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发表于 2004-9-8 01:45
| HBV: Drugs in Current Clinical Development
Christine M. Kukka
HBV Project Manager;
In early 2004, there were two types of drugs available to treat
hepatitis B:
interferons, which boost the immune system to fight the hepatitis B
infection, and antiviral medications, which deliberately interfere with
the
virus's DNA so it can't reproduce efficiently. Below are the drugs that
are
currently approved by the U.S. Food and Drug Administration (FDA) to
treat
hepatitis B, and the up-and-coming drugs that may someday be used to
eradicate a hepatitis B virus (HBV) infection.
Interferons
Interferon has an "immunomodulator effect," which means that it tweaks
the
immune system to produce lymphocytes (specialized immune cells) that
either
attack the virus' antigens directly by creating antibodies, or they
attack
the HBV-infected liver cells.
?B lymphoctyes (B cells) are the immune cells responsible for the
production of antibodies. They zero in on individual antigens, such as
the
HBV's surface, core or "e" antigens, by producing antigen-specific
antibodies to combat and vanquish each antigen.
?Cytotoxic T cells (T cells) are specialized cells that recognize and
kill
HBV-infected liver cells and cancerous liver cells.
Interferons do something else that is very helpful. They enhance the
"expression" or presence of certain antigens on the surface of
HBV-infected
liver cells. When these antigens are expressed," the T cells can find
them
more easily and zero in and destroy the infected cells. This process is
called enhanced cell surface expression of Class 1 Major
Histocompatibility,
or MHC.
Researchers are working to develop a variety of immune stimulants and
enzymes that will trigger T cell, B cell and other immune cell
production so
these "soldier" cells will find and vanquish the HBV infection.
FDA-Approved Interferon
Today, there is only one interferon, called conventional interferon or
interferon alpha 2b, that the FDA has approved for the treatment of
hepatitis B in adults and children. This interferon requires three
injections each week and, unfortunately, has had limited treatment
success.
Only about 30 percent of those treated are able to clear their bodies
of HBV
DNA (the genetic material that signals the presence of the virus in the
blood), and only 33 percent were reported to clear the "e" antigen.
About 12
percent of those treated with conventional interferon achieved normal
liver
enzymes (ALTs) and cleared HBV DNA and "e" antigen.
Interferon in Phase III Clinical Trials
Pegylated interferon is a promising interferon that has been used with
great
success against hepatitis C, another viral liver infection. Pegylated
interferon requires only one injection each week. This interferon has a
time-release formula so it remains present in the liver at a constant
level
to achieve a consistent "immune boosting" level.
Pegylated interferon is also believed to more efficiently distribute
itself
throughout the liver, the main site of HBV infection, than conventional
interferon. According to a study by Roche, the company that developed
the
pegylated interferon called Pegasys, pegylated interferon was twice as
successful as conventional interferon in treating hepatitis B.
Roche researchers reported that Pegasys, given for six months at the
same
180 microgram dose used in the treatment of hepatitis C, showed an "e"
antigen (HbeAg) loss, HBV DNA below 500,000 copies/ml, and
normalization of
ALT in 28 percent of those treated, compared to 12 percent treated with
conventional interferon.
Pegylated interferon is now in Phase III clinical trials for hepatitis
B,
which means it has one step to go before it can be considered for FDA
approval. Because doctors are familiar with pegylated interferon's
safety
record and dosage levels in adults, some adults with HBV in the United
States have been able to enroll in clinical trials or find physicians
who
will prescribe it off-label (on an experimental basis).
One of Roche's studies specifically examined the effectiveness of
Pegasys in
patients with difficult-to-treat hepatitis B, which includes patients
with
the "e" antigen, high HBV DNA (high levels of virus replicating in the
patient's liver), and low ALT levels梐ll of which indicate that the
person's
immune system is not noticing the virus nor attacking infected liver
cells.
Immune Stimulators (Similar to Interferons) Under Development
Immune enhancers or stimulators are similar to interferon, but they
specifically help T cells find and fight tumors and viruses.
HE2000 (Immunitin), developed by Hollis-Eden Pharmaceuticals, is
similar to
interferon in that it spurs the immune system. This substance, however,
stimulates key immune fighting cells necessary to fight infections in
people
with hepatitis B and HIV. This drug is currently in Phase II clinical
trials
for hepatitis B in Singapore.
