#407 ‒ 预防心血管疾病和阿尔茨海默病：早期降低LDL、APOE4以及有前景的新疗法 | Michael Davidson, M.D.

降低了糖尿病风险，但对主要不良心血管事件没有益处。

Reduced the risk of diabetes, but had no MACE benefit.

没有带来任何主要不良心血管事件的益处。

Did not cause any MACE benefit.

主要不良心血管事件。

Major adverse cardiac events.

你说得对，没错。

You're right, right.

心脏病发作或中风的风险降低效果为零。

Heart attack or stroke reduction was nothing.

在这方面没有任何好处。

There was no benefit there.

连趋势都没有，完全持平，但非常安全。

Not even a trend, it was just completely flat, but very safe.

所以这是第二次失败，备受瞩目的失败。

And so that was the second failure, high profile failure.

后来其实又做了另一个试验，结果还是中性，对主要不良心血管事件没有益处。

Actually went to another trial later, still neutral, no benefit on major adverse cardiac events.

这是第二个。

That's number two.

然后是默克？

And then Merck?

然后是礼来。

Then Lilly.

天哪。

Oh my gosh.

然后是礼来的evocetrapib。

Then Lilly, which was evocetrapib.

那个分子不错。

That one's a good molecule.

同样，非常安全，也做了研究，那时候礼来还没有现在这么多资源，所以他们想快点推进。

Again, very safe and was studied, again, it was a time when Lilly did not have the resources it has now, And so they were trying to go fast.

大家都想快点推进，因为这可是个减少心脏病的大好机会，所以关键就是时间。

Everyone was trying to go fast, because again, this could be a huge opportunity to reduce heart disease, so was all about age.

所以他们主要针对急性冠脉综合征做了研究，结果还是那样，LDL降了大概15%到20%，HDL又升了75%左右。

So they went into a study with acute coronary syndrome primarily, and they showed, again, LDL lowering about 15 to 20%, HDL raising again 75 or so.

这个升高HDL的效果非常显著。

A very good HDL raising effect.

不过他们只进行了两年就停了，因为看不到对主要不良心脏事件有什么好处，觉得没希望就终止了。

They only went two years though post starting the trial, and they stopped for futility for no benefit on major adverse cardiac events.

这是在二级预防中。

In secondary prevention.

二级预防。

Secondary prevention.

是高风险的二级预防。

Was a high risk secondary prevention.

顺便说一句，Michael，前两项研究是初级预防还是全都是二级预防？

By the way, Michael, the first two studies were primary or All secondary.

这些都是二级预防，是的。

These are all secondary prevention, yeah.

那个试验的重要之处在于，依折麦布现在很出名，我们经常用它来降低低密度脂蛋白，就是那个Zetia。

What's important about that trial is ezetimibe, is now a well known, we use ezetimibe all the time, Zetia, for lowering LDL.

他们还做了一个急性冠脉综合征的试验，和ACCELERATE试验类似，那个是礼来公司的试验。

They also did an ACF, acute coronary syndrome trial, which was similar to what was done in the ACCELERATE trial, which is the Lilly trial.

我们知道两年时间太短了，因为在依折麦布的类似试验中，依折麦布是经过充分验证的降脂药，大家都认可它的益处，但也要超过两年，曲线才会分开。

We know that two years is too short because in a similar trial with ezetimibe, which is a well proven LDL lowering drug, it has, everyone recognizes the benefit of ezetimibe, it took more than two years for the lines to separate.

两年后，他们的曲线在主要不良心血管事件上没有差异，但两年后它们分开了。

After two years, their lines were, there's no difference in major adverse cardiovascular, but after two years they separated.

所以我们相信，在ACCELERATE试验中，如果时间更长，evacetrapib也会出现类似的结果。

And so the similar would have happened, we believe, with evacetrapib in the ACCELERATE trial.

虽然使用Repatha和Praluent，我们在大约两年时看到了益处。

Although with Repatha and Praluent, we did see benefit at about two years.

但这只是降低了15%的低密度脂蛋白。

This was only a 15% LDL lowering.

