Video在线视频

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.

今天
Today,

我们将讨论结核病相关的新药物
we will talk about new drugs,

新治疗方法和临床试验
new regimens, and clinical trials for TB.

这次将重点探讨抗结核药物发现
This talk will focus on principles of TB drug discovery,

制定治疗方案和临床试验相关理论
regimen-building, and clinical trials.

通过约三十年来一系列的临床试验
We got to our current six-month short-course regimen

我们得到了目前为期六个月的短期治疗方案
through a series of clinical trials over about three decades.

这些研究从链霉素与卧床休息的
These began with the initial trial

早期试验开始
of streptomycin versus bed rest

并且在 20世纪70年代发现
and concluded with the finding in the 1970s

将利福平和吡嗪酰胺与异烟肼
that the inclusion of both rifampin

和链霉素一起使用
and pyrazinamide with isoniazid

可将疗程缩短至6个月
plus streptomycin could shorten treatment

而且复发率尚可
to six months with acceptable relapse rates.

左上角的图示显示都是
In the upper left-hand corner

目前抗易感结核的药物
is shown a graphical representation of current TB treatment for drug-susceptible TB.

红线表示估算的细菌负荷
The red line is meant to indicate estimated bacterial burden

可能在最初的几周内快速地增加
which probably increases quite quickly in the initial weeks

然后缓慢增加
and then more slowly after that,

因为利福平很可能杀死了
as the more slowly-replicating bacterial persisters are finally killed,

更多复制较慢的滞留菌
probably by rifampin.

这里有几个重要理论
There are a couple of important concepts in here.

首先是方案中的药物有不同的作用
First is that the drugs in the regimen work differently

且他们之间协同发挥作用
and they work in companionship with each other.

这些药物具有不同的作用机制
These drugs have different mechanisms of action and more than that,

不止如此 它们可能作用于不同的细菌种群
they probably act on somewhat different bacillary populations,

如左下角图例所示
as shown in the lower left-hand corner for example.

异烟肼对于快速繁殖的细菌效果最好
Isoniazid probably works best against the rapidly-multiplying bacteria

而利福平对偶尔繁殖的滞留菌有较好的活性
whereas rifampin has good activity against the more sporadically-multiplying bacteria,

滞留菌可能是发生复发的原因
the persisters that can be the source of relapse when it occurs.

为什么需要新的抗结核药物
Why are new TB drugs needed?

因为我们试图在不增加复发风险的情况下
They are needed to shorten TB treatment

缩短结核治疗疗程
without increasing the risk for relapse.

较短疗程的治疗可以提高患者依从性
Shorter treatment presumably will improve adherence,

减少临床工作量
reduce clinic workload

且可能降低毒性
and possibly reduce toxicities.

对于耐药结核病来说
For drug-resistant TB,

暂定的合理目标是9-12个月的治疗时间
a reasonable interim goal is 9 to 12 months' duration

而对于易感结核病
and for drug-susceptible TB,

合理的目标是4个月的治疗时间
a reasonable goal is 4 months' duration.

我们还需要新药物降低毒性
We also need new TB drugs to lessen the toxicity

并提高目前治疗耐药结核病的耐受性
and increase the tolerability of our current treatments for drug-resistant TB.

新药物从哪里来
Where do new TB drugs come from?

我着重介绍抗菌药物
I will focus mostly on the antimicrobials, the antibacterials, in this presentation.

但首先
But first,

我要说说宿主导向疗法
a word about host-directed therapies.

很明确宿主免疫应答在结核病中
It is clear that the host immune response

起着重要的作用
plays an important role in tuberculosis.

但同样明确的是
But it is also clear

宿主的应答可能是有害的
that the host response can be damaging.

例如
For example,

组织的破坏
it is involved in the tissue destruction

可导致长期肺损伤
that can lead to long-lasting lung damage.

因此宿主导向疗法是针对两个目标的
So the field of host-directed therapies for tuberculosis is directed towards two goals.

一个是加速细菌根除
The first is hastening bacterial eradication

另一个是预防肺部损伤的策略
but the second is strategies to prevent lung damage.

