慢性乙型肝炎在研抗病毒新药纵览

何寅武; 王建华

doi:10.3969/j.issn.1001-5256.2020.10.031

慢性乙型肝炎在研抗病毒新药纵览

DOI: 10.3969/j.issn.1001-5256.2020.10.031

广州博济医药生物技术股份有限公司

详细信息

中图分类号: R512.62
计量
- 文章访问数: 720
- HTML全文浏览量: 66
- PDF下载量: 237
- 被引次数: 0
出版历程
- 收稿日期: 2020-04-16
- 出版日期: 2020-10-20

An overview of new antiviral drugs under research for chronic hepatitis B

Guangzhou Boji Medical Biotechnology Co.,Ltd.

摘要

摘要: HBV感染引起的慢性乙型肝炎是全球性的公共卫生问题,而实现慢性乙型肝炎的功能性治愈甚至完全治愈一直是药物研发人员追求的目标。目前所广泛使用的核苷(酸)类似物疗法和干扰素疗法的治愈率都不高。对目前在研的病毒进入抑制剂、衣壳抑制剂、HBsAg抑制剂、免疫调节剂以及基因编辑和细胞疗法等多种类型的抗HBV药物/疗法进行了综述,汇总分析了其临床研究结果,以明了该领域研究的最新进展和药物研发的新思路。
- 乙型肝炎,慢性 /
- 分子靶向治疗 /
- 乙型肝炎表面抗原
Abstract: Chronic hepatitis B caused by hepatitis B virus( HBV) infection remains a major public health problem worldwide,and functional cure and even complete cure of chronic hepatitis B are the goals pursued by drug researchers. At present,widely used nucleos( t) ide analogues and interferon therapy fail to achieve a high cure rate. This article reviews the anti-HBV drugs/therapies under research,including viral entry inhibitors,capsid inhibitors,HBsAg inhibitors,immune modulators,gene editing,and cell therapies,and summarizes related clinical research findings,so as to clarify the latest advances in this field and the new ideas in drug research and development.
- hepatitis B,chronic /
- molecular targeted therapy /
- hepatitis B surface antigens

HTML全文

参考文献(47)

[1] SEEGER C,MASON WS. Molecular biology of hepatitis B virus infection[J]. Virology,2015,479-480:672-686.

[2] WANG Z,HUANG Y,WEN S,et al. Hepatitis B virus genotypes and subgenotypes in China[J]. Hepatol Res,2007,37(s1):s36-s41.

[3] FANNING GC,ZOULIM F,HOU J,et al. Therapeutic strategies for hepatitis B virus infection:Towards a cure[J]. Nat Rev Drug Discov,2019,18(11):827-844.

[4] HOU JL,XU D,SHI G,et al. Long-term telbivudine treatment results in resolution of liver inflammation and fibrosis in patients with chronic hepatitis B[J]. Adv Ther,2015,32(8):727-741.

[5] DEGASPERI E,VIGANO M,AGHEMO A,et al. PegIFN-α2a for the treatment of chronic hepatitis B and C:A 10-year history[J]. Expert Rev Anti Infect Ther,2013,11(5):459-474.

[6] VOLZ T,ALLWEISS L,BEN MBAREK M,et al. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus[J]. J Hepatol,2013,58(5):861-867.

[7] WEDEMEYER H,SCHONEWEIS K,BOGOMOLOV PO,et al.GS-13-Final results of a multicenter,open-label phase 2clinical trial(MYR203)to assess safety and efficacy of myrcludex B in cwith PEG-interferon Alpha 2a in patients with chronic HBV/HDV co-infection[J]. J Hepatol,2019,70(1):e81.

[8] SHIMURA S,WATASHI K,FUKANO K,et al. Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity[J]. J Hepatol,2017,66(4):685-692.

[9] GALLAY P,URE D,BOBARDT M,et al. The cyclophilin inhibitor CRV431 inhibits liver HBV DNA and HBs Ag in transgenic mice[J]. PLo S One,2019,14(6):e0217433.

[10] KUO J,BOBARDT M,CHATTERJI U,et al. A pan-cyclophilin inhibitor,CRV431,decreases fibrosis and tumor development in chronic liver disease models[J]. J Pharmacol Exp Ther,2019,371(2):231-241.

[11] China pharmaceutical Innovation Promotion Association,The world’s first release of 9 blockbuster new drugs domestic and foreign clinical research data stunningly unveiled[EB/OL]. http://www. phirda. com/artilce-8439. html? cld=8436.[2017-11-02].(in Chinese)中国医药创新促进会．全球首发9个重磅新药国内外临床研究数据惊艳亮相[EB/OL]. http://www. phirda. com/artilce_8439. html? cId=8436.[2017-11-02].

[12] REN Q,LIU X,LUO Z,et al. Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate(GLS4)[J]. Bioorg Med Chem,2017,25(3):1042-1056.

[13] ZHANG H,NIU JQ,DING HY,et al. Analysis of factors influencing the efficacy and safety of GLS4 treatment in patients with chronic hepatitis B[J]. Hepatology,2019,70(s1):688.

