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Multicenter Phase 2 Trial of Remofovir in Hepatitis B Initiated

Remofovir治疗乙肝开始2期（多中心）临床试验


SAN DIEGO, Aug. 3 /PRNewswire-FirstCall/ -- Metabasis Therapeutics, Inc.


(NASDAQ:MBRX) announced today the initiation of a multi-center, multi-
national Phase 2 study to evaluate the orally administered antiviral
compound remofovir mesylate in chronic hepatitis B (HBV) infected patients.
Metabasis discovered remofovir using its HepDirect(TM) prodrug technology.
In October 2001, Metabasis entered into an exclusive worldwide development
and license agreement with Valeant Pharmaceuticals International, under
which Valeant is primarily responsible for the clinical development and
registration of remofovir.

Metabasis生物制药公司（纳斯达克代号：MBRX）今天宣布，将进行多中心，
多国家的联合2期临床试验，以评估一种口服抗病毒化合物，remofovir甲磺酰盐
治疗慢性乙肝感染者的效果。Metabasis公司应用他们的HepDirect(TM) 前体药物
技术，发现了remofovir。2001年10月，Metabasis公司加入世界范伟的专有开发和注册，和Valeant国际制药公司签署协议，由Valeant主要负责临床开发和注册remofovir。

This Phase 2 study of remofovir is an open-label, randomized, multiple oral
dose study that will enroll 220 patients with compensated hepatitis B
infection at approximately 20 sites in the U.S., Taiwan, Singapore and
Korea. The study consists of five treatment groups: remofovir -- 5, 10, 20
and 30 mg/day, and Hepsera (adefovir dipivoxil) -- 10 mg/day. Treatment
duration will be 48 weeks and an interim analysis will be conducted
following 24 weeks of dosing to evaluate drug safety and efficacy and, if
warranted, will be used for selection of a dose for Phase 3 studies.

remofovir 的2期临床研究是开放的，随机的，多种口服剂量的实验。参加的有220名 ，
代偿期乙肝感染着，大约在美国，台湾，新加坡，韩国等20多个地点。该实验有5
个治疗组：remofovir，剂量分别为5，10，20，30mg/天，和Hepsera（阿地福为）
10mg/天。治疗历时48周，中间分析，跟着24周。评估药物安全性和效果，如果
得到批准，用来为3期临床选择药物剂量。


Remofovir was developed using Metabasis'''' proprietary HepDirect technology, a
broadly applicable, liver-targeting prodrug technology that was recently
described in a Journal of the American Chemical Society article entitled
"Design, Synthesis, and Characterization of a Series of Cytochrome P(450)
3A- Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting
Phosph(on)ate- Based Drugs to the Liver," (J. Am. Chem. Soc. 126, 5154-5163
(2004)). A prodrug is a drug to which a chemical modification has been made
that renders the target drug inactive until enzymes in the body convert it
to its active form. In the case of a HepDirect prodrug, the enzyme that
converts it to an active form is found predominantly in the liver. Remofovir
is a HepDirect prodrug of a compound called adefovir. Adefovir is the active
component of the approved hepatitis B drug Hepsera (adefovir dipivoxil).
Hepsera is also a prodrug, however, it is converted to the active form
predominantly in the plasma. Remofovir is designed to generate an active
form of adefovir primarily in the liver, where the virus resides, while
limiting exposure outside the liver. While the safety and efficacy of this
approach remains to be definitively proven in the clinic, this is
potentially important because while adefovir is associated with significant
decreases in HBV DNA levels, it also appears to be associated with treatment
limiting renal toxicity.

