慢性乙型肝炎（CHB）仍是导致肝脏相关性死亡的首要原因。虽然口服核苷（酸）疗法可预防肝脏疾病的进展，但需要终身服药。由于HBV核心（衣壳）蛋白在病毒复制和持久性的多重作用，HBV核心蛋白抑制剂通过抑制HBV DNA复制、病毒组装、补充cccDNA和肝脏再感染循环，具有提高持久应答率的潜力。 NVR3-778是一种HBV核心蛋白抑制剂，在体外抗HBV活性类似于强效核苷（酸）。我们报告了NVR3-778的剂量范围首次临床Ia期研究，完成于2014年7月。
研究方法
评估40名成年志愿者的NVR3-778安全性和药代动力学（PK），年龄在18-65岁（88％为白人，男性）。开始时，连续8个受试者队列接受单一口服剂量的NVR3-778（50，150，400或800mg）。在每个队列中受试者被随机分为主动NVR3-778胶囊组（6例）或安慰剂组（2例）。所有单一剂量队列的耐受性令人满意，所以最后8个受试者多剂量队列接受每日一次200 mg 14天。安全性评价包括不良事件（AES）、体格检查和与安全性有关的临床实验室（血液学、血清化学和尿液分析）。分析浓缩血浆样品进行PK评估。
研究结果
所有剂量队列的NVR3778耐受性令人满意。没有危急或严重的临床不良事件;所有受试者完成了他们的研究剂量和研究评估。没有明显的与主动研究药物治疗和安慰剂相关的AES或实验室检查结果异常，没有与研究药物剂量或治疗时间（14天和1天）相关的AES或实验室检查结果异常。临床AES一般为轻度（1级），除了2例考虑与研究药物无关的2级AES。实验室结果异常少见、短暂性、轻度（1级），并考虑与研究药物无关。PK结果显示NVR3-778口服剂量的大剂量相关性全身性暴露（C max，AUC）。200mg剂量时达到最大值， NVR3-778的24-hr最低浓度超过50％，高于细胞培养时NVR3-778的HBV抑制浓度。
结论
NVR3-778可能是临床试验最先进的首个HBV核心蛋白抑制剂。 NVR3-778口服给药在所有剂量水平（50-800mg）耐受性均良好。 PK结果表明，每日一次200mg剂量可提供足够的NVR3-778浓度来延长CHB患者的HBV抑制。 NVR3-778目前已经进展到HBV患者的1b期试验。
英文原文
Phase 1a Safty and Parmacokinetics of NVR 3-778, a Potential First-ln-Class HBV Core Inhibitor
Author: E.J.Gane,C.Schwabe;K.Walker;L.Flores;G.D.Hartman;K.Klumpp;S.Liaw;N.A.Brown;
Background: Chronic hepatitis B (CHB) remains a leading cause of liver-related mortality. Although oral nucleos(t)ide therapy may prevent liver disease progression, lifelong administration is required. Due to multiple roles of the HBV core (capsid) protein in HBV replication and persistence, HBV core inhibitors have the potential to boost durable response rates by inhibiting HBV DNA replication, viral assembly, cccDNA replenishment and hepatic reinfection cycles. NVR 3-778 is an HBV core inhibitor with in vitro anti-HBV activity similar to potent nucleos(t)ides. We report the first-in-human Phase la dose-ranging study of NVR 3-778, completed in July 2014.
Methods: The safety and pharmacokinetics (PK) of NVR 3-778 were assessed in 40 adult volunteers, ages 18-65 (88% Caucasian, male). Initially, sequential 8-subject cohorts received sing e oral doses of NVR 3-778 (50, 150, 400, or 800 mg). Within each cohort the subjects were randomized to active NVR 3-778 capsules (6 subjects) or placebo (2 subjects). Tolerance was satisfactory for all single-dose cohorts, so a final 8-subject multidose cohort received 200 mg QD for 14 days. Safety evaluations included adverse events (AES), physical examinations, and safety related clinical labs (hematology, serum chemistries, urinalyses). Intensive plasma sampling was conducted for PK assessments.
Results: Tolerance of NVR 3 778 was satisfactory for all dose cohorts. There were no serious or severe clinical AEs; all subjects completed their study dosing and study evaluations. There was no apparent pattern of AES or lab abnormalities related to active study drug treatment vs placebo, and no pattern of AES or lab abnormalities related to study drug dose or treatment duration (14 days vs 1 day).Clinical AES were general y mild (grade 1) except for 2 grade 2 AES considered unrelated to study drug. Laboratory abnormalities were infrequent, transient, mild (Grade 1), and considered unrelated to study drug. The PK results indicated substantial dose-related systemic exposures (Cmax, AUC) with oral dosing of NVR 3 778. Doses 200 mg produced peak and 24-hr trough NVR 3-778 concentrations that were multifold above the 50% and HBV inhibitory concentrations for NVR 3-778 in cell Culture.
Conclusions: NVR 3-778 may be the first HBV core inhibitor to advance in clinical testing. NVR 3-778 oral dosing was we I tolerated at all dose levels (50-800 mg). PK results indicate that doses 200 mg may afford NVR 3-778 concentrations sufficient for prolonged HBV inhibition in CHB patients with QD dosing. NVR 3-778 has now advanced into Phase 1b testing in HBV patients.
