20240403_德邦证券_生物医药行业深度：代谢相关脂肪肝炎（MASHNASH）无药可治局面被打破巨大市场需求待挖掘_45页.pdf

0 MASH/NASH|2024 4 3 S0120523080003 lijy7 1 MASH NASH NASH NAFLD 5%MASH NAFLD 29.2%10 10%NASH 2.4%-6.1%NAFLD/NASH 2030 NASH 4.9 NASH 322 FDA 2024 NASH NASH THR-FXR GLP-1R PPAR FGF21 THR-FGF21 GLP-1 Madrigal resmetirom THR-2024 3 14 FDA FDA MASH Akero Therapeutics efruxifermin(FGF-21)MASH 96 GLP-1 MASH MASH MASH 1 Inventiva PPAR III AP025 FGF21 II 2 FASN THR-II 3 THR-4 FGF21/GLP-1-Fc 5 GLP-1 MASH ZXEVuNnQpMmNrPpMtOrOqR7NbP8OmOqQpNnRlOqQtPlOqQpQ9PpOoONZoOpNvPoMrM2 01020304NASH MASH MASH CONTENTS3 01 NASHqd0/lvNzBaoK7KNTWgmIiciCYydMK33bsDsO0TSEcfbhhV8oPmDTb5yq0BkvhsH3 41.1 NAFLD MAFLD 5%NAFL NASH NASH NAFLD(NAS)NAS Nonalcoholic Steatohepatitis NASH NASH 5%NASH F0-1 NASH F2-3 NASH F4 NASH(MASH)资料来源:非酒精性脂肪性肝炎治疗药物临床试验技术指导原则，Daniel Ferguson et al.Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus.Nature reviews.Endocrinology,Stephen A.Harrison et al.Challenges and opportunities in NASH drug development、非酒精性脂肪性肝病防治指南(2018年更新版)、德邦医药研究所 NAFLD NASH NAFLD NASH 5 NAFLD 1.1 NASH NASH 15%NASH Mechanisms and disease consequences of nonalcoholic fatty liver disease NAFL NASH NAFL NASH 14 NASH 7 20%NASH 20%NAFLD NASH 20%3-4 NASH HCC 1.5%-2%资料来源：Rohit Loomba et al.Mechanisms and disease consequences of nonalcoholic fatty liver disease，德邦证券研究所 NAFLD NASH61.2 NAFLD 30%2 NAFLD NAFLD 29.2%10 10%NASH 2.4%-6.1%NAFLD NASH 50-59 60 NAFLD/NASH NAFLD/NASH NAFLD/NASH 2030 34%NASH%35.56.924.55010203040NAFLD NASHMaleFemale27.228.232.931.525.34.7 5.17 6.7 6.201020304018-39 40-49 50-59 60-69 70NAFLD NASH NAFLD/NASH 资料来源：诺和诺德医学资讯公众号，德邦证券研究所；Ran Lu MD et al.Epidemiological characteristics and management of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis in China:A narrative review7 NAFLD 2022 5(AACE)(AASLD)T2DM/6 NAFLD NAFLD FIB-4 fibrosis-4 index-4 FIB-4=()AST(U/L)/PLT(109/L)ALT(U/L)1/2 FIB-4 LSM ELF 资料来源：诺和诺德医学资讯公众号，消化医声公众号，中华肝脏病杂志公众号、德邦证券研究所1.3 NASH NASH NASH NASH NASH ASH 5%8 NASH NASH NASH 2016 3.1 2020 3.5 2021-2030 NASH 2030 4.9 2016 17 2020 19 3.2%2030 322 NASH 资料来源：弗若斯特沙利文，派格生物医药招股书，德邦证券研究所 1.4 9 NASH 2020 3,870 2021-2030 NASH 2030 5,550 2016 5 2020 7 5.5%2030 355 NASH 资料来源：弗若斯特沙利文，派格生物医药招股书，德邦证券研究所 1.4 10 02MASH 11 NASH NAFLD NASH NASH NASH NAFLD/-NAFLD/NAFLD NASH 35%-61%Rohit Loomba 等Mechanisms and disease consequences of nonalcoholic fatty liver disease，Suchira Gallage等A researchers guide to preclinical mouse NASH models，德邦证券研究所 NAFLD/NASH 2.1 NASH12 NAFLD/NASH 2.1 NASH 资料来源：Vuppalanchi R,Noureddin M,Alkhouri N,Sanyal AJ.Therapeutic pipeline in nonalcoholic steatohepatitis，德邦证券研究所(NASH)X(FXR)-1 GLP-1R PPAR A(ACC)19(FGF19)FGF21 FASN NASH132.1 NASH 资料来源：Stephen