20230731_兴业证券_医药生物行业阿尔茨海默病深度报告诊疗终现双突破蓝海市场正起航_35页.pdf

请 务必阅读 正文之 后的信 息披露 和重要声 明 industryId investSuggestion(investSuggestionChange 2023 2023-06-28 elatedReport S0190515090001 S0190519020002 S0190522090002 emailAuthor summary AD Lecanemab FDA Donanemab 75 Tau ALZ-801 TB006 A A Os ACU193-1 ANAVEX2-73 AD AD AD 983 AD 3877 MCI AD MCI 5%Lecanemab Donanemab AD 2022 2030 65 AD AD TB006 AD SHR-1707 260mg/kg Vivoryon Varoglutamstat II AD II AD 18F-APN-1607 III p-Tau181 AD title createTime1 2023 7 31 请 务必阅读 正文之 后的信 息披露 和重要声 明-2-1.-4-1.1.-5-1.1.1.-5-1.1.2.Tau.-6-1.1.3.-7-1.2.-8-1.2.1.-8-1.2.2.12.-10-1.2.3.-10-2.-12-2.1.-12-2.1.1.-12-2.1.2.-13-2.1.3.AD.-14-2.1.4.PET.-16-2.1.5.AI.-17-2.2.-17-2.2.1.-18-2.2.2.-30-3.-31-4.-33-5.-34-1 AD.-5-2 A.-6-3 Tau.-7-4 2019 2050.-8-5 60,2015-2018-9-6 60 AD.-9-7 60 MCI.-9-8.-11-9 1990-2019.-11-10 AD.-14-11 1998-2017 AD.-18-12 1998-2017 AD.-18-13.-19-14-.-20-15 Aducanumab.-21-16 Lecanemab III Clarity AD.-22-17 Donanemab III TRAILBLAZER-ALZ 2.-23-18 Galectin-3.-25-19 TB006 Ib/II.-25-YWDWuNsPtQrQtNoNnQqPrQaQcM6MmOqQmOoNlOoOyQfQrRnM7NrQtNMYnMvMuOqQuM 请 务必阅读 正文之 后的信 息披露 和重要声 明-3-20 ALZ-801 AD.-26-21.-31-22.-32-23.-32-1.-4-2 AD VD.-4-3.-7-4 AD 1984-2023.-12-5 AD.-13-6.-15-7 AD PET.-16-8 Lecanemab Donanemab III.-24-9 AD.-29-10 TOP10.-32-请 务必阅读 正文之 后的信 息披露 和重要声 明-4-1.dementia Alzheimers disease AD 6070%AD-Tau 1 6070%(DLB)5-10(FTD)5-10(PDD)3.6%(VD)15 20()5.0 6.4 AD VD 2 AD VD AD VD A/请 务必阅读 正文之 后的信 息披露 和重要声 明-5-/CT/MRI PET/SPECT NMDA ACEIs 1.1.Tau 1 AD Curr Neuropharmacol,2020,18(11):1106-1125 1.1.1.AD APP A A 42-A 42-A-A A A 请 务必阅读 正文之 后的信 息披露 和重要声 明-6-A 2 A The beneficial effects of wine polyphenols on Alzheimers disease Neurology EClinicalMedicine AD 2022 Sylvain Lesn Science A*56 56 kDa A*56 A*56)A AD A A*56 1.1.2.Tau Tau Tau Tau AD Tau NFTs Tau AD-分泌 酶启 动毒 性途 径，导 致 C99 生成 C99 被-分 泌 酶 非 精 确 切 割，产生 大小不一 的 A 片段（主 要 是 A 4 0、A 4 2）和 AICD 片段 可溶性 异常 沉积 的 A 4 2 比 A 4 0 更 易于聚 集 和 形 成 斑 块，神 经 毒 性 更 强 同时，小胶 质细 胞和 星形 胶质 细胞 被 激活并诱导 相关 炎症 反应 和氧 化 可溶 性 A 寡 聚 物 比 纤 维 状 毒 性 更 高，引起对突 触膜 的氧 化损 伤外 还能 诱 导tau 蛋白过度 磷酸 化 请 务必阅读 正文之 后的信 息披露 和重要声 明-7-3 Tau the breakdown of clumped tau proteins to cure Alzheimers disease P-tau181 NFT AD P-tau181 P-tau217 P-tau231 P-tau AD 1.1.3.AD 3 APP 1 2 AD APOE AD AD AD AD AD c ROS A ROS ROS A AD Tau Kappa NFkB Tau 请 务必阅读 正文之 