目前慢性乙型肝炎的治疗很少能够治愈。此外，对于大多数丁型肝炎患者没有可用的有效治疗方法。Myrcludex B是一种许可的新型抑制剂，灭活HBV/ HDV受体NTCP，从而解决了根治疗法需要的可能复制步骤。我们在这里展示Myrcludex B治疗慢性乙肝和丁肝的首次临床试验的研究结果。研究旨在评估Myrcludex B的安全性和耐受性，以及抗病毒疗效。研究结果将在第65届美国肝病协会年会（AASLD）上公布。
研究方法
队列A：40例慢性HBV感染、HBeAg阴性患者（所有HBV DNA>2000 IU/ ml，平均HBV DNA为4.7log10 IU/ml；无肝硬化）每日服用一次Myrcludex B sc 0.5mg、 1mg、 2mg、 5mg 和 10mg 治疗12周（每种剂量8例患者）。接受10mg治疗的患者治疗延长至24周。队列B：24例丁型肝炎患者（代偿期肝病；12.5％为肝硬化）接受聚乙二醇化干扰素α（PEG-IFNα）治疗48周。 8例丁型肝炎患者在治疗前单独接受2mg Myrcludex B治疗24周（B1）; 另外8例患者在第一个24周时加入Myrcludex B（PEG-IFNα）治疗（B2）；剩下的8例患者只接受PEG-IFNα治疗（B3）。
研究结果
Myrcludex B有很好的耐受性，3例Myrcludex B治疗患者(10mg组)发生注射侧皮炎，治疗后消失。1例HDV患者（B2）出现银屑病恶化，导致中止服药。观察到8例接受10mg Myrcludex B治疗的患者中有6例（75％）在第12周出现HBV DNA下降>1log10，而其他剂量组中不经常发生（7/40;17％）。 40例患者中有22例（55％）ALT恢复正常，平均ALT值从治疗前的76 76 U/l下降至12周时的36 U/l（P <0.001）。HBsAg水平没有显著性变化。对于丁型肝炎，可获得数据的Myrcludex B 单一治疗组(B1)7例患者中有6例、 联合治疗组(B2)7例患者中有7例24周时HDV RNA下降>1log10，B3患者在第12周时7例中有7例出现这种反应。24周时2例（B1）患者和5例（B2）患者的HDV RNA转阴。在24周时ALT值下降， B1组为6/7，B2为4/7，B3为3/7（第12周）。B1中1例患者、B2中1例患者在24周时 HDV RNA转阴，ALT恢复正常。1例（B2）患者在第24周时出现HBsAg下降1log10。Myrcludex B治疗在>1mg剂量时诱导前S特异性抗体和胆汁酸升高。
结论
对于有或无HDV合并感染的HBsAg阳性患者，Myrcludex B是安全的，耐受性好。乙肝病毒进入抑制似乎与HBV DNA和HDV RNA下降以及生化疾病活动改善有相关性。
英文原文
A proof-of-concept Phase 2a clinical trial with HBV/HDV entry inhibitor Myrcludex B
Authors:S.Urban;P.Bogomolov;N.Voronkova;L.Allweiss;M.Dandri;M.Schwab;F.A.Lempp;M.Haag;H.Wedemeyer; A.Alexandrov
Introduction: Current therapies for chronic hepatitis B rarely induce cure. Moreover, no effective treatment for the majority of hepatitis D patients is available. Myrcludex B is a first-in-class entry inhibitor inactivating the HBV/HDV receptor NTCP, thereby addressing a replication step possibly required for curative therapy. We here present findings of the first clinical trials of Myrcludex B in chronic hepatitis B and D.
Aim: To evaluate safety and tolerability, as well as antiviral efficacy of Myrcludex B.
Methodology: Cohort A: 40 chronically HBV infected, HBeAg negative patients (all HBV DNA >2000 IU/ml median HBV DNA 4.7 log10 IU/ml; no cirrhosis) were treated for 12 weeks with once daily sc 0.5mg, 1mg, 2mg, 5mg and 10mg Myrcludex B for 12 weeks (8 patients per dose). Treatment was extended to 24 weeks in patients receiving 10mg. Cohort B: 24 patients with hepatitis delta (compensated liver disease; 12.5% cirrhosis) scheduled for 48 weeks of pegylated interferon alpha (PEG-IFNα) therapy. 8 hepatitis delta patients are receiving pre-treatment with 2mg Myrcludex B alone for 24 weeks (B1); Myrcludex B was added to (PEG-IFNa) for the first 24 weeks to another 8 patients (B2) while 8 patients are treated with PEG-IFNa alone (B3).
Results: Myrcludex B was very well tolerated, injection side dermatitis occurred in 3 patients (10mg group) of Myrcludex B, regressed on treatment. A psoriasis exacerbation occurred in one HDV patient (B2) leading to discontinuation.>1log10 HBV DNA decline at week 12 was observed in 6/8 (75%) patients receiving 10mg Myrcludex B while this occurred less often in the remaining dose groups (7/40; 17%). ALT normalized in 22/40 (55%) patients, median ALT values declined from 76 U/l before therapy to 36 U/l at week 12 (p<0.001). No significant changes in HBsAg levels occurred. In hepatitis delta, 6/7 and 7/7 of patients with data available experienced >1log10 HDV RNA decline at week 24 during Myrcludex B monotherapy (B1) or combination therapy (B2) while this response was observed in 7/7 of B3 patients at week 12. HDV RNA became negative in 2 (B1) and 5 (B2) patients at week 24. ALT values declined at week 24 in 6/7 (B1), 4/7 (B2) and 3/7 (B3, week 12) patients. One patient in B1 and one in B2 had negative HDV RNA and normal ALT at week 24. One patient (B2) experienced 1log10 HBsAg decline at week 24. Myrcludex B treatment induced preS-specific antibodies and bile acid elevation at doses >1mg.
Conclusion: Myrcludex B is safe and well tolerated in HBsAg positive patients with or without HDV coinfection. HBV entry inhibition seems to be associated HBV DNA and HDV RNA declines and improvement of biochemical disease activity.