所以有趣的是，在ODYSSEY结局研究里，也就是Praluent那个研究，另一种PCSK9抑制剂，如果你看那些LDL低于100的人群，也就是这个研究里的情况，他们也是在两年之后才分开的。

So it's also interesting, in the, ODYSSEY outcome study, which is the Praluent, which is the other PCSKAT inhibitor, If you look at populations that had LDLs below 100, which is what this, they also didn't separate until after two years.

Fourier研究也一样，哪个是Fourier？Fourier是针对致病性的。

Same with Fourier, which one was more Fourier was for pathogenic.

哪个研究他汀使用得更充分？

Which one was more heavily statinized?

我记不清了。

I can't remember.

但对你来说，那不是急性冠脉综合征人群。

But for you it was not a acute coronary syndrome population.

明白了。

Got it.

那是慢性稳定型。

It was a chronic stable.

他们分开的急性冠脉综合征人群有时候病情很重，事件发生率很高。

They send a separate, acute coronary syndrome populations sometimes can be pretty sick and they get a lot of events.

所以你得等更久才能看到效果。

So you have to go longer to see the benefit.

你的意思是，你觉得礼来那项研究停得太早了吗？

Are you saying that your view is maybe the Lilly study was stopped too soon?

它是因为无效而终止的，但本来应该继续下去的。

It was stopped for futility when it should have kept going.

这对我们的药物，obicetrapib，来说是个大问题。

That was for us a big issue for our drug, obicetrapib.

那是最难解释的一点。

That was the hardest one to explain.

礼来那个药在HDLC和LDL C动力学方面有什么特点？

And what were the features of the Lilly drug in terms of HDLC and LDL C kinetics?

LDL降低大约15%到20%。

Lardelli about 15 20%.

并且提高了HDLC。

And raised HDLC.

PCL又降了75%左右。

PCL again 75% or so.

这药挺好的，你知道，但关键是它很安全。

It's a good, you know, but the thing is it was safe.

它实际上有显著的总死亡率获益，但不是主要不良心血管事件获益。

It actually had a total mortality benefit that was significant, that it was not a major adverse cardiac event benefit.

所以这药本来不会获批，但那不是主要终点。

So drug would never have been, but that was not the primary endpoint.

有意思，它有全因死亡率的获益。

That's interesting, it had an overall all cause mortality benefit.

这归因于哪些其他原因呢？

What other causes was that attributed to?

嗯，主要是心血管方面的，但也有一些非心血管死亡率的降低。

Well, was largely cardiovascular, but it had some non cardiovascular mortality.

所以当心血管死亡率几乎显著时，也有一些非心血管方面的获益。

So when cardiovascular mortality was almost significant, there was also some non cardiovascular benefit as well.

他们有没有预先规定必须在两年时有一个结果？

Did they pre specify that they had to have an outcome at two years?

这就是他们停止试验的原因吗？

Is that why they stopped it?

他们确实预先规定在两年时进行一次分析。

They had pre specified that there would be an analysis at two years.

这里面还涉及一些公司内部的问题。

There were also corporate issues involved.

那时候礼来公司财务上很困难。

It was a tough time for Lilly financially.

跟现在的情况完全不同。

It's very different than where they are today.

他们不得不快速决定优先推进哪些研发项目。

They had to make some quick decisions about prioritizing their pipeline.

大公司就是这样，必须做出这些决定。

As big corporations go, you have to make these decisions.

所以他们决定提前终止这项研究。

So they had decided to cut the study short.

再说，提高高密度脂蛋白，你可能会认为应该已经带来好处了。

Again, HDL raising, you would think would have a benefit already.

所以降低低密度脂蛋白当时并不被认为是主要机制。

So it was the LDL lowering wasn't really thought of as the main mechanism.

那项研究在糖尿病方面有没有显示出改善？

Did that study show any improvement in diabetes?

是的，确实有改善。

It did also, yes.

所有CETP抑制剂，甚至torcetrapib，都显示出对糖尿病的益处，全部都是。

All the CT inhibitors, even torcetrapib showed a diabetes benefit, all of them.