后的信 息披露 和重要声 明-8-5-APOE HSV-1 A NFTs AD()AD 1 Tau AD AD Curr Neuropharmacol,2020,18(11):1106-1125 1.2.1.2.1.2019 5500 2030 7800 CAGR 2019 2030 3.2%2050 1.39 CAGR 2030-2050 2.9%4 2019 2050 Global status report on the public health response to dementia(WHO)2020 60 65 264 018 766 190 635 280 18.70%13.50%2010 2015 2018 1507 60 AD 983 392 132 60 MCI 15.5%3877 2015 请 务必阅读 正文之 后的信 息披露 和重要声 明-9-AD 1677.4 2050 1.8 AD AD 5 60,2015-2018 Lancet Public Health,2020,5(12):e661-e671(2015-2018)2050 2050 60 AD 3003 60 MCI 2050 8029 CAGR 2.5%6 60 AD 7 60 MCI 2020-2050 3877 2020 2030 2040 2050 请 务必阅读 正文之 后的信 息披露 和重要声 明-10-1.2.2.12 1 2 1.2.3.1 1.8 2022 669.3/10 1188.9/10 AD AD AD 60%40-65 PiB FDG MRI p 0.05 2021 APOE 4 tau 2 请 务必阅读 正文之 后的信 息披露 和重要声 明-11-8 Lancet Public Health,2020,5(12):e661-e671 3 AD 5 2022 2019 AD 788.3/10 682.5/10 32 162 23.3/10 22.9/10 AD 1990 10 2019 5 AD 1990 27 2019 15 1990 2019 AD 9 1990-2019 Gen Psychiatr,2022,35(1):e100751 1 慢性阻塞性肺病 2 中风 3 缺血性心脏病 4 下呼吸道感染 5 高血压性心脏病 6 胃癌 7 肺癌 8 肝癌 9 新生儿疾病 10 阿尔茨海默病 1990 年 1 中风 2 缺血性心脏病 3 慢性阻塞性肺病 4 肺癌 5 阿尔茨海默病 6 胃癌 7 高血压性心脏病 8 道路伤害 9 结直肠癌 10 下呼吸道感染 传染性或新生其他 受伤 2019 年 痴呆 轻度认 知障 碍 请 务必阅读 正文之 后的信 息披露 和重要声 明-12-2.2.1.20 MCI AD MCI AD 8-10 2-6 AD AD-8 AI 2.1.1.AD AD AD PCAD Pre-MCI MCI/AD PCAD Pre-MCI 15-20 AD A 42 Tau MCI MCI MCI AD AD 2023 7 16 NIA-AA Revised Clinical Guidelines for Alzheimer s ADPD NIA-AA 3 1)PET 2)3)4 AD 1984-2023 1984 NINCDS-ADRDA AD AD 1993 ICD-10AD 请 务必阅读 正文之 后的信 息披露 和重要声 明-13-1994 DSM-IV-TR AD 2007-2010 IWG 2007 2010 AD 2011-2018 NIA-AA 2011 3 AD AD MCI AD AD AD AD AD 2018 A T N 2014 IWG2 AD A 1-42 tTau p-Tau PET AD PSEN1 PSEN2 APP AD 2022 A-T-N-X A-T-N X X AD X X Xc X Xp Xc Xp 2023 NIA-AA A T N 3/I AD(vascular brain injury,V)(synuclein pathy,S)Nature NIA-AA 2.1.2.AD PET AD AD 5 AD PET/MRI/CT PET 1 MRI 1500 CT 300 CSF 1000-3000-QPCR-请 务必阅读 正文之 后的信 息披露 和重要声 明-14-AD 10 AD 2.1.3.AD 1 2023 7 6 Quanterix LucentAD LucentAD FDA LucentAD Simoa p-Tau 181 singlemolecule array Simoa AD AD p-Tau 181 lecanemab Leqembi Clarity AD 2021 10 11 Quanterix Simoa Tau 181 pTau-181 FDA 50 AD 2 2022 5 4 FDA FUJIREBIO Lumipulse G-Amyloid Ratio 1-42/1-40 Lumipulse 55 Lumipulse G-1-42/1-40 PET PET 3)18 2021 AD 请 务必阅读 正文之 后的信 息披露 和重要声 明-15-p-Tau181 Simoa 6 20202400973 2020 2021/10/28 1-42 A 1-42 20152400854 2015 2020/6/29 Tau1-181 