|2024 08 14 19 证券分析师：马千里010-S0980521070001证券分析师：张佳博021-S0980523050001 AD AD 2016 Global Burden of Diseases AD 1990 2020 2016 4384+117%238 7 2016 AD 1043+5.6%47.7/1/5 AT(N)AD 20 NIA-AA/AT(N)AD/A-PET Tau-PETCSF A t-tau p-tau AD CSF AD AD/ELISA/AD A AD A AD 2010 A Ph3 Lecanemab Eisai/Biogen Donanemab Eli Lilly 2023 7 2024 7 FDA AD Tau Tau AD/A GLP-1RA AD/1 2 3 A Ph2 2WUFUxOrMtQnMtNtQtOoRnM9PcM9PtRmMsQrNeRpPwOeRpOqM7NmNqOwMoOxPuOtQzR AD AT(N)01 A 02Tau03/04 05 AD Alzheimers disease AD dementia 50%70%65 early-onset AD EOAD 65 late-onset AD LOAD sporadic AD SAD familial AD FAD FAD 5%2016 Global Burden of Diseases AD 1990 2020 2016 4384+117%age-standardised prevalence 701/10 712/10+1.7%238 7 2016 AD 1043+5.6%47.7/1/5 Alzheimers disease，AD）50%70%（Dementia with Lewy body，DLB）5%10%Frontotemporal lobar degeneration，FTLD）5%10%（Parkinson disease with dementia，PDD）3.6%（Vascular dementia，VaD）15%20%doi 10.3760/cma.j.issn.0376-2491.2018.13.003 4 AD Prevalence Deaths DALYs2016countsage-standardisedrates,1990-20162016countsage-standardisedrates,1990-20162016countsage-standardisedrates,1990-2016Global 43,835,665 1.7%2,382,129 3.6%28,764,110 2.1%China 10,427,487 5.6%476,898-0.1%6,637,268 0.5%US 4,029,450-0.5%238,895 11.6%2,473,390 3.8%Japan 3,530,611 17.8%224,138 10.2%2,226,531 10.5%South Korea 646,331-4.2%35,814-2.6%426,622-4.5%Singapore 37,905 11.5%2,265 3.2%24,746 6.3%Lancet doi 10.1016/S1474-4422(18)30403-4 DALYs Disability-adjusted life years5WmtVWJGSePWPDoafZ7uPPC4iNkD3XJlIbfvIKRvuXLQbVpoGPtnSb19ni84c1iw AD doi 0.3760/cma.j.issn.1006-7876.2019.02.016 NINCDS-ADRDA National Institute of Neurological and Communicative Disorders and Stroke-Alzheimers Disease and Related Disorders Association-ICD-10AD International Classification of Diseases 10th edition 10 DSM Diagnostic and Statistical Manual of Mental Disorders APA IWG IWG2 International Working Group NIA-AA National Institute on Aging-Alzheimers Association-5 NIA-AA AD AT(N)-IVS AD A AD0 DSM-IV-TR DSM NIA-AA 2011 AD/MCI/3 3 AD/2018 AD AT(N)AD NINCDS-ADRDA AD/AD AD AD AD ICD-10AD IWG2 CSF A42 t-tau p-tau A PET PSEN1/2 APP typical AD+biomarker atypical AD AD+1 biomarker IWG 2007 AD MCI AD MRI FDG PET CSFA/tau 2010 preclinical/prodromal/typical/atypical AD AD AD AD AD AD 1984 1993 2000 2007 2011 2014 2023 AT(N)AD/AD 20 NIA-AA/illness disease AD Core Biomarkers A A CSF/A42/40 amyloid-PET tau T CSF/p-Tau181 CSF/p-Tau217 tau-PET AD N CSF/NfL FDG-PET/I CSF/GFAP AD V-S CSF Syn-SAA NIA-AA AT(N)-IVS Intended Use CSF Plasma