L-FMAU的24周剂量评估显示潜在的抗病毒效果

zasxz

In Dose Escalation Study, Clevudine Shows Potent Anti-HBV Effects 24 Weeks After Cessation of Once Daily Dosing


Current approved therapies for the treatment of chronic hepatitis B virus (HBV) infection are limited in their ability to produce a cure or to durably suppress the virus. Several promising new anti-HBV drug candidates are now in Phase II or Phase III, including entecavir (Phase III), emtricitabine (Phase III; NDA filed), peginterferon alfa-2a (Pegasys) (Phase III), telbivudine (Phase III), valtorcitabine (Phase II), amdoxovir (Phase II), and clevudine (Phase II in US; Phase III in South Korea).

Clevudine is a pyrimidine analog that has demonstrated potent anti-HBV activity in vitro and in animal models. In the US, clevudine (also known as L-FMAU) is in development by Triangle Pharmaceuticals (Durham, NC), a subsidiary of Gilead Sciences (Foster City, CA). Triangle/Gilead and Bukwang (Seoul, South Korea) jointly funded the Phase II dose-escalation study results summarized here.

Treatment Emergent Grade 3 or 4 Laboratory Abnormalities Occurring During Dosing Period and 2 Months After the End of Treatment

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In this multicenter dosing study, researchers evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 ?106 copies/mL or more, had not undergone nucleoside treatment, and were not coinfected with HIV or hepatitis C.

Thirty-two patients were enrolled (5, 10, 10, and 7 patients in the 10-, 50-, 100-, and 200-mg dose groups, respectively); 81% were male, 81% Asian, and 88% were hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum HBV DNA levels ranged from 7.3 to 8.8 log10 copies/mL.

After 28 days, the median HBV DNA log10 change from baseline was -2.5, -2.7, -3.0, and -2.6 log10. Six months after dosing, median changes from baseline were -1.2, -1.4, -2.7 and -1.7 log10 in the 10-, 50-, 100-, and 200-mg cohorts, respectively.

Six of 27 patients lost HBeAg, and 3 of 27 patients seroconverted to HBe antibody. Clevudine was well tolerated, with no dose-limiting toxicities. (All adverse events were graded as mild).

A transient increase in alanine aminotransferase of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186 IU/L) was observed in six patients in the 100-mg cohort, without signs of liver failure. These increases were associated with improved viral suppression. The pharmacokinetic profile of clevudine was proportional to the dose.

The authors conclude, 揟hese results demonstrate the tolerability and potent activity of clevudine in HBV-infected patients and support further clinical study.?/span>

Discussion

Interestingly, those patients with an ALT increase while receiving the drug were those who ultimately showed the greatest sustained viral suppression. Thus, no dose-limiting clinicobiological toxicity was seen after this short duration of dosing.
The long plasma half-life of clevudine in this study supports a once daily administration. Steady state is reached at day 22 with the 50-, 100-, and 200-mg doses, and further accumulation of the drug was not observed.

Nevertheless, the Emax model suggests that the lowest dose of clevudine producing the maximal treatment effect should be close to 30 to 50 mg once daily, say the investigators. Further studies are underway to establish the dose of clevudine to be used in subsequent studies.

As shown in animal models, the drug exerts an ability to delay substantially the time to viral rebound after a short treatment period. The viral suppression after cessation of dosing seen in animal models also was observed in this study at all doses tested. This virological response translated into biochemical and serological responses 6 months after the end of 1 month of therapy.

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The rate of HBeAg loss (22%) and seroconversion (11%) seems unusually high in this short study, especially because the patient characteristics (i.e., most males and Asians having baseline ALT levels less than twice the upper limit of the normal range and high HBV DNA levels at entry) are known to be associated with a poor response.

As an example, after 1 month of entecavir therapy, only 1 of 30 enrolled patients (3%) lost HBeAg at 6 months. After 28 days treatment with adefovir 125 mg, 1 of 15 patients (7%) seroconverted to HBe antibody. After 12 weeks of treatment with lamivudine, 1 of 9 patients (11%) seroconverted to HBeAb.

The viral suppression observed 24 weeks after the end of dosing represents the uniqueness of clevudine. The mechanism of action of clevudine leading to such a feature is speculative, according to the authors.