20152400855 2015 2020/6/29 1-42 A 1-42 20212400023 2021/1/6 Tau1-181 20212400237 2021/2/8 AD7C-NTP 20212400561 2021/4/8 AD7C-NTP 20212400562 2021/4/8 Tau-181 20212400119 2021/4/20 1-42 A 1-42 20212400117 2021/4/20 Tau-181 20212400264 2021/12/29 1-42 A 1-42 20212400265 2021/12/29 Tau-181 20212400825 2021/5/26 Tau-181 20212400388 2021/12/2 A 1-42/A 1-40/T-Tau/p-Tau-181/-synuclein()20232400002 2023/1/10 tau-181 20232400086 2023/1/13 S100-S100-/NSE/GFAP/L1 UCH-L1/6 IL-6/tau P-tau)20232400284 2023/3/27 Tau-181 pTau-181 20232400417 2023/5/15 tau-181 20232400139 2023/7/5 请 务必阅读 正文之 后的信 息披露 和重要声 明-16-2.1.4.PET AD PET PET,A-PET AD,MCI(2B)FDG-PET AD,AD DLB(2B)Tau-PET AD,MCI(2B)4 A 1 Tau PET III florzolotau(18F)18F-APN-1607 7 AD PET()()18F-FC119S FutureChem A flutemetamol F-18 University of Pittsburgh;GE Healthcare A 18F Avid Radiopharmaceuticals A Bayer;Life Molecular Imaging(formerly Piramal Imaging);University of Pennsylvania A flutafuranol(18F);Cerveau Technologies;AstraZeneca;Navidea Biopharmaceuticals III A 11CPIB University of Pittsburgh II A 18F-92 I A 18FP16-129 Five Eleven Pharma I A 18F A 18F-flortaucipir Siemens Healthineers;Avid Radiopharmaceuticals Tau florzolotau(18F)Biogen;Molecular NeuroImaging;National Institute of Radiological Sciences III III Tau izaflortaucipir(18F)Life Molecular Imaging(formerly Piramal Imaging);AC Immune III Tau 18F-THK-5351 Tohoku University II Tau 18F-MK-6240;Merck&Co.;Cerveau Technologies;Roche;Janssen Pharmaceuticals II I Tau 18FGTP1 Genentech II Tau 11C-RO6924963 Roche I Tau 11C-RO6931643 Roche I Tau 请 务必阅读 正文之 后的信 息披露 和重要声 明-17-18F-RO6958948 Roche I Tau 18FMNI-1020 Johnson&Johnson I Tau 18FMNI-815 Molecular NeuroImaging I Tau 18FMNI-952 Molecular NeuroImaging I Tau 11C-ER176 National Institute of Mental Health III TSPO 11C-PBR28 National Institute of Mental Health II TSPO 18F-fluoroethoxybenzovesamicol University of Michigan III V AChT 18F3F4AP Massachusetts General Hospital I VGKC 18FRP-115 Rio Pharmaceuticals I EAAT2 18Fbavarostat Eikonizo Therapeutics I HDAC6 11C-BU99008 Kings College London I I2 receptor 11CMK-6884 Merck&Co.I M4 receptor 18F-SMBT-1 Tohoku University I MAO-B 18FMC225 University Medical Center Groningen I/II not available 18F-LSN3316612 Eli Lilly I OGA 11C-UCB-J UCB II SV2A 2.1.5.AI 1 AI 2 Llewellyn 