AASLD2014:NVR3-778 HBV核心抑制剂Phase1a安全性和药代动力学

StephenW

Final ID: LB-19 Phase1a Safety and Pharmacokinetics of NVR3-778, a Potential First-In-Class HBV Core Inhibitor
E. J. Gane;1, 2;
C. Schwabe;2;
K. Walker;2;
L. Flores;3;
G. D. Hartman;3;
K. Klumpp;3;
S. Liaw;3;
N. A.Brown;3;
1. New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
2. Clinical Trials Unit, Auckland Clinical Studies, Auckland, New Zealand.
3. Pharmacology, Novira Therapeutics, Doylestown, PA, United States.
Abstract Body:
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 1a dose-ranging study of NVR3-778, 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, 95% male). Initially, sequential 8-subject cohorts received single 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 generally 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 90% 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 well 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.

StephenW

FinalID：NVR3-778一个潜在的先入级HBV核心抑制剂LB-19 Phase1a安全性和药代动力学
E. J.甘恩;1，2;
C.施瓦布; 2;
K.沃克尔; 2;
L.弗洛雷斯; 3;
G. D.哈特曼; 3;
K. KLUMPP; 3;
廖学3;
北A.Brown; 3;
1，新西兰肝脏移植单位，奥克兰市医院，奥克兰，新西兰。
2，临床试验单位，奥克兰的临床研究中，新西兰的奥克兰。
3，药理学，Novira治疗，多伊尔斯敦，宾夕法尼亚州，美国。
AbstractBody：
背景：慢性乙型肝炎（CHB）保持肝脏相关死亡的首要原因。虽然口服核苷（酸）IDE疗法可预防肝脏疾病的进展，终身管理是必需的。由于乙肝病毒核心（衣壳）蛋白在病毒复制和持久性的多重作用，乙肝病毒核心抑制剂具有抑制乙型肝炎病毒DNA的复制，病毒装配，补给的cccDNA，肝再感染周期，以提高持久应答率的潜力。 NVR3-778是一个HBV核心抑制剂在体外类似于烈性核苷（酸）的IDE抗HBV活性。我们报告NVR的先入人1a期剂量范围研究
3-778，在2014年七月完成。
方法：NVR3-778的安全性和药代动力学（PK）的40名成年志愿者进行了评估，年龄18〜65（88％白人，
95％为男性）。起初，顺序8受试者队列接收到的单次口服剂量的NVR3-778（50，150，400，或800毫克）。在每一个世代的受试者被随机分配到主动的NVR3-778胶囊（6例）或安慰剂（2例）。
宽容是令人满意的所有单剂量同伙，所以最后的8如有多人的队列接受200毫克每日一次连续14天。安全性评价包括不良事件（AE），体检和安全相关的临床实验室
（血液学，血清化学，尿液分析）。密集的等离子抽样进行PK进行了评估。
结果：NVR3-778的公差是令人满意的所有剂量的同伙。牛逼
这里没有严重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。有相关活动的研究药物治疗组比安慰剂组的不良事件或实验室异常没有明显的图案，以及相关研究药物剂量或用药时间的不良事件或实验室异常没有图案（14天比1天）。临床不良事件一般是轻度（1级），除22级不良事件被认为无关的研究药物。实验室异常频繁，短暂的，轻度（1级），并认为不相关的研究药物。 PK的结果表明，大量的剂量相关的系统性风险（Cmax分别，AUC）与NVR3-778口服给药。剂量≥200毫克产生峰和24小时波谷NVR在细胞培养物的50％和90％的HBV抑制浓度为NVR3-778以上是多方面的3-778浓度。
结论：
NVR3-778可以是第一HBV核心抑制剂在临床试验来推进。 NVR3-778口服给药耐受性良好，在所有剂量水平（50-800毫克）。 PK的结果表明，剂量≥200毫克可负担得起的NVR3-778浓度足以使长期抑制HBV的慢性乙型肝炎患者的QD剂量。 NVR3-778已经提前进入中乙肝患者1b期试验。

别愁

不知中国的甲磺酸莫非赛定进入几期了，情况如何，知道的说一下吧。

newchinabok

回复 别愁 的帖子

前些时问了302医院，二期a阶段，二期a已做完，在数据评估阶段，12月份没消息，我会再打电话302医院

别愁

回复 newchinabok 的帖子

谢啦！

newchinabok

回复 StephenW 的帖子

NVR3-778和nvr1221是一回事吗

StephenW

回复 newchinabok 的帖子

是的.