Imaging DiagnosisA:(A proteinopathy)Amyloid PETT1:(phosphorylated and secreted AD tau)p-tau217Hybrid ratios p-tau181/A42,t-tau/A42,A42/40 p-tau217/np-tau217Staging,prognosis,as an indicator of biological treatment effect A:(A proteinopathy)Amyloid PETT1:(phosphorylated and secreted AD tau)p-tau217Hybrid ratios p-tau181/A42,t-tau/A42,A42/40 p-tau217/np-tau 217T2:(AD tau proteinopathy)pT205,MTBR-243,non-phosphorylated tau fragmentspT205 Tau PETN:(injury to or degeneration of neuropil)NfL NfL Anatomic MR,FDG PETI:(inflammation)Astrocytic activation GFAP GFAPIdentification of co-pathologyN:(injury,dysfunction,or degeneration of neuropil)NfL NfL Anatomic MR,FDG PETV:(vascular brain injury)Anatomic infarction,WMH,abundant dilated perivascular spacesS:(-synuclein)Syn-SAA NIA-AA Revised Clinical Criteria for Alzheimers Disease p-tau phosph-tau tau t-tau total-tau tau NfL neurofilament light GFAP glial fibrillary acidic protein 胶质纤维酸性蛋白 FDG Fluorodeoxyglucose 氟脱氧葡萄糖 WMH White matter hyperintensity Syn-SAA-synuclein seed amplification assay-突触核蛋白种子扩增测定6 AD AD Lancet Neurology doi 10.1016/S1474-4422(12)70291-0 Eisai 7High risk Preclinical AD MCI Mild AD Moderate SevereTau PETPlasma p-tau A-PET PET positron emission tomography/CT AD A tau A-PET AD diagnosis-T 11C-PIB B 18F-florbetapir/Amyvid Eli Lilly 2012 18F-flutemetamol/Vizamil GE HealthCare 2013 18F-florbetaben/Neuraceq Life Molecular Imaging 2014 2017 Neuraceq 2023 9 18F A-PET Tau-PET Tau MCI AD staging/prognosis tau FDA 18F-flortaucipir/Tauvid Eli Lilly 2020 18F-APN-1607 Ph3 18F-MK-6240 Ph1 2020 2019 427 PET/MRI 23 PET/CT 404 PET/CT 1667 860 PET/MR 210 141 PET/CT PET/MR A Tau PET-CT/A 18F Amyvid Eli Lilly/Fuji film 2012.04 18F Vizamil Eli Lilly/GE Healthcare/2023.10 IND 2019.10 18F Neuraceq Bayer/Life Molecular Imaging/2024.02 2023.09 18F NDA 2023.10 18F/Ph1 2023.11Tau 18F Tauvid Eli Lilly/Siemens Healthineers 2020.05 Ph1 2021.0618F-APN-1607 Biogen/Ph3 2021.0918Fizaflortaucipir AC Immune/Genetech/Life Molecular Imaging Ph3 2022.0718FFlornaptitril CereMark Pharma Ph3 2024.0218F-MK-6240 Merck/Cerveau/Ph2 2019.04 Ph1 2022.06 ClinicalTrials 8 CSF AD CSF cerebrospinal fluid A42/40 t-tau p-tau 9 CSF/A42/40 p-tau A PET Nature Review Neurology doi 10.1038/s41582-022-00665-2 FDA Roche Elecsys p-tau181/A42 Elecsys t-tau/A42 Fujirebio Lumipulse A42/40 CSF 55 AD CSF PET-CT PET-CT CSF PET LDT CSF AD 2023 NIA-AA p-tau 181/217/231 pT205/NfL/GFAP e.g.SiMoA/fg/mL CNS e.g.A42/40 A PET/10%NIA-AA accurate plasma assay CSF 90%AD C2N