256 AI CAIDE BDSI 2 AD XGB AI 92%AUC 0.92 MRI 2 60-80%Framingham n=1084 AUC 92.6%88.0%74.4%MCI MCI ChatGPT AI 2.2.AD Tau DBS VNS 请 务必阅读 正文之 后的信 息披露 和重要声 明-18-2.2.1.AD 1 ChEIs AD AD 1A 10mg/d 1A 24mg/d 1A ChEI ChEI 3C 20mg/d AD 1A 2 AD 2B AD 2B 5-AD 2B 3 AD 3C AD 2B EGb761 AD 2B AD 3C AD 2.7%18%3 AD 2018 FDA 2013 AD FDA+AD disease-modifying therapies DMTs 78%III 67%(25%42%)III 19%11 1998-2017 AD 12 1998-2017 AD Alzheimers Medicines:Setbacks and Stepping Stones 请 务必阅读 正文之 后的信 息披露 和重要声 明-19-17%8%13 Alzheimers Dement(N Y),2023,9(2):e12385 2.2.1.1 A A 1 A A A;2 Fc 3 A F(ab)2 Fc 4 A A 5 IgM A 6 请 务必阅读 正文之 后的信 息披露 和重要声 明-20-14-Lancet Neurol,2008,7(9):805-11 FDA Biogen Eisai 2021 Aducanumab Aduhelm 2023 7 6 lecanemab-irmb Leqembi Aducanumab 5.8/2.82/Lecanemab 2.65/Donanemab III 1 Aducanumab AD Neurimmune Biogen Eisai FDA A-AD 2019 3 1748 2 III EMERGE&ENGAGE EMERGE CDR-SB-22%ENGAGE FDA Aducanumab A AD Aducanumab 2020 8 7 BLA 2020 11 6 FDA ENGAGE EMERGE Aducanumab AD 8 1 2 2021 6 7 FDA Aduhelm 9 ARIA 请 务必阅读 正文之 后的信 息披露 和重要声 明-21-(ARIA-E)(ARIA-H)2021 Evaluate 2026 48 Aduhelm 2021 300 2022 480 2022 4 22 15 Aducanumab AD/PD 2021 2)Lecanemab-irmb BioArctic Biogen Eisai AD 2022 12 22 FDA 2023 1 6 Lecanemab Biogen Eisai A Lecanemab 2023 7 6 FDA CMS Lecanemab CMS III Clarity AD Lecanemab CDR-SB 27%Lecanemab 14.0%11.3%ARIA-E Lecanemab 6 7 Lecanemab ARIA 请 务必阅读 正文之 后的信 息披露 和重要声 明-22-16 Lecanemab III Clarity AD N Engl J Med,2023,388(1):9-21 3)Donanemab A pGlu3-A amyloid beta A(p3-42)pE3-A N3pG pGlu3-A III TRAILBLAZER-ALZ 4 Aducanumab A 6 Donanemab 37.9%1.6%7 17 III TRAILBLAZER-ALZ 2 1736 73.0 1182/Tau 552 Tau NCS2 CDR-SB(MMRM)CDR-SB P-tau217 PET vMRI/Tau 76 Donanemab least-squares mean LSM iADRS-6.02-9.27 35.1%76 LSM-10.19-13.11 22.3%Tau CDR-SB 0.67 36.0%0.70 28.9%请 务必阅读 正文之 后的信 息披露 和重要声 明-23-76 Donanemab 205(24.0%)18 2.1%74 8.7%4 0.5%Donanemab 3 1 17 Donanemab III TRAILBLAZER-ALZ 2 JAMA.2023 Jul 17;e2313239 Donanemab Lecanemab CDR-SB 30%ADAS-cog Donanemab Tau Lecanemab ARIA Donanemab Lecanemab Donanemab 4 Tau 75 请 务必阅读 正文之 后的信 息披露 和重要声 明-24-8 Lecanemab Donanemab III Lecanemab(Biogen)Donanemab()Clarity AD TRAILBLAZER-ALZ 2 10mg/kg 2 700 mg 1400 mg 4 CDR-SB iADRS PET,ADAS-cog14,ADCOMS,ADCS-MCI-ADL ADAS-Cog13,CDR-SB,MMSE,ADCS-iADL,PET,vMRI,PK,vs=898 vs 897 Tau vs=588 vs 594 