Zadaxin is thymosin alpha 1, a thymic hormone that enhances the
maturation
of T-cells. The drug's developer, SciClone Pharmaceuticals, reported
that
when this drug was combined with conventional interferon, it produced a
71
percent long-term sustained response rate in patients with
difficult-to-treat hepatitis B after one year of treatment. This
sustained
response rate compares favorably to only 20 percent of patients using
interferon alpha in combination with lamivudine, and 10 percent of
patients
using interferon alpha alone. After administration, thymosin alpha 1
circulates at 50 to 100 times its normal level in the body. Zadaxin has
been
approved for sale in more than 30 countries. This drug is currently in
Phase
II clinical trials.
Quick Reference Chart
Phase II Phase III FDA Approved
HE2000- (Immunitin) Interferon alpha 2a (Pegasys) Interferon alpha 2b
(Intron A)
Thymosin alpha 1 (Zadaxin) L-deoxythymidine or LdT (Telbivudine)
Lamivudine
(Epivir-HBV)
Tenofovir (Viread) ETV (Entecavir) Adefovir (Hepsera)
Ampligen FTC, Emtriva (Emtricitabine)
L-FMAU (Clevudine)
BAM-205
Antiviral Medications or Nucleoside Analogs
Nucleoside analogs (also called nucleoside reverse transcriptase
inhibitors,
or NRTIs) and non-nucleoside antivirals prevent the hepatitis B virus
from
replicating. These drugs interfere with the HBV's DNA and the viral
proteins
that orchestrate its reproduction. Most antiviral medications are pills
that
are taken daily.
When an antiviral enters a hepatitis B virus, it is able to inhibit
certain
cellular functions that are necessary for DNA production or viral
replication. As a result, the virus is unable to replicate in liver
cells.
These antivirals are valuable because they lower the rate of HBV
replicating
in the liver. Generally, when viral load drops, liver damage declines
because there are fewer viruses invading liver cells, and ALT levels
also
normalize. Researchers hope that one day a combination of immune
enhancers
and antiviral medications will be developed that can produce a strong
immune
response and lower viral load, resulting in the eradication of an HBV
infection.
FDA-Approved Antiviral Medications
There are two FDA-approved antiviral medications available to
HBV-infected
patients: lamivudine, approved for adults in 1998 and for children in
2000,
and adefovir, approved for adults in 2002, and currently in clinical
trials
for children.
Lamivudine: Administered as a daily pill or oral solution, lamivudine
generally produces normal ALT levels and undetectable HBV DNA in about
65
percent of the adults who take it.
While lamivudine is safe and rarely causes side effects, it is not a
permanent or complete cure. It keeps the virus in check for only as
long as
it is taken. When treatment stops, HBV DNA and ALT levels usually
rebound.
Lamivudine has one serious drawback. Some hepatitis B viruses develop
resistance to lamivudine's antiviral punch. Over time, the
non-resistant
viruses decline, but the lamivudine-resistant HBVs rebound until viral
load
and ALT levels start to climb once again. After four years of
lamivudine
treatment, more than 60 percent of patients develop
lamivudine-resistant
HBV.
Adefovir: Adefovir appears to have all of lamivudine's antiviral clout,
but
none of its viral resistance. Today, doctors frequently switch patients
to
adefovir who have developed viral resistance to lamivudine.
Adefovir also appears effective against hepatitis B viruses that are
able to
replicate without secreting HBeAg. The immune system has a hard time
identifying and zeroing in on this type of hepatitis B virus. When an
HBV
infection exists and lab tests can't find the "e" antigen, despite high
viral loads and elevated ALT, it is called HBeAg-negative hepatitis.
Antivirals in Development
There are four experimental antiviral medications currently in Phase
III or
late-stage clinical trials.
Telbivudine (L-deoxythymidine or LdT) stops HBV replication and
normalizes
ALT levels better than lamivudine, based on early studies. One Phase
III
clinical trial compared the two antivirals and, after one year,
telbivudine-treated patients had healthier ALT levels and lower viral
load
than those treated with lamivudine. Telbivudine, to date, appears to
cause
no adverse side effects and there have been no reports of viral
resistance
to this drug. Idenix Pharmaceuticals is developing telbivudine. A Phase
III
trial, involving 1,200 patients in Asia, Europe and North America, was
ongoing in early 2004.
Entecavir (ETV) is a potent inhibitor of HBV replication. In lab tests,
this
antiviral has shown the ability to reduce viral CCC DNA levels, which
are
believed to promote development of liver cancer. In studies that
compared
entecavir with lamivudine, entecavir was more effective in reducing HBV
DNA
levels, even when ALT levels were only slightly elevated. Early studies
also
suggest that entecavir-treated patients had a more sustained response
to the
drug, even after treatment ended, including those with HBeAg-negative
hepatitis B. There have been a couple reports of viral resistance to
entecavir developing, but nearly all occurred in patients who had
already
developed lamivudine-resistant viruses. Bristol-Myers Squibb is
expected to
apply for FDA approval for entecavir in late 2004.