所以这也是我们为什么在obicetrapib上关注这一点。

So this is again why we're focusing on that with obicetrapib as well.

所以重要的研究是默克的那项，它实际上挽救了整个类别，尽管该药物本身由于不同原因未能上市。

So the important study that was the Merck study, that actually saved the class, even though the drug itself didn't make it to market for different reasons.

这得归功于默克公司，我是说，他们一开始启动试验时，也是完全围绕HDL的，但看到礼来和达塞曲匹的情况后，他们就想确保试验有足够的统计效力，以便可能捕捉到LDL方面的获益。

It was, to Merck's credit, I mean, they started the trial, again, all about HDL, but when they saw what happened with the Lilly drug and dalsetrapib, they wanted then to make sure the study was adequately powered to maybe pick up an LDL benefit.

他们招募了三万名患者。

They had 30,000 patients.

这可能是史上规模最大的结局研究。

That's perhaps the largest outcome study ever done.

而且他们进行了四年。

And they went for four years.

所以这是一项非常大型的研究。

So a very large study.

他们进行了四年。

They went for four years.

基线LDL是60。

The baseline LDL was 60.

所以我们已经是在谈论较低的LDL了。

So we're talking about already low LDL.

他们的LDL降低了17%，绝对LDL降低了每分升11毫克。

They got a 17% LDL lowering, 11 per deciliter absolute LDL lowering.

他们获得了9%的相对风险降低，这符合预期，甚至比预期的还要好。

They got a 9% relative risk reduction, which is what you'd expect, if not more so than what you'd expect.

所以这证明了通过CTE抑制降低LDL可以转化为心血管获益，这对我们来说是一项关键研究。

And so it proved the LDL lowering benefit with CTE inhibition can translate into a cardiovascular benefit, and that was the key study for us.

那么，这种药物没有继续推进的原因是它在脂肪组织中会有不良沉积，而且这种沉积不会停止。

Now, reason why the drug didn't go forward was it had this unfortunate deposition in fat tissue that wouldn't stop depositing.

所以如果你服用了它，实际上几年内都无法将药物完全排出体外。

And so if you took it, you would not wash the drug out for years, actually.

而且还有环境问题。

So there's also environmental issues.

它会进入供水系统。

It gets in the water supply.

对于具有这种药代动力学特征的药物，默克公司需要处理的问题实在太多了。

There was just a lot of issues that Merck would have to deal with with a drug with that type of pharmacokinetic profile.

那他们是怎么在大型三期试验中才发现这个问题的，而二期试验时却不知道呢？

And how did they figure that out only in the large phase three study without knowing it in say a phase two?

是什么引起了他们的注意？

Like what was it that even brought that to their attention?

随着试验的进行，他们在二期试验中开始获得更多数据，但他们没有关注药物的长期清除情况，也没有做药代动力学研究。

As the studies went along and they started getting more in the phase two studies, they didn't look at long term clearance of the drug, it didn't started They didn't do the PKs.

他们做了药代动力学，知道半衰期很长，但没意识到有多长，也没意识到药物沉积了多少。

They did the PK, they knew it was a long half life, they didn't realize how long, they didn't realize much it got deposited.

我参与了一些。

I did some of them.

他做了，他实际上做了脂肪活检，看看脂肪组织中有多少药物。

He did, he actually did fat biopsies to see how much drug was in the fat tissue.

这是口服药吗？

And this was an oral drug?

口服药，亲脂性的，是的。

Oral drug, lipophilic, yes.

哇。

Wow.

是啊，所以很不幸，因为这个原因，它作为商业药物根本行不通。

Yeah, so it was unfortunate in that it was just not a viable commercial drug for that reason.

尽管它的安全性很好，能降低主要心血管不良事件，但因为MACE获益的幅度不大，人们没意识到这对药物营销是个问题。不过从概念验证的角度，证明药物能降低LDL并减少事件，这项研究很棒，证实了CTB抑制剂降低LDL确实能带来心血管获益。

Even though it had good safety profile, it lowered MACE, but also because the magnitude of the MACE benefit was modest, people don't realize it's an issue for how you market the drug, but from a proof of concept of proving the drug works to lower LDL and reduce events, it was a great study to confirm that the LDL lowering with the CTB inhibitor can in fact result in a cardiovascular benefit.