vs=860 vs 876 71.4 vs 71.0 74.3 vs 74.3 73.0 vs 73.0 CDR-SB 3.17 vs 3.22 3.7 vs 3.7 4.0 vs 3.9 CDR-SB 1.21 vs 1.66 18 27%1.20 vs 1.88 76 36%1.72 vs 2.42 76 29%CDR-SB 31%7.5 39%7.5 iADRS-6.02 vs-9.27 76 35%-10.19 vs-13.11 76 22%ADAS-cog 4.14 vs 5.58 18 26%3.17 vs 4.69 18 32%5.46 vs 6.79 76 19.5%PET(centiloids)55.48 vs 3.64 18 59.12 centiloids 84%vs 1%,18 APOE CDR-SB 1 MCI Donanemab iADRS 60%CDR-SB 46%AD iADRS 30%CDR-SB 38%2 75 n=542 Donanemab iADRS 48%CDR-SB 45%75 n=551 Donanemab iADRS 25%CDR-SB 29%3 ARIA-E()12.6%vs 1.7%24%vs 2.1%ARIA-H()17.3%vs 9.0%31.4%vs 13.6%6 vs 7 16 vs 10 3 vs 1 N Engl J Med,2023,388(1):9-21 JAMA.2023 Jul 17;e2313239 Donanemab MMRM CDR-SB NCS2 Remternetug LY3372993 AD N3pG 2023 1 Remternetug 4 CDE Remternetug Remternetug 3 AD 请 务必阅读 正文之 后的信 息披露 和重要声 明-25-2025 3 1 J1G-MC-LAKB 41 Remternetug 169 24 18 4 Galectin-3-3 Gal-3 A TB006 Gal-3 Gal-3 Gal-3 A 2022 11 18 TrueBingding TB006 Ib/II AD MMSE 2-24 36 25.4%CDR-SB 1 9.7%p=0.016 104 63%-0.44 TB006 TB006 A 42 TB006 3.5 ARIA TrueBinding 2023 2 28 FDA TB006 I/IIA FDA B IIB/III TB006 2023 7 2025 3 IIB 2025 4 2026 12 III 2027 1 2027 6 BLA 18 Galectin-3 19 TB006 Ib/II Truebinding 请 务必阅读 正文之 后的信 息披露 和重要声 明-26-5)A ALZ-801 ALZ-801 40%A 3-SPA 3-NRM5074 A 42 A A A AD 3-SPA ALZ-801 ALZ-801 II AD Tau 2025 20 ALZ-801 AD Alzheon 6)A UB-311 A ACU193 FDA A UB-311 A 1-14 B Th UBITh UBITh UB-311 FIH AD 100%请 务必阅读 正文之 后的信 息披露 和重要声 明-27-ACU193 A AOs AD AO A ACU193 A AOs 7 17 Acumen A Os ACU193 I p=0.01 60 mg/kg Q4W 63 25%25 mg/kg Q2W 70 21%3 SAEs ACU193 AEs ARIA-E 10.4%ARIA-H 8.3%COVID-19 6.3%6.3%7 BACE-A 2.2.1.2 Tau Tau AD 1 II AD 2 CDK5 roscovitine AD Tau flavopiridol RCT AD 3 Tau MB Tau Tau 6 4 Epothilone D I NAP ADNP II RCT MCI 12 NAP AD TPI-287 AD MMSE 54%Tau AADvac1 17.1%24.1%84.6%81.0%AADvac1 104 AADvac1 NfL P-tau217 Tau IgG4 IgG1 IgG4 BIIB092 ABBV-8E12 RO7105705 IgG1 BIIB076 LY3303560 JNJ-63733657 UCB66 请 务必阅读 正文之 后的信 息披露 和重要声 明-28-2.2.1.3-1 AD AD-3 NMDAR-1 ANA VEX2-73 Blarcamesine-1R AD PD Tau-1-1-1-1 2022 12 Anavex ANA VEX2-73 Blarcamesine 509 IIb/III 1:1:1 ANA VEX2-73 84%ADAS-Cog 0.50 ANA VEX2-73 ADAS-Cog 4.03 ANA VEX2-73 167%ADCS-ADL 3.5 ANA VEX2-73 AD ADAS-Cog ANA VEX2-73 45%ANA VEX2-73 CDR-SB 0.42(p=0.040)27%TEAE ATTENTION-AD 96 2.2.1.4 FK506 APP/PS1/NFAT II AD GLP-1 GLP-1 RA CA1 A Tau 12 AD 2021 