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发表于 2004-11-18 13:21
| LB80380 一种新药(AASLD Nov. 2004)
LB80380, new HBV Drug Reported by Jules Levin "Phase I/II Double-Blind, randomized, placebo-Controlled Trial of a Novel Agent LB80380/ANA380 in patients with Chronic HBV Infection" Man-fung Yuen reported these results in an oral hepatitis B session at AASLD (Oct 29-Nov 2, 2004). Yuen provided this background----Desirable properties for HBV drugs: potent activity against HBV including resistant strains; high barrier to viral resistance; minimum side effect profile; minimum side effect/toxicity; long half-life to allow at least once daily dosing. LB80380/ANA380, an ester prodrug of phosphonate nucleoside analogue of guanosine monophosphate, has potent activity against HBV. The drug is designed to overcame problems of currently approved HBV drugs such as resistance to lamivudine and concerns of renal toxicity of adefovir dipivoxil. LB80380/ANA380 is an orally available drug that is converted after dosing to LB80331 and subsequently to LB80317, a novel guanosine phosphonate nucleotide analogue that exhibits activity against HBV in vitro, including HBV variants resistant to LB80380, new HBV Drug, 由Jules Levin报道，“一种新型药物，LB80380/ANA380，的1/2期双盲，随机，安慰剂对照实验，用于慢性HBV感染”，Man-fung Yuen 在AASLD (Oct 29-Nov 2, 2004)报告了这种口服HBV药物实验结果。Yuen提供了这些背景——理想的HBV药物特征: 有力的抗HBV活性，包括耐药株病毒；高病毒耐药屏障；最小副作用；最小毒性；长半衰期，可以每天一次服用。 LB80380/ANA380，一种膦酸酯类药物前体，核苷类似物，鸟嘌呤核苷单磷酸盐，有很强的抗HBV活性。该药物设计用来战胜目前已批准的药物存在的问题，比如拉米夫定的耐药性，阿地福为的肾毒性。LB80380/ANA380是种口服药物，由LB80331/ LB80317转换而来。LB80331/ LB80317都是新型的鸟嘌呤核苷单磷酸盐类型的核苷类似物，在实验室中表现出抗HBV活性，包括拉米耐药株。 lamivudine. The compound has a favourable toxicity profile in vitro, including low potential for renal toxicity. Animal toxicology studies confirmed the favourable tolerability of LB80380/ANA380, and studies in woodchucks showed reductions in serum viral titre greater than six log after four weeks of dosing. Phase I studies in healthy volunteers demonstrated good safety, tolerability, and pharmacokinetics consistent with once daily dosing. We report the final study results of a Phase I/II study designed to assess the safety, pharmacokinetics, and antiviral activity of LB80380/ANA380 in HBeAg positive, HBV DNA positive patients. PRECLINICAL DATA In vitro antiviral activity against wild-type & YMDD mutants EC50 (uM) AdefovirLB80317Wild-type 1.3 0.5rtM204I 2.5 1.0rtM204V 1.5 5.4rtL180M/M204I 1.2 1.5rtL180M/M204V 2.0 2.0 This study was a double-blind, randomised, 该化合物在实验室有很好的毒性特征，包括低的潜在的肾毒性。动物毒型研究证实LB80380/ANA380很好的毒理，旱獭研究表明，用药4周，血清病毒滴度减少超过6个数量级。1期临床研究，健康志愿者显示好的安全性，耐受性，药物代谢动力学支持每天1次服药。我们报告1/2期临床最终研究结果，用来评估LB80380/ANA380安全性，药物代谢动力学，对HbeAg阳性，HBV DNA阳性患者的抗病毒活性。 实验室中的临床前数据，对抗野生株，YMDD变异株 placebo-controlled, multiple ascending dose evaluation of LB80380/ANA380 dosed once daily for 28 days at 30mg, 60mg, 120mg, and 240 mg. Cohorts of seven patients were randomised (6:1 active: placebo) at each dose level, and safety was established at each dose prior to dose escalation. Patients were followed for 12 weeks after completing the dosing phase. The median age and male: female ratio was 27.5 years and 20:8 respectively. Serum HBV levels at screening ranged from 1x107 to 5x109 (Amplicor HBV Monitor Assay), serum HBV DNA 8.1 to 9.1 log copies/ml. ALT <5 x ULN, serum ALT 25-80 IU/mL. All patients 有安慰剂对照的，多种剂量的LB80380/ANA380评估，28天每天服药1次，药量30mg,60mg,120mg,240mg. 其中7组患者（药物：安慰剂 6：1）随机分为不同药量，随药物剂量增大，安全性得到确认。患者完成服药阶段后还要继续跟踪12周。中值年龄27.5岁，性别比男女20：8。血清HBV水平从1X10的7次方，到5X10的9次方（扩增法测试），血清HBVDNA8.1到9.1个数量级，ALT在正常值5倍以下，血清ALT25~80 IU/mL。所有患者都是亚洲人。所有都是HBsAg & HBeAg阳性。 LB80380所有人都能耐受，没有因治疗引起严重或一般的副作用。所有接受LB80380/ANA380治疗的患者都观察到HBVDNA减少。跟随观察发现又反弹到治疗前的水平。经过28天治疗，中值血清HBV减少3~4个数量级。停药后，HBVDNA很快反弹。 Yuen提供了其他HBV药物经过4周和52周治疗,HBVDNA降低的结果： 拉米夫定: 2.3数量级（52周3~4数量级）阿地福为：2个数量级（52周3.5数量级）恩地卡为（0.5mg）：2.8~3数量级（52周 4~5数量级；本届AASLD的论文报告5~7数量级）LDT(400~600mg): 3.8数量级；LB80380 (60-240 mg)：3.4数量级； 副作用包括感染，鼻咽炎，流感，尿道感染，头痛，头晕，恶心，上腹痛: 大多发生在240mg剂量组，一些发生在120mg组。Yuen推断，使用LB80380/ANA380剂量240mg治疗28天，有很好的耐受性和安全性。在所有剂量组中都看到了切实的抗病毒作用。这些结果鼓励进行进一步的研究，更长的时间，更多的研究人群。 were ethnic asian. All HBsAg & HBeAg positive. LB80380 was well tolerated, with no serious or moderate adverse events attributed to treatment. Systemic exposure to LB80331 and LB80317 was proportional to LB80380/ANA380 dose. HBV DNA reductions were observed during treatment in all patients receiving LB80380/ANA380, and returned to pre-treatment levels during follow-up. Median log serum HBV reductions on day 28 of treatment were 3 to 4 log. HBV DNA rebounded immediately after drug was stopped. Yuen provided reported 4-week & 52-week HBV DNA reductions for other HBV drugs: lamivudine -2.3 log (52-week: -3 to 4 log); adefovir -2 log (wk 52: -3.5 log); entecavir (0.5 mg): -2.8-3 log (52 wk: -4 to 5 log, studies at this AASLD show 5-7 log median HBV DNA reductions); LdT (400-600 mg): -3.8 log; LB80380 (60-240 mg): -3.4 log. Side effects included: infection, nasopharyngitis,influenza, urinary tract infection, headache, dizziness, GI, nausea, abdominal pain upper. Most of these adverse events occurred in the high dose 240 mg and several occurred at the 120 mg dose. Yuen concluded that treatment with LB80380/ANA380 for 28 days at doses up to 240mg was well tolerated and safe in this study population. Substantial anti-HBV effects were observed at all doses of LB80380/ANA380. These results encourage additional investigation for longer duration and in other study populations.
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