Quest Quanterix SiMoA LDT laboratory developed tests/ELISA/AD ICL 10 AD/AD/C2N DiagnosticsPrecivityAD A42/40，SiMoA PrecivityAD2 1 p-tau 217/np-tau 217 2020 2023 55 ADQuest Diagnostics AD-Detect（A42/40，Quanterix 2023 7 LucentAD（p-tau 181，SiMoA Fujirebio A 42/40 p-tau 181 2023 7 Beckman Coulter Dxl9000 Access AD Roche Diagnostics2023 3 Lilly AD Elecsys Amyloid Plasma Panel EAPP EAPP p-tau 181 APOE4 AD AD p-tau 181(SiMoA/AD/p-tau 181 A 40 A 42 A 42/40 NfL SiMoA NfL/GFAP SiMoA A 42 p-tau 181 A 42/t-tau/p-tau 181 2024 4 A1-40 A1-42 p-Tau181 p-Tau217 GFAP NfL 4 Tau /AD NIA-AA Stage 0 genetically determined AD/AD/6080%FAD AD 5%PSEN1/2 APP SAD AD 95%GWAS APOE4 SAD AD/Lancet doi 10.1016/S0140-6736(20)32205-4 GWAS genome-wide association studies AD MAF minor allele frequency X AD Y OR=1 AD OR1 AD OR1 11 PSEN1/2 Presenilin1/2 1/2-1 FAD 60%PSEN1 A42 2 5%C APP A42 APP Amyloid Precursor Protein-/-/-APP A AD APOE4 APOE E A APOE2/3/4 APOE2 AD APOE4 AD 12 34x/915x 2021 2022 APOE AD AD 20192030 65 NIA-AA 2024 1PET A42/40 p-tau181/A42 t-tau/A42 60 PET/CT AD 250 120 AD A42/A40 p-tau 181 AD(MCI)2021 AD 291.4 AD 1699 2021 60 MCI 15.5%2023,60 2.97 2035 60 4 3 60 MCI 4650 20%10%2%2000 2000 1500 186 93 14 PET/CT 4%2%0.5%PET/CT 5000 3000 3000 PET/CT 93 28 7 2021 2024 AD AT(N)01 A 02Tau03/04 05 A AD amyloid protein A Amyloid cascade hypothesis AD senile plaque A AD crucial early impetus tau A A APP/-/-secretase APP non-amyloidogenic pathway Leu17 sAPP 83 C CTF Asp1 sAPP 99 C C99 A CTF A Signal Transduction and Targeted Therapy doi 10.1038/s41392-023-01484-7 14 A soluble monomers A40/42 A-Oligomers A 2 3 9,12,A protofibrils A fibrils plaque A42C A42 A40 A 1 A-/-siRNA/ASO 2 A A42 3 A A 4 A 2010 A Ph3 Bapineuzumab Pfizer/J&J A N ARIA-E 0.5/1.0mg/kg q13W A 5CL Solanezumab Eli Lilly Crenezumab Roche A A Gantenerumab Roche N A A 200mg 20CL CSR-SB Aducanumab Biogen/Eisai A EMERGE/ENGAGE 78 A 64CL/54CL EMERGE CDR-SB FDA 2021 6 A Aducanumab CMS Aduhelm A A 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30IgG/D A E F R H D S G Y E V H H Q K L V F F A E D V G S N K G ABapineuzumab IgG1 M=FGantenerumab IgG1 MFCrenezumab IgG4 MFAducanumab IgG1 MFLecanemab IgG1 MFDonanemab IgG1 M=F*Nature Review Drug Discovery doi 10.1038/s41573-022-00391-w Eisai A Lecanemab 1-16 2129 A Lecanemab Donanemab pE3A A Donanemab 15 Lecanemab FDA AD Lecanemab LEQEMBI/Eisai/Biogen A protofibrils IgG1 aducanumab lencanemab small protofibrils large protofibrils 100 x/25x FcR A 2023 7 FDA AD 2.65/q2W 10mg/kg 75kg