揑n conclusion,?they note, 搕his short-term study of clevudine in patients chronically infected with HBV demonstrates that the drug is well tolerated and has substantial antiviral activity. The delayed time to viral recrudescence observed in association with biochemical and serological response is in agreement with the preclinical profile of clevudine. The virological response led to HBeAg seroconversion after just 28 days of therapy. Further studies with clevudine are underway to clarify its safety and efficacy at a larger scale.?

Commentary

To date, clevudine clearly shows good tolerability, significant potency, durable viral suppression, and a favorable toxicity profile. If future studies continue to demonstrate these favorable characteristics (along with a unique resistance profile), clevudine might emerge as a potential breakthrough drug for chronic hepatitis B. Researchers, patients, clinicians, and treatment advocates all anxiously await the results of future studies.

Hopital Beaujon, Clichy, France, Triangle Pharmaceuticals, Inc./Gilead Sciences Inc., Durham, NC, Viridiae, Vancouver, British Columbia, Canada (deceased),
Queen Mary Hospital, University of Hong Kong, Hong Kong SAR, China, Centre d'Investigation Clinique, H魀ital Saint Louis, Paris, France, H魀ital Brabois, Nancy, France, University of British Columbia, British Columbia, Canada
Hotel Dieu, Lyon, France, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, and Seoul National University Hospital, Seoul, South Korea.

This study was funded by Triangle Pharmaceuticals, (a subsidiary of Gilead Sciences) and Bukwang Pharmaceuticals.

08/02/04

Reference
P Marcellin and others. A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B. Hepatology 40(1): 140-148. July 2004.

ardejiang

似乎文章的发表已经有一段时间了呢？

zasxz

经过一天一粒服用24周后停药效果显示Clevudine具有潜在的抗病毒效果
目前公认的治疗HBV以达到治愈或长期压制病毒的方法有限。几种有前景的新药都在II期或III期，包括恩替卡韦（III期），恩曲西它平（III期,已申请FDA证书）,长效干扰素(III期)，特比夫丁（III期），瓦特西它平（II期），阿莫德西韦（II期）和Clevudine可莱夫丁（美国II期，韩国III期）
Clevudine可莱夫丁是一种嘧啶类似物，在体外和动物实验中已经表现出潜在德抗HBV性。在美国，可莱夫丁(也被称为 L-FMAU) 是由Triangle Pharmaceuticals三角医药公司 (Durham, NC), 葛兰素的子公司 (Foster City, CA)研制成功的. 三角公司/葛兰素公司和Bukwang (汉城, 韩国)的合资进行了II期剂量研究，结果如下。

在本次多中心的剂量研究中，研究者评估了可莱夫丁的10, 50, 100, 和 200 mg/天 28天的结果。符合用药的条件是HBV DNA水平 3X10^6 copies/mL 或更多, 没有经历过核苷酸治疗，没有感染HIV或HCV。

32名病人参加，其中5, 10, 10, 和7 名分别放在10-, 50-, 100-, 和 200-mg 剂量组。 81% 是男性，81% 是亚裔，还有88% 是e抗原阳性. 平均治疗前的HBV DNA 水平是7.3--8.8 log10 copies/mL.

28天后，平均HBV DNA log10水平从基础线下降 -2.5, -2.7, -3.0, 和 -2.6 log10. 6月后，平均HBV DNA log10水平从基础线下降 -1.2, -1.4, -2.7 和 -1.7 log10 在 10-, 50-, 100-, 和 200-mg 组。

27名中6名病人E抗原消失，而且27名中3名发生血清转换。可莱夫丁耐药性好，高剂量无毒性。(所有副作用都是评为温和).

100mg组中的6个病人中，有一例的ALT上升到上限的7.8倍 (从20上升到186 IU/L)。没有迹象显示肝脏的损伤。这种上升和病毒压制改善有关。药动力学曲线和剂量成正比。