你提到过这个好几次了，我想确保大家明白为什么会这样。

You've referred to this a couple of times, so I just want to make sure people understand why this is the case.

这其实要回到我们之前关于因果关系的讨论。

It actually goes back to sort of our argument earlier about causality.

当你把所有一级预防试验、所有二级预防试验、所有孟德尔随机化研究和所有流行病学数据都排在一起，以LDL C为横轴，事件率为纵轴作图，它们都是一条条向下倾斜的线。

When you line up all of the primary prevention trials, full stop, all of the secondary prevention trials, full stop, all of the Mendelian randomizations and all of the epidemiology and you plot on the x axis LDL C and on the y axis event rate, they're all a bunch of lines going down.

所以，它们是四条不同的线，斜率不同，基于不同的……而且，鉴于这些回归线拟合得如此紧密，很容易预测结果。

So, they're four distinct lines, different slopes based on different And therefore, given how tight those regressions are, it becomes very easy to predict what you're getting at.

我只是想让听众明白，为什么你说如果LDL C从60降到49，降幅17%，预期事件相对减少9%，等等。

I just want make sure the listener understands why it is that you're saying if you have a 17% reduction in LDL C from 60 to 49, you would expect an event reduction on a relative basis of 9%, etcetera.

对，这个公式很简单，已经很成熟了。

Yeah, the formula is easy, it's well established.

每降低一毫摩尔，也就是每分升38.8毫克的低密度脂蛋白，相对风险就能降低22%。

For a one millimole, which is 38.8 per deciliter of LDL, you get a 22% relative risk reduction.

而且这基本上是线性的。

And that's largely linear.

对，是线性的。

It's linear, right.

但关键看绝对值，不是百分比。

But absolute is the key, not percent.

你得看低密度脂蛋白的绝对降幅，然后才能算出获益。

You gotta look at the absolute LDL lowering, and then you can calculate the benefit.

我们显然是在为我们的结果研究做这个。

We're doing that for our, obviously, outcome study.

根据我们在PREVAIL试验中希望达到的绝对低密度脂蛋白降幅，我们可以预测出获益。

We can have a predicted benefit based on our absolute LDL lowering that we hope to achieve in our PREVAIL trial.

你根据这个来设计研究，就能看到好处有多大。

You power studies accordingly, you can see what the benefits.

而且还得把时间拉得足够长，这也是另一个关键点。

As long as you go long enough too, that was the other key thing.

治疗第一年，最多只能获得一半的益处。

In the first year of treatment, you get half the benefit at best.

两条曲线需要时间才会分开。

It takes time for the lines to separate.

这就回到你之前提到的那个点，所有这些回归分析都跟你用什么方法无关。

And that's what gets back to the other point you made earlier, which is all of these regressions are independent of how you do it.

孟德尔随机化研究是说我们通过基因来降低它。

The Mendelian randomization says we're going to lower it genetically.

决定你我的LDL水平的是基因彩票。

It's the genetic lottery that determined your LDL versus mine.

一级和二级预防试验是基于各种药物的混合，流行病学数据也一样，它结合了基因和药物两种因素。

The primary and secondary prevention trials are based on a potpourri of drugs, same with the epidemiologic stuff, which combines both genetic and drugs.

所以，这再次印证了LDL的因果关系，因为无论怎么降低，效果都是一样的。

So, again, it speaks to this idea that reinforces the causality of LDL because independent of how it's lowered, you're getting the same effects.

你常听人说，这些药确实改善了结果，很难否认，但如果你要否认LDL的作用，那肯定不是降低LDL本身带来的效果。

You'll often hear people say things like, Well, it's hard to deny that these drugs improve outcomes, but it must be something different than LDL lowering if you want to deny that LDL plays a role.

他们会说这些药有多效性作用之类的，但当你看到全部证据时，这些说法显然就有点站不住脚了。

They'll talk about pleiotropic effects of these drugs or things like that, but obviously those arguments become a little bit silly when you consider the totality of the evidence.