A.Harrison 等Clinical Trial Landscape in NASH，Therapeutic pipeline in nonalcoholic steatohepatitis，医药魔方，药明康德公众号、德邦证券研究所 NASH FXR GLP-1R PPAR FGF21 THR-GLP-1 FGF21 FGF21-21 FGF21 FXR FXR FXR FXR FGF19 FXR PPAR PPAR 3 NASH THR-THR-THR-NASH DGAT2i/ACCi A MPC MPC-3-3 Galectin-3 NASH GLP-1-1(GLP-1)GLP-1 GLP-1 NASH NASH142.1 THR-FGF21 GLP-1 NASH 2024.3.14 III 资料来源：医药魔方，德邦证券研究所 resmetirom THR-Madrigal Pharmaceuticals;Roche;Via Pharmaceuticals cenicriviroc CCR2;CCR5Dong-A Pharma;Tobira Therapeutics(AbbVie);Takeda PharmaceuticalsIII III III efruxifermin FGF21 Akero Therapeutics;Amgen III belapectin galectin-3 Galectin Therapeutics II/III II/III GLP-1R Novo Nordisk III III III III HMG-CoA reductase IZSP1601 PDE;III PPAR PPAR PPAR;Hepalys Pharma;Inventiva III III IIIelafibranor PPAR PPAR Ipsen;Genfit;Terns Pharmaceuticals III III Aramchol SCD1 Galmed Pharmaceuticals II III II SGLT2 Eli Lilly;Boehringer Ingelheim II II SGLT2 AstraZeneca;Bristol-Myers Squibb III not available ServierCA-NASH not available CureApp III azemiglitazone not available Cirius Therapeutics;Metabolic Solutions Development II15 2022-2023 NASH 2022 9 Akero Efruxifermin FGF21 NASH IIb 2022 12 Madrigal Resmetirom THR-NASH III MAESTRO Madrigal 268%40 2023 6 GLP-1 NASH 2023 6 Gastroenterology&Hepatology GLP-1 NASH II 2023 6 MSD efinopegdutide GLP-1/GCGR NAFLD IIa efinopegdutide 2023 6 Retatrutide GIP/GLP-1/GCG NASH Retatrutide NASH 2023 9 13 Madrigal Resmetirom THR-NASH FDA PDUFA 2024 3 14 2024 2 06 SYNERGY-NASH NASH:74%13%2024 3 04 Akero Therapeutics HARMONY 96 IIb efruxifermin(EFX)MASH NASH 2 3 F2-F3 2024 3 14 FDA Resmetirom Rezdiffra FDA NASH 2.2 MASH资料来源：医药魔方公众号，医脉通公众号，CPHI制药在线公众号，德邦证券研究所16 03173.1 NASH Intercept Intercept NASH 2002 OCA X FXR FXR FDA PBC III NASH 2023 6 22 Intercept Pharmaceuticals NASH FDA CRL Intercept NASH 2023 9 26 Intercept Pharmaceuticals Alfasigma Alfasigma 8 Intercept 资料来源：医药魔方公众号，Chemicalbook官网、药时代公众号、同写意公众号、Clinical Trial Landscape in NASH，德邦证券研究所 2015 NASH FDA 2019 Intercept FDA NASH NDA 1 NASH 18 23%1 NASH 12%51%19%LDL-C 17%7%FDA NASH 2022 7 Intercept REGENERATE 22.4%1 NASH 9.6%p0.0001 55%33%24%2023 6 22 Intercept Pharmaceuticals FDA CRL CRL NASH NDA REGENERATE 183.2 THR-Resmetirom:NASH FDA THR-LDL-C THR-NASH THR-THR-MASH TGF-NASH THR-10 3 14 Resmetirom FDA NASH 资料来源：医药魔方，凯莱英药闻，德邦证券研究所 THR-NASH resmetirom THR-Madrigal Pharmaceuticals;Roche;Via Pharmaceuticals ASC41 THR-II II HSK31679 THR-II II TERN-501 THR-Terns Pharmaceuticals II VK2809 THR-Viking Therapeutics;MetabasisTherapeutics(Ligand Pharmaceuticals)II ALG-055009 THR-Aligos Therapeutics I ASC43F FXR;THR-I ECC4703 THR-I Kylo-0603 THR-ASGPR I I RJ4287 THR-I I19 2024 