[14] BERKE JM,DEHERTOGH P,VERGAUWEN K,et al. Antiviral properties and mechanism of action studies of the hepatitis B virus capsid assembly modulator JNJ-56136379[J]. Antimicrob Agents Chemother,2020.[Online ahead of print]

[15] ZOULIM F,YOGARATNAM JZ,VANDENBOSSCHE JJ,et al. Safety,pharmacokinetics and antiviral activity of novel HBV capsid assembly modulator,JNJ-56136379,in patients with chronic hepatitis B[J]. Hepatology,2018,68(s1):74.

[16] GANE E,SCHWABE C,LENZ O,et al. JNJ-64530440(JNJ-0440),A novel,class N capsid assembly modulator(CAM-N):Safety,tolerability,pharmacokinetics and antiviral activity of multiple ascending doses in patients with chronic hepatitis B[J]. Hepatology,2019,70(s1):89.

[17] GANE E,LIU A,YUEN MF,et al. RO7049389,a core protein allosteric modulator,demonstrates robust anti-HBV activity in chronic hepatitis B patients and is safe and well tolerated[J].J Hepatol,2018,68:s101.

[18] GANE E,YUEN MF,BO Q,et al. FRI-219-RO7049389,a core protein allosteric modulator,demonstrates robust decline in HBV DNA and HBV RNA in chronic HBV infected patients[J]. J Hepatol,2019,70(1):e491.

[19] YUEN MF,AGARWAL K,GANE EJ,et al. Safety,pharmacokinetics,and antiviral effects of ABI-H0731,a hepatitis B virus core inhibitor:A randomised,placebo-controlled phase 1 trial[J]. Lancet Gastroenterol Hepatol,2020,5(2):152-166.

[20] MA X,LALEZARI J,NGUYEN T,et al. LBO-06-Interim safety and efficacy results of the ABI-H0731 phase 2a program exploring the combination of ABI-H0731 with Nuc therapy in treatment-naive and treatment-suppressed chronic hepatitis B patients[J]. J Hepatol,2019,70(1):e130.

[21] SULKOWSKI MS,AGARWAL K,FUNG S,et al. Continued therapy with ABI-H0731+Nrt I results in sequential reduction/loss of HBV DNA,HBV RNA,HBe Ag,HBcrAg and HBs Ag in HBe Ag-positive patients[EB/OL]. AASLD,Boston,USA,November 8-12,2019:Poster LP1. https://investor.assemblybio. com/static-files/97f173d3-6aad-4f9c-bcfc-82cc80a9ead7.

[22] YUEN MF,AGARWAL K,GANE E,et al. The second-generation hepatitis B virus(HBV)core inhibitor(CI)ABI-H2158is associated with potent antiviral activity in a 14-day monotherapy study in HBe Ag-positive patients with chronic hepatitis B(CHB)[EB/OL]. AASLD,Boston,USA,November 8-12,2019:Poster LP14. https://investor. assemblybio. com/static-files/5b2547c8-53b1-4666-aaf5-ace722e3983e.

[23] HUANG Q,SIMON H,ZHOU Y,et al. PS-073-Preclinical profile of HBV core protein inhibitor,ABI-H3733,a potent inhibitor of cccDNA generation in HBV infected cells[J]. J Hepatol,2019,70(1):e48.

[24] CARTHEW RW,SONTHEIMER EJ. Origins and mechanisms of miRNAs and siRNAs[J]. Cell,2009,136(4):642-655.

[25] CROOKE ST,WITZTUM JL,BENNETT CF,et al. RNA-targeted therapeutics[J]. Cell Metab,2018,27(4):714-739.

[26] NIKAM RR,GORE KR. Journey of siRNA:Clinical developments and targeted delivery[J]. Nucleic Acid Ther,2018,28(4):209-224.

[27] GANE E,LOCARNINI S,LIM TH,et al. Dose response with the RNA interference therapy JNJ-3989 combined with nucleos(t)ide analogue treatment in expanded cohorts of patients with chronic hepatitis B[EB/OL]. AASLD,Boston,USA,November 8-11,2019. https://ir. arrowheadpharma. com/static-files/66178cc7-10ce-4db2-8400-1c0495271e35.

[28] YUEN MF,LOCARNINI S,GIVEN B,et al. First clinical experience with RNA interference-based triple combination therapy in chronic hepatitis B:JNJ-3989,JNJ-6379 and a nucleos(t)ide analogue[EB/OL]. AASLD,Boston,USA,November8-11,2019. https://ir. arrowheadpharma. com/static-files/6d7edbe7-c5a2-46c5-9990-a9cdfec854a9.

[29] HAN K,CREMER J,ELSTON R,et al. A randomized,double-blind,placebo-controlled,first-time-in-human study to assess the safety,tolerability,and pharmacokinetics of single and multiple ascending doses of GSK3389404 in healthy subjects[J]. Clin Pharmacol Drug Dev,2019,8(6):790-801.