我从来不是多效性的支持者，实际上，我是一直在争论这个问题的人。

I've never been a pleiotropic, in fact I was the one who always debated that issue.

我一直认为，就是LDL，就是LDL。

I've always been, it's LDL, it's LDL.

现在我觉得这个论点更强了：他汀类药物除了非常有效且耐受性好之外，没什么特别的，而他汀降低LDL带来的好处，并不比其他能同样降低LDL的药物更大。

Now I think the argument is stronger, that there's nothing special about statins other than they're very effective and well tolerated, but there's nothing special about the LDL lowering about statins that result in a greater benefit than any other LDL lowering drug that can achieve the same levels in a patient.

有了这些背景，现在我们来谈谈obicetrapib，你和John以及团队的工作。

So with all of that as background, now let's talk about obicetrapib, the work that you and John and the team, of course.

但先说说，你们是怎么决定第五次尝试这个方向的？

But let's just talk about how you decided it was worth going after this for a fifth time.

我之前把我的公司卖了，那家公司是做一种针对心脏病炎症的白介素六抗体的。

I had sold my previous company an interleukin six antibody for heart disease, inflammatory.

就是IL-6，不知道你熟不熟悉，它是关键的炎症细胞因子，那个研究今年就会出结果。

It's a IL-, I don't know you're familiar with IL-six, but it's the key inflammatory cytokine, and that study's actually coming out this year.

那个试验叫ZEUS试验。

It's called the ZEUS trial.

那是个非常大的研究，马上就要出来了。

It's a big, big study coming up.

所以我把Corvidia卖了之后，约翰说，咱们把obicetrapib从安进那里拿回来吧。

So I had sold Corvidia, and John said, Let's get obicetrapib back from Amgen.

安进当时把它搁置了，因为Repatha上市时卖得不太好。

Amgen had put it on the shelf because Repatha had struggled on its launch.

他们把它降了优先级，所以就一直放在那儿，本来准备进入二期，甚至可能直接进三期。

They deprioritized it, so they kind of had it sitting there, ready to go into phase two, maybe even right into phase three potentially.

所以我们俩联手，成立了NewAmsterdam Pharma。

So we teamed up together and started NewAmsterdam Pharma.

那是多少年前的事了？

How many years ago was it?

现在差不多五年了，这已经是第六年了。

This is five, almost, this is our sixth year now.

这很有意思，因为瑞帕塔是2015年上市的。

That's so interesting because Repatha launches in 2015.

他们把奥贝曲帕放在架子上放了五年？

They kept obi on the shelf for five years?

我记得他们是2017年收购的。

I think they bought it in 2017.

他们是2017年收购的。

They bought it in 2017.

有意思。

Interesting.

他们其实在生产和工艺方面做了很多出色的工作。

They actually did a lot of great work on the manufacturing, the process.

他们做了改进，让生产成本更低了。

They worked on it, made it much more cost effective manufacture.

但他们没有做任何临床试验。

But they didn't do any clinical trials.

他们只是把它放在货架上。

They just kept it on the shelf.

它在美国已经有IND了，还是说，不，它有二期数据。

It already had an IND in The US or this was No, it had phase two data.

在美国？

In The US?

在美国，是的。

In The US, yeah.

好的。

Okay.

它已经准备好了。

It was ready to go.

所以我们最初考虑过他汀耐受性，想用它作为快速进入市场的途径，但我们意识到FDA对Cd抑制的看法，因为历史原因，我们确实没有路可走。

So we initially thought about statin tolerance and using it for those patients as a quick route to the market, but we realized the FDA view on Cd inhibition because of the history, we really didn't have a path there.

FDA不喜欢把他汀耐受性作为适应症。

The FDA does not like statin tolerance as an indication.

他们甚至怀疑它是否真的存在，信不信由你。

They're very wary of it even really being a true thing, believe it or not.

我是说，你我都看到了，我们大家都看到了，但在学术界和FDA，他们并不真的相信这是一个真实的现象。

I mean, you and I see it, don't if we all see it, but in the academic world and in the FDA, they don't really believe it as a true phenomenon.