讲回抗菌药物
So back to the antimicrobials.

新的抗结核药物通常有两个来源
New TB antimicrobials generally come from two sources.

一个是新的化学药物
The first is that they can be new chemical entities,

可以是全新的
either completely new,

比如贝那喹胺
as in the case of bedaquiline,

或者是现有药品的衍生物
or derivatives of existing agents,

增强了抗TB活性
that have enhanced activity against TB.

目前正在研究碳青霉烯类药物
There is ongoing work in carbapenems to find identified derivatives

发现及鉴别具有更强的抗结核活性的衍生物
that have much more potent activity against TB.

新的结核病药物也可能来自现有的药物
New TB drugs can also come from existing drugs,

例如最初研发用于其他适应证的药物
for example, drugs originally developed for other indications

如氟喹诺酮类药物
that are found to have good TB activity,

发现具有较好的抗TB活性
such as the fluoroquinolones.

另外
Additionally,

目前使用的结核病药物
there are TB drugs that we currently use

我们并没有优化其使用方法
that we do not use optimally for example,

比如剂量或给药间隔方面
with regards to their dose or dosing interval.

利福霉素就是这方面的例子
And therifamycin is an example of this.

结核病药物开发是一个漫长
TB drug development is a long,

有风险且昂贵的过程
risky and expensive process.

它通常始于鉴定先导物
It typically starts with identification of a lead.

先导物可以通过几种不同方法确定
Leads can be identified in a couple of different ways.

一种常见的方式是通过全细菌筛选
One common way is through whole-bacterial screening.

另一种方法是筛选现有的化学品库
Another strategy is through screening of existing chemical libraries

以鉴别出对某些被认为
to identify chemicals that act on certain prespecified targets

与结核病相关的特定部位起作用的化学品
that are thought to be relevant for TB.

一旦确定了化学先导物
Once a chemical lead is identified,

它通常会经历一个优化过程
it typically undergoes an optimization process

以增强其抗结核活性
to augment its anti-TB activity

并确保它在药学上是适用的
and also to ensure that it is pharmaceutically appropriate.

之后通常会在临床前
Subsequently, preclinical in-vitro studies

进行体外研究和动物研究来确定效果
as well as animal studies typically are performed to identify how well the drug works,

以及它与其他药物联合使用的效果
and how well it works in combination with other agents.

对于活性良好和毒性尚可的药物
For drugs that appear to have good activity and acceptable toxicity,

会开始临床研发试验
usually a clinical development phase then commences,

包括1期 2期和3期临床试验
which includes phase-1, phase-2, and phase-3 human clinical trials.

在药物研发中存在一些障碍
There are a number of obstacles to TB drug development.

资金受限以及对当前的治疗方案
There are financial disincentives,

感到满意等因素
and there has also been complacency with current TB treatment regimens,

大大限制了我们在药物研发方面的进展
significantly limiting our progress in drug development,

还有我们对细菌持久生存的理解不足
our insufficient understanding of bacterial persistence,

以及我们缺乏好的治愈替代指标
and also our lack of good surrogate markers for cure.

通过替代指标
By surrogate markers,

也就是试验或测量
I mean tests or measurements

可以替代真正的临床结果
that can substitute for an outcome of real clinical interest.

这里显示的是新型结核病药物临床试验的
Shown here are the typical stages in the clinical testing

普遍阶段
of a new TB drug.

通常情况下
Typically,

它们分为一期 二期 三期
these are broken down into phase 1 or early stage,

或者说是早期阶段中期阶段 晚期阶段
 phase 2 or mid-stage and phase 3 or late stage.

新药的一期研究
Phase-1 studies of new drugs

通常在健康的成年人身上进行
are typically undertaken in healthy adults.

只有少数参与者
They involve small numbers of participants

主要是确定合适的剂量范围
and they are focused on identifying the right dose range

以及这些剂量的安全性和耐受性
and also the safety and tolerability of those doses.

二期临床试验通常是为了了解
Phase-2 clinical trials in TB typically are aimed at understanding

与其他结核药物联合使用时的杀菌活性
the antimicrobial activity of the drug when it is given in companionship with other TB drugs.