作者概括，这些结果显示可莱夫丁的耐药性和抗病毒性将支持未来的灵床研究。

讨论

令人感兴趣的是，那些服药期间ALT增加的病人却正是那些最终显示病毒持续压制最好的病人。因此短时间的剂量上应该没有临床生物学毒性方面的限制。

可莱夫丁的血浆半衰期显示每天一粒就够了。稳定态在 50-, 100-,和 200-mg 剂量的22天达到。未来的药量积累并没有所改善。

此外，Emax模型建议的最小剂量可莱夫丁是 30 到 50 mg 每天。进一步的研究正在进行中。

在动物模型的试验中，可莱夫丁展现了断时间治疗后延迟病毒反跳的能力。在所有剂量试验中，停药后病毒压制仍然存在。治疗1个月后，病毒学反应和血清反应维持了6个月之久。

E抗原消失率 (22%) 和血清转换率 (11%) 短期看来是不寻常的高，尤其是应为患者的特征和较低的反应有关系。 (例如，绝大多数的男性和亚裔的ALT水平没有超过2倍的正常值，而且 HBV DNA 水平也不高)

例如，1个月的恩替卡韦的治疗，30个人中只有1人(3%)在第六月E抗原消失。28 天的阿地福韦治疗125 mg后, 15个中1个病人 (7%) 发生血清转换。12周拉米治疗后， 9个中1个(11%)发生血清转换。

停药后6月的病毒压抑显示可莱夫丁的独特性。可莱夫丁的机理导致这种特点是有点投机性的。

总而言之，他们提到短期的可莱夫丁治疗HBV慢性病人显示该药具有很好的耐药性和持续的病毒压抑性。病毒反跳的延迟时间和生物化学和血清学反应有关，并和可莱夫丁的潜伏期曲线一致。28天的治疗后病毒反应导致血清转换。更多的试验正在进行中，用来检测安全性和有效性。

评论

目前，可莱夫丁的清楚的反应出良好的耐药性，重要的潜在性，长期的病毒压抑性和最好的病毒曲线。如果未来研究继续显示较好的特点 (带有独特的耐药曲线),可莱夫丁可能成为HBV的一个突破性的药物。研究者，病人， 临床医生和治疗提倡者都焦急得等待进一步得结果。

Hopital Beaujon, Clichy, France, Triangle Pharmaceuticals, Inc./Gilead Sciences Inc., Durham, NC, Viridiae, Vancouver, British Columbia, Canada (deceased),
Queen Mary Hospital, University of Hong Kong, Hong Kong SAR, China, Centre d''''Investigation Clinique, H魀ital Saint Louis, Paris, France, H魀ital Brabois, Nancy, France, University of British Columbia, British Columbia, Canada
Hotel Dieu, Lyon, France, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, and Seoul National University Hospital, Seoul, South Korea.

This study was funded by Triangle Pharmaceuticals, (a subsidiary of Gilead Sciences) and Bukwang Pharmaceuticals.

08/02/04

Reference
P Marcellin and others. A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B. Hepatology 40(1): 140-148. July 2004.

[此贴子已经被作者于2004-8-2 16:43:28编辑过]

zasxz

是的，7月14日HEPATOLOGY上发表的，HTTP://WWW.HIVANDHEPATITIS.COM上8月2日又头版报道，应该是替代拉米的最新药物，我翻成可莱夫丁，是沿用长笛大师尼可莱的音译。可莱夫丁如果真的比拉米好，耐药和持续抗毒，将成为我们的救星，堪称拉米第二。只可惜我们国家还没有临床应用。

[此贴子已经被作者于2004-8-2 16:41:42编辑过]

ardejiang

"治疗1个月后，病毒学反应和血清反应维持了6个月之久"  疗效看起来确实不错呢，另外潜在的问题是，HBVER可能要长期用药了，吃一个月，停六个月，呵呵，是不是这么说的，可能逻辑有问题，期望它的进一步临床结果。如果一直抑制不反跳，HBV有望！！！

forrestfu

与恩替卡韦相比如何？

ardejiang

克拉夫定

克拉夫定(clevudine，L-FMAU)的化学结构为2'-氟代-5-甲基-β-L-阿糖呋喃糖腺嘌呤-尿嘧啶。在临床前的体外实验中，对土拨鼠和鸭模型中的乙肝病毒均有较强的抑制作用［35-37］。在土拨鼠模型中,10 mg·(kg·d)-1,给药12周,血清病毒量下降达9 log(10) copies·ml-1，停药后随访56周，3/4动物未见病毒反跳。I/II期临床试验表明]26]10 mg·d-1和50 mg·d-12种剂量治疗28天均可有效抑制病毒复制，HBV DNA量分别下降2.49和2.69 log(10)copies·ml-1。ALT从114 U·L-1,降至66 U·L-1。但由于目前临床试验的病例数尚少，还有待于进一步研究。