3 14 Madrigal FDA Resmetirom Resmetirom THR-LDL ApoB Resmetirom NASH LDLC Resmetirom F2/F3 47400 MAESTRO-NASH:Resmetirom 资料来源：Madrigal官网材料，德邦证券研究所3.2 Madrigal NASH FDA Resmetirom:NASH FDA203.2 Viking VK2809 THR-THR-Viking VK2809 Metabasis/Viking Therapeutics NASH THR-2b VOYAGE VK2809 12 VK2809 MRI-PDFF 38%55%85%VK2809 30%NASH LDL-C 52 2024H1 资料来源：Viking官网，德邦证券研究所 VOYAGE Study:VK2809 2b VK2809213.3 FGF21 Akero FGF21 FGF FGF FGF 22 22 FGF 7 FGF21 FGF19 FGFR NASH 14 FGF21 FGF21 NASH 资料来源：医药魔方，Mohammad Zarei et al.Targeting FGF21 for the Treatment of Nonalcoholic Steatohepatitis，德邦研究所Akero 89Bio efruxifermin FGF21 Akero Therapeutics;Amgen III pegozafermin FGF21 89Bio;Teva Pharmaceutical III AP025 FGF21-Fc;II II HEC88473 FGF21/GLP-1-Fc()II II LLF580 FGF21 Boston Pharmaceuticals;Novartis II NN9499 FGF21 Novo Nordisk II II fazpilodemab FGF21;anti-KLB/FGFR1 Roche II pegbelfermin FGF21 Ambrx(Johnson&Johnson);Bristol-Myers SquibbII I AP026 FGF21/GLP-1-Fc;I I B1344 FGF21;I BMS-986171 FGF21 Bristol-Myers Squibb I DR10624 GLP-1R;GCGR;FGF21 I I NNC0194-0499+GLP-1R;FGF21 Novo Nordisk I YH25724 GLP-1-Fc;FGF21-Fc Boehringer Ingelheim;Yuhan I 22 Efruxifermin EFX FGF21 FGF21 Fc FGF21 3-4 1 2 1 2018 6 Akero Efruxifermin 1.2 12 8 Akero Efruxifermin NASH/MASH NAFLD/MASLD III NASH III FGF21 Efruxifermin FGF21 Efruxifermin NASH F2-F3 Efruxifermin NASH F4 3.3 Akero:Efruxifermin NASH 2023 10 3 efruxifermin F2 F3 NASH 2b efruxifermin 50 mg 24 NASH 76%P 0.001 24 1 NASH 41%P 0.001 NASH 2023 10 10 Akero Therapeutics FGF21 Efruxifermin NASH F4 2b EFX NASH Resolution 28mg EFX 56mg EFX 1 stage NASH Resolution 9%21%14%Efruxifermin 资料来源：Akero官网、医药魔方、德邦研究所23 3 4 Akero HARMONY 96 IIb efruxifermin(EFX)MASH NASH 2 3 F2-F3 96 24%Efruxifermin 50mg 75%p0.001 28mg 46%p=0.07 24 96 Efruxifermin MASH 50mg Efruxifermin3.3 Akero:Efruxifermin 资料来源：Akero公司官网、医药魔方等，德邦研究所 EFX NASH 1 MASH243.3 Efruxifermin 96 资料来源：Akero公司官网、德邦研究所Efruxifermin=2 NASH=1 NASH 96253.3 89BIO:FGF21 Pegozafermin Pegozafermin NASH SHTG 21 FGF21 Pegozafermin FGF21 FDA NASH(BTD)2023 9 14 Pegozafermin NASH New England Journal of Medicine F2 F3 NASH pegozafermin 15 mg 30 mg 2 44 mg 2 1 NASH NASH Pegozafermin NASH F2-F3资料来源：Rohit Loomba et al.Randomized,Controlled Trial of the FGF21 Analogue Pegozafermin in NASH,药明康德公众号、iNature公众号，德邦研究所 24 1 NASH 7%Pegozafermin 30 mg 26%Pegozafermin 2 44 mg 27%24 NASH 2%Pegozafermin 30 mg 23%Pegozafermin 2 44 mg 26%pegozafermin Pegozafermin 15 mg 22%Pegozafermin 15 mg 37%Pegozafermin 2b FDA BTD26 24 NASH NASH 1 NASH Pegozafermin Pegozafermin 30mg QW 44mg Q2W.2024 2 Pegozafermin NASH 3 F4 F2 F3 3.3 89BIO:FGF21 Pegozafermin Pegozafermin 2b FDA BTD资料来源：89bio公司官网、德邦研究所273.4 