二期研究还提供了
Phase-2 studies also provide more information

更多安全性和耐受性相关的信息
about safety and tolerability.

通常在结核病患者中进行
They are typically undertaken in TB patients,

常用样本量为50到200名参与者
and typical sample sizes for each arm range from about 50 to 200 participants.

最后
And then, finally,

三期临床试验旨在评估治愈持久性
phase-3 clinical trials are aimed at assessing durable cure.

使用治愈持久性作为临床结果
Durable cure is used as the clinical outcome,

也就是说参与者在完成治疗后
which means that participants are followed up for six months to about two years

还需要随访6个月到2年左右
after completing their treatment.

三期临床试验研究规模很大且费用昂贵
Phase-3 studies are large and typically very expensive to undertake.

只有二期临床试验中最成功的药物
Only the most successful drugs

才能进入三期临床试验
in phase 2 progress to phase 3.

结核病药物研发和临床试验
There are several ways in which TB drug development

可以通过几种方式提高效率
and TB clinical trials could be made more efficient.

一是通过鉴定生物标志物
One is through the identification of biomarkers

来作为治愈持久性的替代指标
that are good surrogate markers for durable cure.

替代指标周围的三个区域正在进行工作
Work is underway in three areas around surrogate markers.

二是确定更好的细菌学替代指标
One is identifying better bacteriologic surrogate markers.

也可以用放射学技术作为替代指标
There is also interest in identifying radiographic surrogate markers,

例如PET-CT
for example PET-CT.

最后
Finally,

也可以识别源自宿主的替代指标
there is interest in identifying host-derived surrogate markers,

例如基因转录模式
for example gene transcription patterns.

创新的试验设计也可以提高效率
Efficiency also might be gained through innovative trial designs,

例如适应性试验设计
for example, adaptive trial designs.

最后
Finally,

还需要监管层面的创新
there is a need for regulatory innovations,

即针对高度耐药性感染的新试验框架
that is for new trial frameworks

和新批准机制等方面的创新
and new approval mechanisms for highly-resistant infections.

一旦确定了新的药物
Once a new drug is identified,

就需要在其他抗结核药物存在的环境中
there is a need to go about determining

确定如何最好地使用该药物
how best to use that drug in the context of other TB drugs.

需要考虑很多因素
There are a number of considerations in doing this.

这里列出一部分
Some of them are listed here.

一些因素涉及该药物对结核病的效果
One set of considerations involves the effects of that drug on TB.

首先是可能会考虑新药是否灭菌
One might consider whether the new drug is sterilizing versus bactericidal,

与其他药物作用机制是否有重叠
whether it has overlapping mechanisms of action with other drugs,

与其他药物是否有拮抗或协同作用
whether is it is inhibitory or synergistic with other drugs,

以及与其他药物是否有交叉耐药性
and whether it has cross-resistance with other drugs.

其次是新药对人类宿主的影响
Secondly are the effects of that new drug on the human host,

尤其是可能存在与其他药物毒性重叠
especially with regard to potential for overlapping toxicities with other drugs

和药物之间的相互作用
and drug-drug interactions.

总之
In summary,

目前的药物敏感性结核的短期治疗方法
the current short-course treatment for drug-susceptible TB

是几十年临床试验的成果
is the result of decades of clinical trials.

迄今为止
To date,

结核病治疗方案需要多种药物
TB regimens require multiple drugs,

实现不同的作用机制
with different mechanisms of action

和可能靶向不同的细菌群体
and probably different bacillary population targets.

结核病治疗的抗菌药物正在探索中
Antimicrobials, that is new chemical entities and repurposed existing drugs,

包括新型化学药物和再利用的现有药物
as well as host-directed therapies

以及宿主导向疗法
are being explored for TB treatment.

药物开发是一个漫长的 多步骤的过程
Drug development is a lengthy multi-step process.

由于我们在细菌生存持久性的
For TB,

生物学知识方面了解不甚理想
it is hindered by our suboptimal understanding of the biology

和缺乏现有的替代指标
of bacillary persistence

因此结核病的研究受到阻碍
and our existing poor surrogate markers.

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