInnovative approach to hemophilia A and B,with or without inhibitorsDemonstrated reduction in annualized bleeding rateAdd

54、itional Phase 3 data with lower doses expected late 2023NDA submission expected 202422Multiple Drivers of Future GrowthTTR Franchise LeadershipExpansion Beyond Rare DiseasesEngine for Sustainable Innovation23Two-Decade Track Record of Industry Leadership in RNAi Sourcing novel,genetically validated

55、targets Secured access to large PheWASdatabases Proven ability to uncover novel gene targetsHuman Genetics Novel conjugates with variety of ligands for delivery beyond liver C16 conjugate provides robust target knockdown with wide biodistribution and long duration of action in CNS Peptide and antibo

56、dy-based approaches being explored for targeted siRNA delivery to new tissuesExtrahepatic Delivery IKARIA enables robust target knockdown with annual dosing potential Reversir provides tailored control of RNAi pharmacology GEMINI combines siRNAs for simultaneous silencing of two transcriptsPlatform

57、DesignsGEMINIIKARIAReversir12 months24Expanding Beyond Liver with First CNS Program in ClinicMultiple Patient Populations with High Unmet NeedAPP:amyloid precursor proteinAlzheimers Disease(AD)Over 5M people affected by AD in U.S.(30M+WW)Current therapies not shown to halt disease progression ALN-AP

58、P could reduce both intracellular and extracellular drivers of disease pathologyCerebral Amyloid Angiopathy(CAA)Second-leading cause of ICH after hypertension No specific treatments available for CAA ALN-APP could lower all A isoforms including A40,primary component of vascular amyloid depositsDurab

59、le Effect in NHPTime(Days)CSF sAPP and sAPP Protein Knockdown(Single Intrathecal Dose in NHP)Protein Knockdown(%remaining relative to baseline)NHP1-sAPPNHP2-sAPPNHP3-sAPPNHP1-sAPPNHP2-sAPPNHP3-sAPPBroad Distribution in NHPDose escalation in Part A ongoingTopline Phase 1 data expected early 2023ALN-A

60、PP lowers APP production at its source,upstream of pathogenic process25Alnylam 2023 Goals*Not approved for any indication and conclusions regarding the safety or effectiveness of these drugs have not been established.Early is Q1-Q2,Mid is Q2-Q3,and Late is Q3-Q4 EarlyMidLateCombined Net Product Reve

61、nue Guidance to be Provided at Q4/YE 2022 EarningsPATISIRANATTR AmyloidosisFDA Approval of sNDAVUTRISIRANATTR AmyloidosisBiannual Dosing Regimen DataSubmit sNDA for Biannual Dosing RegimenALN-TTRsc04*ATTR AmyloidosisPhase 1 Topline ResultsZILEBESIRAN*HypertensionComplete KARDIA-2 EnrollmentKARDIA-1

62、Phase 2 Topline ResultsKARDIA-2 Phase 2 Topline Results(at or around year-end)ALN-APP*Alzheimers DiseasePhase 1 Topline ResultsALN-KHK*Type 2 DiabetesInitiate Phase 1 StudyPhase 1 Topline ResultsADDITIONAL PROGRAMSFile 2-4 New INDsPARTNERED PROGRAM MILESTONESFITUSIRAN*(Sanofi)HemophiliaATLAS Phase 3

63、 Topline ResultsALN-HBV02*(Vir)Chronic HBV/HDV InfectionPhase 2 ResultsALN-PNP*(Regeneron)NASHInitiate Phase 1 Study26Alnylam 2023 Goals*Not approved for any indication and conclusions regarding the safety or effectiveness of these drugs have not been established.Early is Q1-Q2,Mid is Q2-Q3,and Late

64、 is Q3-Q4 EarlyMidLateCombined Net Product Revenue Guidance to be Provided at Q4/YE 2022 EarningsPATISIRANATTR AmyloidosisFDA Approval of sNDAVUTRISIRANATTR AmyloidosisBiannual Dosing Regimen DataSubmit sNDA for Biannual Dosing RegimenALN-TTRsc04*ATTR AmyloidosisPhase 1 Topline ResultsZILEBESIRAN*Hy

65、pertensionComplete KARDIA-2 EnrollmentKARDIA-1 Phase 2 Topline ResultsKARDIA-2 Phase 2 Topline Results(at or around year-end)ALN-APP*Alzheimers DiseasePhase 1 Topline ResultsALN-KHK*Type 2 DiabetesInitiate Phase 1 StudyPhase 1 Topline ResultsADDITIONAL PROGRAMSFile 2-4 New INDsPARTNERED PROGRAM MILE

66、STONESFITUSIRAN*(Sanofi)HemophiliaATLAS Phase 3 Topline ResultsALN-HBV02*(Vir)Chronic HBV/HDV InfectionPhase 2 ResultsALN-PNP*(Regeneron)NASHInitiate Phase 1 Study Commercial execution across four products Ten clinical readouts from proprietary and partner-led programs Potential label expansion for ONPATTRO in ATTR amyloidosis with cardiomyopathy First human data for RNAi therapeutic in CNS 2-4 new INDs27Nurturing a Winning CultureCommitment to PeopleScientific InnovationDiversity,Equity,&InclusionSocial Responsibility28Thank You!