Remofovir是使用Metabasis公司专利的HepDirect技术发现的。该技术用途
广泛，肝脏目标筛选药物技术最近在美国化学协会期刊上作了描述，题目
是“HepDirec技术在肝脏药物上应用的“
/*  "Design, Synthesis, and Characterization of a Series of Cytochrome P(450)
3A- Activated Prodrugs (HepDirect Prodrugs) Useful for Targeting
Phosph(on)ate- Based Drugs to the Liver," (J. Am. Chem. Soc. 126, 5154-5163
(2004)).  
*/
前体药物是指，一种药物作化学改性后，产生的目标药物没有活性，直到身体
里的特定酶将它转变成活性形式。HepDirect前体药物情况是，能使它转变成活性
形式的酶，主要存在于肝脏内。Remofovir是种HepDirect 前体药物，是化合物
adefovir阿地福为的前体。阿地福为是种被证明有抗乙肝活性的化合物，其片剂即Hepsera
（贺普喜）。贺普喜也是种前体药物，然而，它主要在血液中转换成活性形式。
Remofovir被设计用来主要在肝脏中产生阿地福为的活性形式，病毒在那里存在，可以
限制暴露在肝外的药物。虽然该方法的安全性和效果还要在临床验证，这可能是非常
重要，因为阿地福为可以显著降低HBV DNA水平，也同治疗的肾毒性限制有关。
"We expect this new clinical trial to build on the pre-clinical and clinical
results we have seen to date with remofovir," commented Dr. Paul Laikind,
Metabasis'''' Chairman, President and CEO. "Valeant submitted an abstract to
the American Association for the Study of Liver Diseases (AASLD) describing
the safety, tolerance, pharmacokinetic and pharmacodynamic results from a
recently completed clinical trial of remofovir in patients infected with
hepatitis B virus. If the abstract is accepted, the results of this trial
would be presented at the 55th Annual Meeting of the AASLD in Boston in
October/November 2004. The findings from that trial led to the decision to
proceed with the Phase 2 study announced today. This new study is designed
to assess the maximally effective dose of remofovir and assist in dose
selection for the pivotal Phase 3 studies that are expected to begin next
year should the results warrant it."

Metabasis的CEO，Dr. Paul Laikind评论说：
“我们对这项新临床试验的期望建立在临床前研究和1期临床结果上。Valeant
公司提交给美国肝病联合会(AASLD)的摘要，描述了刚完成临床试验治疗HBV
的安全性，耐受性，药效，药物代谢，等结果。如果该摘要被接受，这个试验
结果将会在波士顿举行的255届AASLD年会上发表（October/November 2004）。
该实验发现导向了今天开始的2期临床。这项新研究计划用来评估remofovir的最大
效果的剂量，并帮助为3期临床选择剂量，希望明年将开展3期临床。“

Hepatitis B remains a significant medical problem that affects an estimated
300 million people worldwide and can cause severe liver damage leading to
liver cirrhosis and primary liver cancer. The World Health Organization
estimates that hepatitis B infection results in more than one million deaths
each year worldwide.

HBV是个重要的医学问题，估计感染了世界上3亿人，能造成严重肝损伤，
导致肝硬化，原发性肝癌。世界卫生组织估计HBV感染每年造成1百万人
死亡。

Dr. Mark Erion, Executive Vice President of Research and Development at
Metabasis stated, "In addition to representing an important milestone in the
development of remofovir, the initiation of this study also gives us further
confidence in the potential of our HepDirect technology. In addition to
remofovir, the HepDirect technology was used to develop MB07133, a HepDirect
prodrug of an oncolytic agent. MB07133 is currently being studied in
patients with primary liver cancer, a deadly disease with few treatment
options. The HepDirect technology is also being used in our collaboration
with Merck & Co., Inc. to discover novel products for the treatment of
hepatitis C. Finally, we continue to evaluate the technology and its use in
certain other programs."

Metabasis研发副总裁Dr. Mark Erion说：“这不仅标志remofovir开发重要里程碑，
该研究的启动，也给我们HepDirect技术更多信心。除了remofovir以外，HepDirect
技术还应用在开发MB07133，一种抗肿瘤前体药物。MB07133目前研究用于原发性
肝癌，一种很少治疗手段的致命疾病。HepDirect技术还被我们的合作公司，
Merck & Co., Inc，用来发现治疗HCV的药物。最后，我们持续评估该技术，并应用
在其他项目。“


Source: Metabasis Therapeutics, Inc.

[此贴子已经被作者于2004-9-28 23:34:26编辑过]

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