A Clarity AD Lecanemab Eisai/Biogen A aggregates 10mg/kg q2W i.v.Ph3 Clarity AD Tau PET Substudy Low Tau Intermediate/High Tau Lecanemab PBO Lecanemab PBO Lecanemab PBO Lecanemab PBO 18mo MCI（60%）、mild-AD（40%）898 897 175 167 70 71 105 96 71.4 71.0 71.8 72.4 72.6 71.8 71.2 72.8CDR-SB 3.2 1.3 3.2 1.3 3.4 1.3 3.3 1.3 3.4 1.4 3.2 1.4 3.4 1.2 3.4 1.3ADAS-Cog14 24.5 7.1 24.4 7.6 22.7 6.7 22.9 7.0 21.4 6.6 20.6 6.3 23.5 6.7 24.6 7.0ADCS-MCI-ADL 41.2 6.6 40.9 6.9 40.7 6.9 40.7 6.7 38.8 6.9 40.4 6.8 41.9 6.7 40.9 6.6MMSE 25.5 2.2 25.6 2.2 25.6 2.2 25.6 2.1 25.5 2.0 25.9 2.1 25.7 2.3 25.5 2.1Amyloid PET CL 77.9 44.8 75.0 41.8 70.7 46.8 73.8 41.0 36.4 35.8 50.4 37.6 93.5 38.8 91.0 34.5 CDR-SB+1.2 vs+1.7-0.5-0.5-0.6-0.5ADAS-Cog14+4.1 vs+5.6-1.5-1.0-1.7-0.8ADCS-MCI-ADL-3.5 vs-5.5+2.0+1.9+3.3+0.7Amyloid PET CL-55.5+3.6 SAE 14.0%11.3%AE 0.7%0.8%ARIA-E 12.6%1.7%ARIA-H 17.3%9.0%Eisai 16 Lecanemab Clarity AD OLE 18 Early start Delay start Lecanemab 10 mg/kg i.v.q2W 24 CDR-SB ADAS-Cog14 ADCS MCI-ADL18 24 Lecanemab CDR-SB ADNI 36ANDI 0.95 OLE 24 CDR-SB Eisai ADNI Alzheimers Disease Neuroimaging Initiative Clarity AD 18 Core Study 1218 17 OLE 24 ADAS-Cog14/ADCS MCI-ADL Eisai ADAS-Cog14 ADCS MCI-ADL Lecanemab Tau Tau PET Tau tau PET SUVr40 CL 1000 5 mg/kg q2Wx6+10 mg/kg q2Wx86+10 mg/kg q4Wx120 4 216 PACC5 A-PET Tau PET CDR-SB/ADAS-Cog14/ADCS MCI-ADL Eisai 18 Lecanemab FDA FY2023 LEQEMBI 42.5 2700 2023 7 FDA traditional approval CMS Centersfor Medicare&Medicaid Services Medicare PartB deductible 80%2.65/5300 2023 9 2024 1 LEQEMBI FY2024Q1 LEQEMBI 63 4000+123%4/5/6 9/16/21 FY2024 2024Q22025Q1 565 3.6/435/100/30 2.7/0.6/0.3 2024Q1 LEQEMBI IV maintenance treatment 10 mg/kg qM FDA sBLA SC-AI maintenance treatment 360 mg qW BLA FY2023 LEQEMBI Eisai JPY USD=1:0.0063 FY2023 2024Q119 FY20232024 Eisai 4001800350052007000010002000300040005000600070008000FY2023 FY2024 1Q FY2024 2Q FY2024 3Q FY2024 4Q0.72.910.628.363.00.72.910.424.446.0010203040506070Q1 FY2023 Q2 FY2023 Q3 FY2023 Q4 FY2023 Q1 FY2024global US Donanemab pGlu3-A Donanemab KISUNLA Eli Lilly pGlu3-A A A(p3-42)pE3-A N3pG pGlu3-A 50%A 20 Clarity AD Donanemab Eli Lilly pGlu3-A 700 mg q4Wx3，1400 mg q4W i.v.Ph3 TRAILBLAZER-ALZ TRAILBLAZER-ALZ 2 Donanemab Placebo Donanemab PBO Donanemab tau PBO tau 18mo MCI（20%）、mild-AD（80%）131 126 860 876 558 594 75 75.4 73.0 73.0 74.3 74.3iADRS 106.2 13.0 105.9 13.2 104.1 14.3 103.6 14.0 105.7 13.8 105.5 13.7CDR-SB 3.6 2.1 3.4 1.7 4.0 2.1 3.9 2.1 3.7 2.1 3.7 2.0ADAS-Cog13 27.6 7.7 27.5 7.6 28.7 