Emtricitabine (FTC, Emtriva), already approved by FDA for treatment of
HIV,
has been found to be effective in lowering HBV DNA. Gilead Sciences
reported
treatment with emtricitabine reduced liver fibrosis in 62 percent of
patients who received the drug, compared to 25 percent of patients who
received a placebo, and substantially lowered HBV DNA in 56 percent.
However, researchers have found some instances of viral resistance to
emtricitabine.
Clevudine (L-FMAU) has demonstrated potent antiviral activity and the
ability to produce a sustained response, even months after treatment
has
ended. In one study, 71 percent of patients who took clevudine
maintained
normal ALT levels six months after treatment ended, which is longer
than
with other antivirals. Clevudine, produced by Gilead, appeared to be
well-tolerated, and no HBVs have developed resistance to clevudine to
date.
BAM-205, developed by Novelos, also interferes with proteins involved
in
viral reproduction. BAM-205 was approved for use in Russia in 2001.
Preclinical studies support BAM-205's anti-viral effects in more than
250
Russian hepatitis B patients studied. Viral load was reduced and ALT
levels
also declined. According to Novelos, more than 700 Russian hepatitis
patients have been treated successfully with BAM-205. Commercialization
of
BAM-205 is underway in Russia, and plans are underway to develop and
sell
BAM-205 in China. In the United States, BAM-205 is in Phase II/III
clinical
trials.
Antivirals in Phase I/II Clinical Trials
Tenofovir (Viread): Several studies have found that the antiviral
tenofovir,
developed by Gilead Sciences, is effective against both HIV and HBV.
One
study showed that treatment with tenofovir resulted in 0.6-log decrease
in
HIV level and a five-log decrease from baseline for HBV level.
Similarly,
another coinfection study showed a four-log decrease in HBV DNA level
by
week 24 and an increase in CD4 cells. However, there have been reports
of
renal toxicity and hypophosphatemia associated with tenofovir therapy.
Clinical trials exploring the safety and effectiveness of tenofovir to
treat
people coinfected with HIV and hepatitis B are continuing.
Ampligen: Currently in Phase II trials for treatment of hepatitis B
with
Hemispherx Biopharma, Ampligen is a nucleic acid drug that mimics DNA
and
RNA, and which inhibits production of certain enzymes that HIV and
hepatitis
B viruses need for viral reproduction. Ampligen can also control the
growth
of certain human tumor cells. Administered intravenously twice a week,
it is
also being studied for possible applications in renal carcinoma and
malignant melanoma. To date, it has caused no dangerous side effects.
For more information about hepatitis B, contact the following
organizations:
Hepatitis B Foundation
1-215-489-4900, www.hepb.org
Hepatitis B Support List
www.hblist.org
Hepatitis Foundation International
1-800-891-0707, www.hepfi.org
To Post a message, send it to:
[email protected]
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Viread) 一些研究有发现那 antiviral
tenofovir,
被 Gilead 科学发展,反对两者的爱滋病毒和 HBV 是有效的。
一
研究展现有 tenofovir 的治疗造成 0.6 个圆木的减少
在
为 HBV 水平的来自基线的爱滋病毒水平和一个五个圆木的减少。
同样地,
另外的 coinfection 研究展现了一个～方面的四个圆木的减少～ HBV DNA 水平
被
星期 24 和～的增加 CD4 细胞。 然而, 已经有报告
被 tenofovir 治疗联合的肾脏毒性和 hypophosphatemia。
临床的审判探究 tenofovir 的安全和效力到
宴飨
有爱滋病毒和肝炎 B 的人们 coinfected 正在继续。
Ampligen: 现在为肝炎 B 的治疗在时期 2 审判中
由于
Hemispherx Biopharma, Ampligen 是一种 nucleic 酸药那个模仿的 DNA
而且
RNA, 和禁止某酵素那个爱滋病毒的制造和
肝炎
B 病毒对～的需要滤过性毒菌的再现。 Ampligen 能也控制那
生长
某人类的肿瘤细胞。 静脉内的一个星期两次管理,
它是
也对可能的申请是有计划的在肾脏的癌中和
有恶意的 melanoma。 为了要约会,它没有引起危险的副作用。
对於关於～的较多资讯～肝炎 B, 连络下列各项
组织:
肝炎 B 基础
1-215-489-4900,www.hepb.org
肝炎 B 支持 Listwww.hblist.org
国际的肝炎基础
1-800-891-0707, www.hepfi.org
邮寄一个信息,送它给:
肝炎