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本帖最后由 肝胆速递 于 2012-10-5 15:26 编辑
消息来源：2012 AASLD
Myrcludex to be presented at AASLD in Nov 2012
新型HBV和HDV进入抑制剂Myrcludex首次人体药物安全试验成功
Successful first administration of Myrcludex B, a first-in-class Hepatitis B and D Virus entry inhibitor, in humans
肝胆速递：只是表明，该药物在人体内是初步安全的，后面还有很长的临床实验要完成。
摘要：
目前抗乙肝和丁肝感染治疗手段有限且不能治愈，需要发展新的干扰病毒复制的其他过程。Myrcludex B是H一个脂肽，源自HBV膜蛋白，能特异性使分化的肝细胞上HBV/HDV受体失活。Myrcludex B在动物模型上对HBV和HDV非常有效，成功完成临床前研究，是新型HBV和HDV的进入抑制剂。我们进行了一个前瞻性、公开的、非随即控制的健康志愿者Phase 0/1临床研究，用来判断其安全性、耐受性、药代动力学和免疫原性。
方法：
Myrcludex B静脉注射单次给药(0.3, 3, 10, 100, 800, 3000, 和5000 µg)或者800ug皮下注射到3组人群，检测28天。给药剂量从小剂量开始，通过安全性评估和实验室、临床分析后给药剂量逐次升高。血液中药物浓度通过HPLC-MS测定72小时后重复样品确定，药代动力学参数通过二室模型计算，免疫原性通过放射免疫测定。
结果：
24位受试者记录了53例副作用反映，但都不严重。所有副作用反映均为短暂的，恢复不留后遗症，和药物作用方式没有病理生理的联系，表现出剂量非依赖，未涉及肝脏的副反应。3mg以内药物的药物动力学是呈线性关系，当使用5mg时，血液内药物浓度大幅上升，药物清除速度降低，显示药物在肝内已饱和。该结果和其他动物实验一致，如猩猩。对药物的抗体未检测到。
结论：
Myrcludex B在健康志愿者耐受很好（最高可5mg静脉注射或者0.8mg皮下注射），药物动力学和动物实验相符，为人体连续给药实验打下基础。
ABSTRACT BODY: Background and aims: Current antiviral therapies for
chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) infections
are limited and mostly non-curative. This requires the development of
novel strategies interfering with hitherto unaddressed steps of virus
replication. Myrcludex B an HBV envelope-protein derived lipopeptide
specifically inactivates an essential HBV/HDV-receptor on
differentiated hepatocytes. Myrcludex B is highly effective against
HBV and HDV in animal models, has successfully passed preclinical
studies and represents the first-in-class entry inhibitor for HBV/HDV
infection. We have conducted a prospective, open-label,
non-randomized, non-controlled Phase 0/1 clinical study to evaluate
safety, tolerability, pharmacokinetics (PK), and immunogenicity of
single ascending doses of Myrcludex B in healthy volunteers.
Methods: Single doses of Myrcludex B (0.3, 3, 10, 100, 800, 3000, and
5000 µg) were administered IV or SC (800 µg) to cohorts of 3
participants, followed up for 28 days. Dose escalation to the
subsequent higher dose was performed after positive safety evaluation
of comprehensive clinical and laboratory data by an independent Data
Safety Monitoring Board. Plasma concentrations were determined by
HPLC-MS from repeated samples collected up to 72h after dosing and PK
parameters were calculated using a two-compartment model.
Immunogenicity was studied by RIA.
Results: 24 participants were exposed and 53 adverse events were
recorded (none was serious). All events were transient, recovered
without sequelae, did not show a pathophysiological relation to the
study drug’s mode of action, and appeared dose-independent. No signs
of liver involvement were detected. PK in humans was linear up to the
dose of 3 mg. At dose exposures of 5 mg, markedly increased plasma
concentrations and decreased clearance were observed possibly
indicating saturation of the central compartment (liver). This result
was consistent with in vivo studies in different species, including
chimpanzee. No anti-drug antibodies (ADA) were detected.
Conclusion: Myrcludex B was very well tolerated in healthy volunteers
for all investigated doses for up to 5 mg IV and 0.8 mg SC. The PK
profile is in line with the expectations based on animal studies.
Continuation to multiple dose human studies is encouraged by these
results.
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发表于 2012-10-2 23:44