因为当你看看安慰剂对照试验，它的发生率很低，只有百分之四点九。

Because when you look at the placebo controlled trials, it's very low It's four point nine percent.

是的，但即使是真正的他汀耐受性也很难找到。

Yeah, but even true statin tolerance is very hard to find.

我是说，在试验中确实有。

I mean, it's in the trials.

不管怎样，它存在，它存在。

Anyway, it exists, it exists.

那是我们的第一条路。

That was our first path.

但是，当我们和FDA会面后，意识到我们需要走完整的LDL降低路线，这是一个更大的项目。而且，因为历史原因，我们知道在药物上市时必须要有结局研究。

However, once we met with the FDA and realized we need to go into a full boat LDL lowering path, which is a much more larger program, And also, we know we had to have outcome study at the time of the launch of the drug because of the history.

那你们在收购时，二期数据是什么样的？

But what were the phase two data that you had at the time of acquisition?

我们有一个TULIP研究，那是John在之前的公司主导的研究。

We had a TULIP study, which was the study that John had led in a predecessor company.

对，你能提醒我和听众们那个研究是什么样的吗？它显示LDL降低了45%。

Yeah, can you remind me and the listeners what that study So it showed looked that 45% LDL lowering.

好的，那OB有什么不同？

Okay, so what was different about OB?

它更有效，其他的CT抑制剂都在100毫克以上，而且它们降低LDL，就像我提到的。

It's a much more potent, so it's only, the other CT inhibitors are all in the one hundred milligram plus range, and they lowered LDL, as I mentioned.

那你们是10毫克。

Then you're at ten milligrams.

你用的是十毫克，甚至我们最初还有五毫克的剂量，在试验中也能把低密度脂蛋白降低40%到45%到50%这个范围。

You're at ten milligrams, even five milligrams we had initially too, lowered LDL in that 40 to 45 to 50% range in the trials.

那高密度脂蛋白的提升呢？

And the HDL raising?

150%。

150%.

所以它在降低低密度脂蛋白和提升高密度脂蛋白两方面都更有效。

So it's a lot more effective on both lowering LDL and raising HDL.

它就是一种更有效的CETP抑制剂。

It was just a much more potent CETP inhibitor.

TULIP研究持续了多长时间？

And the duration of the TULIP study was how long?

那只是一个短期研究。

It was just a short term study.

我记得大概是八到十二周，是个相对较短的研究。

I think it was eight to twelve weeks, something It like was relatively short study.

它非常有效，而且耐受性很好。

It was very effective, very well tolerated.

对LDL的改善效果真的很不错。

It was a really nice LDL benefit.

所以我们想用它来降低LDL。

So we wanted to look at it for LDL lowering.

与此同时，除了默克的数据，所有孟德尔随机化研究，差不多在同一时间，都证实了降低LDL能带来心血管方面的益处。

Again, the meantime, all the Mendelian randomization studies, besides the Merck data, at the same time, or roughly the same time, all the Mendelian randomization study confirmed that LDL lowering translates into cardiovascular benefit.

迈克尔，不好意思打断一下，这些不就是那些表明提升HDL对CETP抑制剂的益处没有贡献的研究吗？

Weren't these the same study, sorry to interrupt Michael, that suggested that the HDL raising had nothing to do with the benefit of CETP inhibition?

没错。

Exactly.

好的。

Okay.

其他提升HDL的基因也没有显示出益处。

And other HDL raising genes saw no benefit.

至少这个益处不能归因于高密度脂蛋白的作用。

At least the benefit could not be explained by the HDL effects.

如果你看那些与较低风险相关的高密度脂蛋白升高基因，它们通常还伴随其他因素，比如低密度脂蛋白降低或甘油三酯降低。

It was, if you looked at HDL raising genes that are associated with lower risk, they also had other things like LDL lowering or triglyceride lowering.

没有哪个单纯升高高密度脂蛋白的基因与保护作用相关。

There was no pure HDL raising gene that was associated with protection.

这是《自然》杂志上的一篇论文，大约在，对，那时候。

This was a paper in Nature circa Yeah.