GLP-1 MASH&GLP-1 NAFLD T2DM GLP-1 GLP-1 NASH GLP-1 NASH GLP-1 NASH 资料来源：医药魔方，Bifari et al.Multiple target tissue effects of GLP-1 analogues on non-alcoholic fatty liver disease(NAFLD)and non-alcoholic steatohepatitis(NASH)，德邦研究所 GLP-1R Novo Nordisk III GLP-1R Novo Nordisk III III GLP-1;GLP-1R Eli Lilly II II GLP-1R;GIPR Eli Lilly II survodutide GLP-1R;GCGR Boehringer Ingelheim;Zealand Pharma II II cotadutide OXM;GLP-1R;GCGR MedImmune(AstraZeneca)II/III II/III HEC88473 FGF21;GLP-1 II II bamadutide GLP-1R;GCGR Sanofi II efinopegdutide OXM;GLP-1R;GCGRHanmi Pharmaceuticals;Merck&Co.;Johnson&Johnson II II efocipegtrutide GLP-1;GLP-1R;GIP;glucagon;GCGR;GIPRHanmi Pharmaceuticals II pemvidutide GLP-1R;GCGR Altimmune II AZD9550 GLP-1R;GCGR AstraZeneca I/II28资料来源：默沙东公告，药明康德微信公众号，中国医学论坛报今日内分泌公众号，德邦研究所-:2023 6 Gastroenterologv&Hepatology NASH Il 2.4 mq NASH 48,23(49%)30%(13%)Efinopegdutide 2023 6 MSD EASL-1 GLP-1/efinopegdutide NAFLD IIa efinopegdutide GLP-1 Efinopegdutide 24 72.7%42.3%Retatrutide GIP/GLP-1/GCG 98 NAFLD Retatrutide NASH K-18 Pro-C3 8 mg 12 mg 80%8 mg 12 mg 70%80%8 mg 12 mg 48 85%tirzepatide 2024 2 4 GLP-1 tirzepatide MASH 2 tirzepatide 73.9%1 MASH efinopegdutide NASH MAFLD MASH Retatrutide NASH SYNERGY-NASH MASH 3.4 GLP-1 MASH293.5 PPAR PPARs 3 PPARs NASH M1 M2 PPARs NAFLD/NASH NASH PPAR 12 saroglitazar magnesium 2020 3 NASH 资料来源：医药魔方，国际内分泌代谢杂志2022年9月第42卷第5期，德邦证券研究所 PPAR NASH III PPAR PPAR Zydus Lifesciences elafibranor PPAR PPAR Ipsen;Genfit;Terns Pharmaceuticals III PPAR Eli Lilly;Takeda Pharmaceuticals III PPAR PPAR PPAR;Inventiva III III PPAR Kowa II PPAR EPAAmarin;Mochida Pharmaceutical;Neopharm(Insys Therapeutics);II PPAR GSK II PPAR PPAR PPAR II II seladelpar PPAR Johnson&Johnson;Kaken Pharmaceutical;CymaBayTherapeutics II PXL065 PPAR DeuteRx;Poxel II ZSP0678 PPAR I I+SGLT2;PPAR Kowa I 303.5 PPAR NASH Saroglitazar magnesium Zydus Lifesciences PPAR 2013 9 2 2020 1 2 2020 3 NASH NASH 2 EVIDENCES IV 106 saroglitazar magnesium ALT 44.39%MRI-PDFF 16 资料来源：药明康德公众号，GawriehSaroglitazar,a PPAR/Agonist,for Treatment of NAFLD:A Randomized Controlled DoubleBlind Phase 2 Trial，德邦证券研究所313.5 Inventiva PPAR FDA Lanifibranor PPAR Inventiva lanifibranor PPAR 2020 10 lanifibranor FDA NASH/MASH 2024 3 Inventiva PPAR lanifibranor SGLT2 empagliflozin MASH/NASH 2 T2D 2 LEGEND 2022 9 21 Inventiva Inventiva Lanifibranor NASH Inventiva 1200 500 Inventiva 2.9 24 资料来源：医药魔方、药明康德公众号，德邦证券研究所32 04 NASH334.1 NASH NASH 2024.02 ZSP1601 PDE;III PPAR;HepalysPharma;InventivaIII PPAR II HTD1801 bile acid II FAS Sagimet Biosciences;II AP025 FGF21;II ASC41 THR-II HEC88473 FGF21;GLP-1 II HEC96719 FXR II HSK31679 THR-II VSA006-HSD13 