8.8 29.3 8.9 27.5 8.5 27.8 8.4ADCS-MCI-ADL/66.3 8.6 66.4 8.3 66.7 8.5 66.9 8.5MMSE 23.6 3.1 23.7 2.9 22.4 3.8 22.2 3.9 23.1 3.6 22.8 3.8Amyloid PET CL 107.6 36.0 101.1 33.3 103.5 34.5 101.6 34.5 102.4 34.7 100.9 35.1 iADRS-6.9-10.1-10.2-13.1-6.0-9.3CDR-SB+1.2+1.6+1.7+2.3+1.2+1.8ADAS-Cog13+2.9+4.8+5.5+6.8+3.2+4.7ADCS-MCI-ADL/-4.4-6.1-2.8-4.6MMSE-2.4-3.0-2.5-2.9-1.6-2.1Amyloid PET CL-87.0-0.7-88.0+0.2 SAE/17.4%15.8%AE 0.8%1.6%0.4%0.1%ARIA-E 27.5%0.8%24.0%1.9%ARIA-H 11.4%7.2%19.7%7.4%Eli Lilly Donanemab A Donanemab 76 A 87 CL-84%/No/Very-Low Low-Medium High Tau A 86%/85%/80%P-tau217 56%/39%/33%GFAP 22%/21%/18%Tau Donanemab Disease-Relevant Biomarkers 24/52/76 30%/66%/76%Donanemab A 24.1 CL A Re-accumulation rate 2.8 CL/47 CDR-SB Donanemab 76 A PCNS 21 CDR-SB PCNS Remternetug pGlu3-A Remternetug Eli Lilly pGlu3-A Ph1 J1G-MC-LAKB 41 MCI AD MMSE16 A PET-CT 37CL 2502800mgRemternetug 4 Remternetug A 169 1400/2800mg A 24.1CL 41 10 ARIA 700-1400 mg 1 ARIA-E ARIA-H ARIA ApoE4 85/169 A AD/PD 2023 22 Ph3 TRAILRUNNER-ALZ-1 600 AD MMSE 2028 p-tau/Remternetug 52 52 A 85/169 A AD/PD 2023 Trontinemab A Trontinemab Roche A Brainshuttle A 1 TransferrinReceptor 1 TfR1 TfR1 trontinemab brain exposure CNS biodistribution Brainshuttle AD Ph1b/2a q4W 0.2/0.6/1.8/3.6 mg/kg 3.6 mg/kg A 12 119 CL 21 CL 5/8 24.1 CL 4/8 11 CL 1.8 mg/kg A 12 100CL 40 CL 28 9 CL Trontinemab TfR-1 Roche Neurology Update BBB blood brain barrier microglia 23 Trontinemab 28 A Roche Neurology Update CL Centiloid units PET QPCT/QPCTL Vivoryon 2 pGlu3-A pGlu3-A QPCT glutaminyl-peptide cyclotransferase A N Gln Glu pGlu AD QPCT 24 PQ912/Varoglutamstat PBD-C06 AD biopharmadealmakers QC=QPCT Varoglutamstat PQ912/SIM0408 QPCT/QPCTL QPCT-like QPCT pGlu3-A QPCTL CCL2 QPCTL CCL2 pE-CCL2 neuro-inflammation tau tau-pathology Ph2a SAPHIR 12+4 Varoglutamstat CSF QPCT NTB One Back Test EEG Electroencephalogram CSF Neurogranin/YKL-40 PBD-C06 IgG1 pGlu3-A ARIA 2021 6 Vivoryon Varoglutamstat PBD-C06 5.65 Vivoryon 2022 2 Varoglutamstat SIM0408 APP RNAi ALN-APP ALN-APP Alnylam Regeneron APP siRNA C16 2-O-hexadecyl+APP mRNA siRNA IT intrathecally Ph1a 20 EOAD MCI CDR=0.5or1.0 MMSE 20 25/50/75mg CSF sAPP sAPP 75mg 84%/90%70%3 6 55%/65%10 33%/39%2 CSF A42/A40 49%/71%NfL ALN-APP Ph1a 10 CSF Alnylam sAPP soluble APP APP25 A AD A e.g.e.g.MCI AD A A 1 A AN-1792 A42 A42 T aseptic meningitis 2 A B N A/Amilomotide/CAD-106 ABvac40 UB-311 Novartis Araclon Biotech Vaxxinity/A1-6+Q VLP A33-40 2 A1-14+2 UBITh 450g IM 1/7/13 3 q13W 0/1/2/3/4 