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大家好
Hello,

我是Susan Dorman
my name is Susan Dorman,

来自约翰•霍普金斯大学医学院
from Johns Hopkins University School of Medicine.

在第二部分中
In part 2,

我们将谈谈当代抗结核药物研发
we will talk about contemporary examples

和临床试验的案例
in TB drug development and clinical trials.

这里展示的是新型结核病药物的程序图
Shown here is the pipeline for new TB drugs.

左边是此过程极早期的药物
On the left are drugs that are very early on in the process,

右边是正在进行二期或三期临床试验的药物
and on the right are drugs currently in phase-2 or phase-3 trials.

需要注意的是
It is important to note that,

虽然程序图的左侧看起来很强大
although the left side of the pipeline looks robust,

但对于我们目前的需求来说
it is probably insufficiently robust

可能还不够稳健
for our current needs

因为这些化合物中的大多数
because most of these compounds will never make it further

将永远不会进入图的右侧
towards the right side of the diagram

也不会进入二期或三期临床试验
and will not make it into phase-2 or phase-3 clinical trials.

我想简要介绍
I would like to share briefly several examples of new drugs

一些用于结核病治疗的新药案例
that are being used for TB

并简要说明它们研发过程的重点内容
and just describe some of the main points in their development.

第一个案例是贝达喹啉
The first example is that of bedaquiline.

这是一种二芳基喹啉类药物
This is a diarylquinoline

它的靶点是结核分枝杆菌的ATP合成酶
and it targets the ATP synthase of Mycobacterium tuberculosis.

贝达喹啉半衰期很长
Bedaquiline has a long half-life

并在组织中蓄积
and it accumulates in tissues.

它还与利福平有重要的药物相互作用
It also has an important drug-drug interaction with rifampin.

贝达喹啉的研发在临床试验过程中
The bedaquiline drug development in clinical trial process took place

历时约10至15年
over about 10 to 15 years.

贝达喹啉是通过全细菌筛选方法发现的
Bedaquiline was discovered through a whole-bacterial screening approach.

早期的小鼠研究发现了
Mouse studies early

它具备缩短疗程的潜力
on suggested a treatment shortening potential.

之后
After that,

进行了一系列的二期试验研究
a series of phase-2 studies were undertaken.

有趣的是
Interestingly,

贝达喹啉的早期杀菌活性
the early bactericidal activity of bedaquiline

被发现是适度和延迟的
was found to be modest and delayed.

尽管如此
Nevertheless,

它已被纳入临床2b期试验研究
it was taken forward into clinical phase-2b studies

将贝达喹啉添加到
in which bedaquiline was added to existing treatment

现有的耐多药结核病治疗方案中
for multidrug-resistant tuberculosis.

总的来说
Overall,

这些2b期试验研究表明
these phase-2b studies showed that bedaquiline,

耐药结核病治疗药物方案中
when added to other drugs

加入中贝达喹啉时
for drug-resistant TB,

大大缩短了痰培养转阴的时间
significantly reduced the time to sputum culture conversion.

在已完成的2b期试验中
In the second phase-2b trial that was done,

贝达喹啉组中出现较多死亡病例
there were more deaths in the bedaquiline arm

所以贝达喹啉的包装标签上有警告标志
and this led to a warning specific to bedaquiline on the package labeling.

贝达喹啉在2012年
Bedaquiline received accelerated USFDA approval

获得了美国FDA的加速批准
in 2012,

随后在世界卫生组织2013年指南中
followed by World Health Organization guidance

得到认可
in 2013.

另一类新药物是硝基咪唑类药物
A second new class of TB drugs is the nitroimidazoles.

这些药物抑制细胞壁合成和细胞呼吸
These drugs inhibit cell-wall synthesis and cellular respiration.

它们是前体药物
They are prodrugs and are selectively active

并且被结核分枝杆菌复合物有选择活化
against Mycobacterium tuberculosis complex.

迪拉马尼（Delamanid）
Delamanid

已被欧洲药品管理局批准使用
has been approved for use by the European Medicines Agency

Pretomanid目前仍在临床试验中
and pretomanid remains in clinical trials at this time.