II BGT-002 ACL I/II GH509 not available I/II GLP-1R I HPG1860 FXR I TQA3526 FXR;bile acid I ENN0403 not available I GST-HG151 ASK1;I Kylo-0603 THR-ASGPR I RJ4287 THR-I SYHA1805 FXR I TQA3563 caspase I XZP-5610 FXR I ZSP0678 PPAR I 资料来源：医药魔方，德邦证券研究所 GLP-1R Novo Nordisk III SGLT2 AstraZeneca;Bristol-Myers Squibb III cenicrivirocCCR2;CCR5 Dong-A Pharma;Tobira Therapeutics(AbbVie);Takeda PharmaceuticalsIII GLP-1;GLP-1R Eli Lilly II Aramchol SCD1 Galmed Pharmaceuticals II cagrilintide amylin Novo Nordisk II cilofexorFXR Phenex Pharmaceuticals;Gilead Sciences II survodutideGLP-1R;GCGR Boehringer Ingelheim;Zealand Pharma IIAZD2693PNPLA3 Ionis Pharmaceuticals;AstraZeneca II NGM313FGFR1;KLB NGM Biopharmaceuticals;Merck&Co.II NN9499 FGF21 Novo Nordisk II clesacostat ACC Pfizer II efinopegdutideOXM;GLP-1R;GCGR Hanmi Pharmaceuticals;Merck&Co.;Johnson&JohnsonII ervogastat DGAT2 Pfizer II firsocostatACC2;ACC1 Gilead Sciences;Nimbus Therapeutics II licogliflozinSGLT2;SGLT1 Novartis II344.2 4;Inventiva III III AP025 FGF21-Fc;II II TQA3526 FXR;bile acid I I TQA3563 caspase I I WO2021073643 caspase&NASH NASH Inventiva III AP025 II NASH 4 PPAR FGF-21 资料来源：医药魔方，中国生物制药官网，德邦证券研究所35 PPAR NATIVE IIb F1-F3 MASH MASH MASH FDA MASH 2023 3 CDE 7 CDE III F2/F3 MASH Inventiva2024 3 7 III 2024 III MASH 4.2 Lanifibranor NASH NASH 资料来源：中国生物制药官网,Inventiva官网、正大天晴药业集团公众号、德邦证券研究所364.2 4 TQA2225 AP025)21 FGF21 TQA2225 FGF21 TQA2225 FGF21 FGF21 FGF21 FGF21 MASH Akero Efruxifermin IIb FGF21 MASH 2022 4 AP025 AP026 NASH II T2DM TQA2225 II MASH 资料来源：正大天晴公众号，德邦证券研究所374.3 资料来源：歌礼制药官网，德邦证券研究所 2019 NASH FASN FXR384.3 ASC40(FASN):IIb ASC40 Denifanstat TVB-2640 Sagimet FASN Fatty Acid Synthase,FASN,FASN NASH ASC40 NASH 2b FASCINATE-2 NCT04906421 Denifanstat NASH NAS 2 36%13%P=0.002);Denifanstat NAS 2 52%20%P=0.0001 ALT AST PDFF Sagimet 2024 Denifanstat NASH III 资料来源：歌礼制药官网、药渡公众号、医药经济报公众号、德邦证券研究所 ASC40IIb FASCINATE-2 FASN39 ASC41 II ClinicalTrials.gov:NCT05462353 180 NASH 1:1:1 ASC41 2 4 52 4 42 12 ASC41 52 12 ASC41 4mg(NASH)68.2%12 93.3%30%(LDL-C)(TC)(TG)27.7%23.4%46.5%ASC41 ALT AST ASC41 资料来源：歌礼制药官网，德邦证券研究所 ASC41 ASC41(n=14)2(n=13)4(n=15)18.2%17.8%18.9%-13.1%-55.0%(p=0.0001)-68.2%(p 0.0001)-5.8%-48.8%-70.1%30%21.4%92.3%(p=0.0002)93.3%(p 0.0001)MRI-PDFF 12404.4 THR THR-HSK31679 THR-1 2022 1 2023 6 180 HSK31679 NASH 2023 11 2024 1 资料来源：医药魔方，德邦证券研究所 HSK31679 HSK31679 1:HSK31679:80mg:HSK31679 Tablets:80mg 2 160mg:NA:52 1:HSK31679:80mg:HSK31679 placebo:80mg 2:NA:52 II 2023/3/17Active II 2023/4/3Active II 2023/11/9Active41 II III III II 42 2023 2023 S0120523080003 1.6 6 20%5%20%-5%+5%5%2.A 500 10%-10%10%10%43 44 600 N1 9+86 21 68761616+86 21 68767880400-8888-128