大概2012年左右？

What, twenty twelve ish?

对，没错，就是这样。

Yeah, right, exactly.

是的，是的，那是另一个重要的点，我觉得这一点没有得到足够的关注。

Yeah, yeah, that was the other So that was the other important I feel like that doesn't get enough attention.

你说得对，你看，现在还有很多医生和病人跟我说，嗯，我讨厌这个词，我讨厌这个词，但大家知道我说的是什么意思。

To your point, you said, look, are still a lot of doctors out there, a lot of patients I hear saying, well, I hate the term, I hate the term, but people know what I mean when I say this.

我的好胆固醇很高，所以我没事。

My good cholesterol is high, so I'm okay.

所以，尽管用词不当，即使他们说我的高密度脂蛋白胆固醇很高，我没事，答案也是不对的。

So, notwithstanding the nomenclature flub, even if they were to say my HDL cholesterol is high, I'm okay, the answer is no.

我们十多年前就知道这不是真的。

We've known for over ten years that that is not true.

你注意到我一直在努力避免说“好胆固醇”这个词。

You notice I've really worked hard to avoid saying the term good cholesterol.

我避免用这个词，因为我们共同的朋友讨厌它，我们知道，但这样表达是错误的。

I'm avoiding using that term because our mutual friend hates it, as we know, but it's the wrong way to phrase it.

这样表达是错误的。

It's the wrong way to phrase it.

但再说一次，我觉得听到病人这么说是一回事，他们可以被原谅，因为他们不生活在这个领域，但当我听到医生说“是的，但他的高密度脂蛋白胆固醇很高”时，我真的很难接受。

But again, I think it's one thing to hear patients say that and they can be forgiven because they don't live in this world, but I really struggle when I hear physicians say, Yeah, but his HDL cholesterol is high.

所以，我们没事。

So, we're okay.

我有一个病人来找我，他们的低密度脂蛋白胆固醇高得离谱，高密度脂蛋白胆固醇也高，然后他们说，'嗯，是的，但我的医生告诉我，因为我的高密度脂蛋白胆固醇这么高，甘油三酯又低，所以我没事，对吧？'

I have a patient that comes to me and their LDL C is through the roof and their HDL C is high and they say, Well, yeah, but my doctor told me that because my HDL cholesterol is so high and my triglycerides are low, I'm fine, right?

所以高密度脂蛋白真的很有意思。

So HDL is really interesting.

我们认为，如果以正确的方式提高它，它可能仍然有一些心血管方面的益处。

We believe it could still have some cardiovascular benefits if you raise it the right way.

而且，因为高密度脂蛋白，确实有一些遗传因素会提高高密度脂蛋白，从而增加风险。

And also, because HDLs, there are definitely genetic factors that raise HDL that increase risk.

比如SRB1，那是一个已知的高密度脂蛋白基因，确实会增加风险。

Like SRB1 for example, that's a known high HDL gene that does increase risk.

我们知道酒精会提高高密度脂蛋白，并导致各种更高的死亡率问题。

We know alcohol raises HDL and causes all kinds of higher mortality issues.

所以当你看到高密度脂蛋白时，高密度脂蛋白高是一件复杂的事情。

So when you look at HDL, it's a complicated thing to have a high HDL.

我们可以用一整期播客来讨论如何评估高密度脂蛋白高的患者，以及我们如何思考、如何建议他们这意味着什么。

We can talk about a whole podcast about how we evaluate a high HDL patient and how we think about, how to advise them about what it means.

因为有时候高密度脂蛋白高可能是件好事。

Because sometimes it could be quite good.

我有一个朋友，高密度脂蛋白胆固醇非常高，大概100毫克每分升，低密度脂蛋白胆固醇中等，可能也是100到110毫克每分升。

I have a friend with very high HDL cholesterol, about 100 milligrams per deciliter, and modest LDL cholesterol, so maybe also one hundred, one hundred and ten milligrams per deciliter.

他一直以为自己完全没有风险。

And he had always assumed he was totally risk free.