5+6 1 300g IM 0/4/12 3 q3M q6M Ph3（Ph2 Ph2 NCT02565511 AB1601 V203-AD 713 124（a-MCI=80，vm-AD=44）66 APCC=78.0 5.5RBANS=104.4 12.0CDR-SB=0.1 0.28MMSE=25.8 1.81ADAS-Cog:23.7 7.8MMSE：23.3 2.1ADCS-ADL：64.7 5.7CDR-SB：3.1 1.3 APCC：-1.1 vs-2.0（26w）+0.9 vs+1.4（52w）+0.2 vs-0.7（78w）-1.4 vs+0.3（104w）ABvac40 MMSE 38%RBANS TMTABvac40 CDR-SB ADCS-ADL-MCI TMT-B IGE EQ-5D-5L 78w q3/6M CFB ADAS-Cog=-1.85/-0.99MMSE=+0.38/+1.71ADCS-ADL=+4.65/+3.36CDR-SB=-0.59/-0.17A-0.91CL vs+8.37CL SUVR CFB=0.008 vs 0.013 52w PET SUVR-0.51%vs-0.34%（52w）24mo MRI 1.48%/ARIA-E：2.4%vs 0%ARIA-H：4.8%vs 0%ARIA-EARIA-H ARIA-EARIA-H：7%vs 0%ClinicalTrials RBANS TMT 26 A A AD/Remternetug Eli Lilly N3pG-A Ph3 2022.08 Ph3 2023.02Sabirnetug/ACU-193 Acumen soluble A oligomers Ph2/3 2024.03ABBV-916 Abbvie N3pG-A Ph2 2022.03Trontinemab Roche A Ph1/2 2020.11SHR-1707 A Ph2 2023.12PRX012 Prothena A Ph1 2022.03PMN 310 ProMIS Neurosciences A（oligomer）Ph1 2023.10CM383 A Ph1 2024.05ALIA-1758 Alida Therapeutics N3pG-A Ph1 2024.05 ABvac40 Araclon Biotech A33-40Ph2 2017.03ACI-24.060 AC Immune/Takeda A1-15Ph2 2018.05UB-311 Vaxxinity A1-14Ph2 2015.09ALZ-101 Alzinova soluble oligomeric A Ph1 2021.10AV-1959D Nuravax A1-11Ph1 2024.06ALZ-801 Alzheon prodrug of homotaurine Ph3 2021.02CT1812 Cognition Therapeutics Sigma2-RA Ph2 2018.04varoglutamstat/SIM0408Vivoryon/QPCTL/QPCT Ph2 2020.07 IND 2022.02ALX-001 Allyx Therapeutics/BMS mGluR5 Ph1 2021.03RP902 A Ph1 2023.02CS6253 Artery Therapeutics ABCA1 ApoE A Ph1 2023.07PRI-002 Priavoid GmbH A42 Ph1 2023.12PK501 PharmaKure APP IND 2024.01 ClinicalTrials 27 1 2 AD A 2030CL A A tau MCI AD Lecanemab Donanemab 18 CDR-SB+1.21 vs+1.66=0.45-27%+1.66 vs+2.33=0.67-29%CDR-SB 018 MCI AD 0.56 30%0.5 MCI AD clinically meaningful Lecanemab 201 ADNI Eisai Lecanemab MCI AD AD MCI/AD 2.5/3.1/2.3 Lencanemab AD Eisai 28 2 A AD MCI AD Lecanemab Donanemab tau tau/A Lecanemab Donanemab preclinical-AD AHEAD 3-45 Eisai 2020 A3 Trial A AD early preclinical AD A2040 CL 400 A45 Trial A AD A40 CL 1000 4 216 PACC5 A-PET TRAILBLAZER-ALZ 3 3300 TICS-m A/tau Donanemab 700mg q4Wx3 1400mg q4Wx6 CDR-GS 182 Donanemab PNCS 29 Tau Donanemab CDR-SB PNCS 3 AD 71.4%97.2%MCI PET-CT/CSF e.g.A42/40 AD-DMT Eisai DMT Disease-Modifying TherapyPrevalence of Early AD MCI&mild-AD Diagnosed with Early ADA testA positiveTreated with an AD-DMT30 A PET-CT AD APET-CT CMS 2023 10 APET-CT Medicare 20%PET-CT 4 ARIA Amyloid Related Imaging Abnormalities A A ARIA-E edema MRI ARIA-H hemosiderin deposition ARIA ApoE4 MRI Lecanemab Do