[30] YUEN MF,HEO J,JANG JW,et al. Phase 2a,randomized,double-blind,placebo-controlled study of an antisense inhibitor(ISIS 505358)in treatment-nave chronic hepatitis B(CHB)patients:Safety and antiviral efficacy[EB/OL].AASLD,Boston, USA, November 8-12,2019. https://www. natap. org/2019/AASLD/AASLD_34. htm.

[31] YUEN MF,HEO J,KUMADA H,et al. Results after 12 weeks treatment of multiple doses of GSK3389404 in chronic hepatitis B subjects on stable nucleos(t)ide therapy in a phase 2a double-blind,placebo-controlled study[EB/OL]. AASLD,Boston,USA,November 8-12,2019. https://www. natap.org/2019/AASLD/AASLD_33. htm.

[32] ROCHE. Roche to acquire Santaris Pharma to expand discovery and development of RNA-targeting medicines[EB/OL].[2014-08-04]. https://www. roche. com/media/releases/med-cor-2014-08-04. htm.

[33] HAN X,ZHOU C,JIANG M,et al. Discovery of RG7834:The first-in-class selective and orally available small molecule hepatitis B virus expression inhibitor with novel mechanism of action[J]. J Med Chem,2018,61(23):10619-10634.

[34] VAILLANT A. REP 2139:Antiviral mechanisms and applications in achieving functional control of HBV and HDV infection[J]. ACS Infect Dis,2019,5(5):675-687.

[35] ROEHL I,SEIFFERT S,BRIKH C,et al. Nucleic acid polymers with accelerated plasma and tissue clearance for chronic hepatitis B therapy[J]. Mol Ther Nucleic Acids,2017,8:1-12.

[36] BAZINET M,PANTEA V,PLACINTA G,et al. Safety and efficacy of 48 weeks REP 2139 or REP 2165,tenofovir disoproxil,and pegylated interferon alfa-2a in patients with chronic HBV infection nave to nucleos(t)ide therapy[J]. Gastroenterology,2020.[Oline ahead of print]

[37] BAZINET M,PANTEA V,PLACINTA G,et al. Achieving functional cure of HBV and HBV/HDV co-infection with REP2139:Completed follow-up in the REP 401 and REP 301-LTF studies[EB/OL]. HepDART,Kauai,Hawaii,USA,December 8-12,2019. http://replicor. com/wp-content/uploads/2019/12/Replicor-REP-401-301-LTF-Completefollow-up-poster-P15-HEPDART-2019-FINAL. pdf

[38] GANE EJ,LIM YS,GORDON SC,et al. The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection[J]. J Hepatol,2015,63(2):320-328.

[39] AGARWAL K,AHN SH,ELKHASHAB M,et al. Safety and efficacy of vesatolimod(GS-9620)in patients with chronic hepatitis B who are not currently on antiviral treatment[J]. J Viral Hepat,2018,25(11):1331-1340.

[40] LI C,HERSCHKE F,CREUS AD,et al. P1-015:Oral administration of JNJ-4964(AL-034/TQ-A3334),a selective toll-like receptor 7 agonist,in AAV/HBV mice for 12 weeks,resulted in potent and sustained anti-HBV activity with HBs Ag seroconversion and detectable HBs Ag-specific T cells and B cells[J]. J Viral Hepat,2018,25(s2):40.

[41] GANE E,PASTAGIA M,CREUS AD,et al. FRI-198-A Phase,double-blind,randomized,placebo-controlled,first-in-human study of the safety,tolerability,pharmacokinetics and pharmacodynamics of oral JNJ-64794964,a tolllike receptor-7 agonist,in healthy adults[J]. J Hepatol,2019,70(1):e478.

[42] GANE E,ZHAO Y,TAN SK,et al. Efficacy and safety of oral TLR8 agonist selgantolimod in virally suppressed adult patients with chronic hepatitis B:A phase 2,randomized,doubleblind, placebo-controlled, multicenter study[EB/OL].AASLD, Boston, USA, November 8-12,2019. https://www. natap. org/2019/AASLD/AASLD_79. htm

[43] GILMORE S,TAM D,DICK R,et al. Antiviral activity of GS-5801,a liver-targeted prodrug of a lysine demethylase 5 inhibitor,in a hepatitis B virus primary human hepatocyte infection model[J]. J Hepatol,2017,66(1):s690-s691.

[44] LIU H,HOU J,ZHANG X. Targeting cIAPs,a new option for functional cure of chronic hepatitis B infection?[J]. Virol Sin,2018,33(5):459-461.

[45] ERKEN R,STELMA F,ROY E,et al. First clinical evaluation in chronic hepatitis B patients of the synthetic farnesoid X receptor agonist EYP001[J]. J Hepatol,2018,68(s1):s488-s489.

[46] BLOOM K,MAEPA MB,ELY A,et al. Gene therapy for chronic HBV-Can we eliminate cccDNA?[J]. Genes(Basel),2018,9(4):e207.

[47] BERTOLETTI A,TAN AT,KOH S. T-cell therapy for chronic viral hepatitis[J]. Cytotherapy,2017,19(11):1317-1324.

施引文献

资源附件(0)

访问统计