恶唑烷酮类药物（Oxazolidinones）
Oxazolidinones

包括再利用的药品
include repurposed agents,

如利奈唑胺
such as linezolid,

以及其他正在研发的结核病相关的
and other new chemical entities

新型化学药品
that are being developed specifically for tuberculosis.

作为一类药物
As a class,

这些药物阻止蛋白质合成
these agents block protein synthesis.

重要的是
Importantly,

它们阻断细菌蛋白质的合成
they block protein synthesis of bacteria but also of human mitochondria.

但也阻断人体线粒体蛋白质的合成
The net result is that their efficacy and their toxicity

最终结果是它们的功效和毒性
is due to similar mechanisms

都归因于相似的机制
and thus their usability in the clinic

因此它们的临床可用性
depends on their differential effects on the bacteria

取决于对细菌与人体线粒体的不同作用
versus the human mitochondria.

多年来
For a number of years,

利奈唑胺已被用于治疗高度耐药的结核病
linezolid had been used for the treatment of highly-resistant TB

有传闻说它是有效的
and there were anecdotal reports of its success.

然而2012年进行的一项临床试验
A clinical trial performed in 2012, though,

明确表明利奈唑胺和其他药物联用
clearly showed the activity of linezolid

治疗高度耐药结核病时的活性
when added to other drugs in the treatment of highly drug-resistant tuberculosis.

这里展示的只是一些正在进行的
Shown here are just some of the clinical trials

耐药结核病治疗的临床试验
that are ongoing for the treatment of drug-resistant TB.

总的来说
In general,

这些试验有三个重要的思路和目标
there are three important ideas and goals of these trials.

一是将治疗时间缩短至不到18个月
One is to shorten treatment to appreciably less than 18 months' duration.

二是消除对注射类药物的需求
A second goal is to eliminate the need for an injectable drug.

最后
And finally,

为了克服目前耐药模式的问题
there is a need for totally novel regimens

需要全新的治疗方案
in order to circumvent current drug-resistant patterns.

氟喹诺酮类药物是再利用药物的例子
Fluoroquinolones are an example of repurposed drugs.

也就是说
That is,

氟喹诺酮类药物是针对其他传染病而开发的
fluoroquinolones were developed for other infections

但是被发现具有结核病的活性
but were then noted to have TB activity.

有一段时间
For a while,

氟喹诺酮类药物
fluoroquinolones have been commonly used

已被广泛用作耐药结核病的二线药物
as second-line drugs for drug-resistant TB

有时也用于对一线药物不耐受的患者
and also sometimes in patients intolerant of first-line agents.

应该指出的是
It should be noted

连续几代氟喹诺酮类药物的
that the successive generations of fluoroquinolones

抗结核分枝杆菌活性递增
have increasing activity against Mycobacterium tuberculosis.

关于药物敏感性结核病
With regards to drug-susceptible TB,

氟喹诺酮类药物
the activity of fluoroquinolones in mouse models of TB

在小鼠结核病模型中的活性研究
led to interest in fluoroquinolones

发现氟喹诺酮类药物
for shortening the duration of treatment

可缩短药物敏感性结核病的治疗时间
for drug-susceptible TB.

进行了一系列二期临床试验
A series of clinical phase-2 trials were undertaken,

这些试验明确表明
and these showed clearly

喹诺酮类药物安全性且耐受性良好
that quinolones were safe and well-tolerated.

但最好情况下
But the results

抗微生物的活性也是有点混杂和微弱
with regard to antimicrobial activity were somewhat mixed and modest, at best.

随后进行了多项用氟喹诺酮类药物
A number of phase-3 clinical trials with fluoroquinolones

治疗药物敏感性结核病的三期临床试验
for treatment of drug-susceptible TB were subsequently undertaken.

不幸的是这些试验的结果是一致的
The results of these trials unfortunately were consistent.

在保持可接受治愈率的前提下
Replacing ethambutol with a fluoroquinolone

用氟喹诺酮替代乙胺丁醇
was not sufficient to shorten drug-susceptible TB treatment

药物敏感结核病治疗时间
to 4 months

不足以缩短至4个月
while still maintaining acceptable cure rates.