3 AD MCI 2.2.1.5 A Tau I A SHR-1707 RP902 2023AAIC 260mg/kg SHR-1707 PK PD SHR-1707 请 务必阅读 正文之 后的信 息披露 和重要声 明-29-Ib NCT05681819 Vivoryon Therapeutics 2 AD Varoglutamstat PBD-C06 Varoglutamstat QPCT 2021 12 FDA PBD-C06 IgG1 N3pE ARIA Vivoryon 5.65 6.1 2018 10 IIb 2023 9 AD()Lecanemab Biogen;BioArctic;Eisai A Aducanumab Biogen;Neurimmune III A Rybelsus Emisphere Technologies III GLP-1R Donanemab Eli Lilly III pGlu3-A Remternetug Eli Lilly III pGlu3-A Genentech;AC Immune III A III AChE;BuChE JK-50561 II RAC1 II not available Varoglutamstat;Vivoryon Therapeutics II QPCTL;QPCT KH110()II not available;II not available;II not available;II AChE;II NMDA receptor 请 务必阅读 正文之 后的信 息披露 和重要声 明-30-;II not available BT-1 II vitamin B1 HEC30654 I 5-HT6 receptor OAB-14;I not available RP902 I A SHR-1707 I A;I Tau;TRPML1;calcium channel;AChE HECB1701301 I not available;Biscayne Neurotherapeutics I AChE JNJ-63733657 Johnson&Johnson I Tau NextPharma KH110 2.2.2.2.2.2.1.AD 1 DBS Meynert NBM DBS 2 VNS iVNS nVNS iVNS 12 70%nVNS AD 3 rTMS DLPFC AD 2 20Hz rTMS 4 rTMS 2021 4 tDCS/tACS AD AD tDCS DLPFC 请 务必阅读 正文之 后的信 息披露 和重要声 明-31-21 Int J Mol Sci,2021,22(15):8208 2.2.2.2 Ed Boyden II OVERTURE NCT-03556280 AD 6 76 50 40Hz n=20 6 n=33 ADCS-ADL 84%MMSE 83%n=19 n=30 6 AD 61%3.AD AD AD 48.53%AD 10.06%36.79%1 42.67%1 22.81%24.39%AD 77%60%请 务必阅读 正文之 后的信 息披露 和重要声 明-32-5%1 2 40.86%30.23%2019 86.58 82%2019 15.39 2014-2019 CAGR 16%22 23 85%2015-2019 12.28%14.55%2021 62.22%57.30%10 TOP10 2019 2020 2021H1 2021H 1 50.57%31.84%27.93%-63.07%2 29.04%37.66%24.63%-62.56%3 5.24%7.67%12.36%7.05%4 2.23%5.12%10.43%40.00%5 0.41%1.97%4.80%120.71%6 0.03%1.37%4.01%173.54%7 0.00%0.68%2.63%268.48%8 0.96%1.08%1.98%15.38%9 5.51%8.26%1.66%-88.75%10 0.00%0.07%1.47%/95.7 108.0 112.8 100.8 91.5 86.6 2014 2015 2016 2017 2018 20197.3 8.7 10.2 11.7 13.1 15.4 2014 2015 2016 2017 2018 2019 请 务必阅读 正文之 后的信 息披露 和重要声 明-33-4.AD A 2 A FDA Lecanemab FDA CMS Donanemab 7.5 Lecanemab Donanemab 75 Tau A ARIA Lecanemab ALZ-801 TB006 A A Os ACU193-1 ANA VEX2-73 AD A AD AD 3 2025 Lecanemab 2030 250 Lecanemab 2030 70 AD 983 AD 3877 MCI 5%Lecanemab Donanemab 2022 2030 65 AD AD AD 请 务必阅读 正文之 后的信 息披露 和重要声 明-34-5.AD 10 2.7%请 务必阅读 正文之 后的信 息披露 和重要声 明-35-12 A 300 500 15%5%15%-5%5%-5%/1934 15a-6/36 15 200135 6 SK 32 01-08 100020 5001 T2 52 518035