利福霉素作为一类药物
The rifamycins, as a class,

目前用于治疗包括结核分枝杆菌
are currently used for the treatment of mycobacterial infections

在内的分枝杆菌感染
including TB.

它们抑制细菌RNA聚合酶
They inhibit the bacterial RNA polymerase

是结核病治疗的关键杀菌成分
and are key sterilizing components of TB treatment.

动物以及人群研究的证据表明
There is evidence in animal studies as well as in human studies

我们目前的利福平剂量
that our current dose of rifampin,

即每天10㎎/㎏
that is 10 milligrams per kilogram per day,

不是最理想的
is suboptimal.

几十年前选择当前剂量的一个主要原因
One of the main reasons for the selection of the current dose some decades ago,

是利福平的成本
was driven by the cost of rifampin.

目前正在研究
There is work underway to understand

如何更好地使用利福霉素类药物
how to better use the rifamycin class of drugs,

以及如何从这类药物中获得更多益处
how to get more out of this class of drugs.

有两个重要的研究路线正在进行
There are two important lines of inquiry being undertaken.

首先要了解的是
The first is to understand whether,

对利福平而言
for rifampin,

10㎎/kg是否是最佳剂量
10 milligrams per kilogram is the optimal dose.

目前正在进行的重要临床试验
There are important clinical trials underway currently

已将利福平的剂量
that have increased the dosage of rifampin given daily

增加到每天35㎎/㎏以上
to up to 35 milligrams per kilogram per day and beyond.

通过增加利福平的剂量
So there is hope that increased doses of rifampin

有希望缩短药物敏感性结核病的治疗时间
may hold promise for shortening the treatment of drug-susceptible TB.

关于利福霉素类药物的第二个路线
The second line of enquiry with regards to the rifamycin class

是利福平是否是利福霉素类中的最佳药物
is whether rifampin is the optimal agent within the rifamycin class.

其他旨在研究利福喷丁
There are other ongoing trials

是否可以缩短
that seek to understand whether rifapentine,

药物敏感性结核的治疗时间的
which is a rifamycin with a longer half-life than rifampin,

试验正在进行中（利福喷丁的半衰期比利福平长）
might shorten the duration of treatment for drug-susceptible TB.

临床试验中结核病药物研发
There are some notable gaps

存在一些显著差距
in TB drug development in clinical trials.

后期的候选药物数量不足
There are an insufficient number of drug candidates  at later stages of development.

真正需要包括儿童和青少年结核病患者的
There is a real need for TB clinical trials that include the important populations of children

重要人群相关的临床试验
and adolescents with TB.

还需要进行旨在解决肺外结核病的临床试验
There is also a need for clinical trials that address non-pulmonary TB,

尤其是结核性脑膜炎
perhaps especially TB meningitis.

需要更好的替代标记物
There is a need for better surrogate markers,

尤其是灭菌活性的替代物
especially surrogates for sterilizing activity.

还需要继续加强建设分枝杆菌学实验室的
There is also a need for continuing to build mycobacteriology laboratory capacity

能力和质量控制以支持开展临床试验
and quality management to support clinical trials.

除了试验新药之外
There are a number of opportunities with respect to clinical trials

临床试验方面还有很多机会
beyond trialing new medications.

需要推进新型结核病药物治疗相关的
There is a need for advances in pragmatic clinical trials

临床试验
around new TB drug treatments.

总而言之
In summary,

过去十年在向耐药结核病患者
the past decade has seen some progress in bringing new TB drugs

提供新药物方面取得了一些进展
to patients with drug-resistant TB.

这些的例子是贝达喹啉 硝基咪唑类药物
Examples of these are bedaquiline, the nitroimidazoles,

恶唑烷酮类药物和氟喹诺酮类药物
the oxazolidinones, and the fluoroquinolones.

对于药物敏感性结核病
For drug-susceptible TB,

目前仍在努力将治疗时间
efforts remain underway to shorten therapy to meaningfully

缩短到6个月以内
less than 6 months of duration.

非常感谢您的聆听
Thank you very much for your attention.