也许他的低密度脂蛋白甚至更低。

Maybe his LDL was even lower than that.

可能低密度脂蛋白在90到100之间，高密度脂蛋白在100到110之间。

It might have been 90 to 100 with HDLC of 100, 110.

我成功说服了他。

And I was able to convince him.

我说，你看，从统计学的角度来说，你是对的。

I said, Look, you're right statistically speaking.

你的高密度脂蛋白胆固醇可能确实反映了某种好的或保护性的因素。

Your HDL cholesterol is probably reflective of something good or protective.

但我读过文献里足够多的病例，知道我们可能面对的是功能严重异常的HDL。

But I've read enough cases in the literature to see that we could be looking at highly dysfunctional HTLC.

所以，你介意做个CT血管造影吗？

So would you mind getting a CT angiogram?

他做了，结果发现血管里有不少斑块。

Which he did and he had significant burden of disease.

所以他很可能有SRB1突变。

So he probably has the SRB one.

这个突变主要在德系犹太人中比较常见，但总体来说还是相对罕见的。

That's Ashkenazi Jewish predominantly, it's where we find it most commonly, it's still relatively rare.

我们在利比诊所见过一些病例，就是因为SRB1导致高HDL的。

We see, I have a series on that in my Libbey clinic that have the high HDL due to SRB1.

还有内皮脂肪酶，总共有三种升高HDL的基因，要么不保护，要么反而增加风险。

There's endothelial lipase, there's like three HDL raising genes that either don't protect or increase risk.

然后还有酒精这个因素。

And then you have alcohol.

所以你把那个加进去，就会得到一个非常复杂的故事，说HDL高是保护性的。

So you throw that in the mix, you can get a very complicated story about HDL being high, being protective.

我们有理由相信，我们仍然对obicetrapib提高HDL能带来心血管益处抱有希望，但我们也主要关注其他HDL益处可能是什么，比如我们稍后还会谈到的，像预防糖尿病和阿尔茨海默病。

The reasons to believe, we still have hope that obicetrapib's HDL raising benefit can result in a cardiovascular benefit, but we're also focusing primarily on what the other HDL benefits could be, like we're still talking about later, like diabetes prevention and Alzheimer's.

这就是我们希望与HDL升高益处相关联的。

That's what we hope is linked to the HDL raising benefit.

我们现在正在所有研究中调查这一点。

We're investigating that now in all our studies.

所以当约翰上播客时，我想大概是四年前，但自那以后发生了很多事情。

So when John was on the podcast, again, I think it was four years ago ish, but a lot has happened since then.

那么，让我们谈谈今天的进展。

So, let's talk about where we are today.

目前对obicetrapib的理解状况如何？

What is the state of understanding of obicetrapib?

我们先从心血管开始，因为约翰当时预测的是，这将对心血管疾病有益，但也会对代谢疾病有益，还会对阿尔茨海默病有益。

And let's start with cardiovascular because what John predicted at the time was this is going to have benefits in cardiovascular disease, but it's going to have benefits in metabolic disease, it's going to have benefits in Alzheimer's disease.

那我们就按这个顺序来吧。

So, let's take them in that order.

那我们先说说目前已知的情况，ROSE试验是最新的吗？

So, let's start with what is known today based on the ROSE trial is the most recent?

Broadway的Broadway的Tandem，对。

Broadway's Broadway's Tandem, yeah.

我们现在已经完成了另外两项二期试验和三项非常大的三期试验。

So we've now done two more phase two trials and three very large phase three trials.

这些试验都已完成，而且我们实际上已经提交到欧洲申请批准了。

And they're all been completed and were actually filed in Europe for approval.

在美国，我们正在等待名为PREVAIL的结果研究，以确定时机。

In The US, we're waiting to time it on the outcome study called PREVAIL.

所以我们启动了PREVAIL。

So we started PREVAIL.

我们当时有勇气和远见，在三期试验的同时启动了结果研究。

So we had, I hope, the courage and the foresight to start our outcome study at the same time as our phase III trials.

作为一家小公司，我们很幸运，虽然一开始就有钱完成试验，但我们是边做边筹钱，现在我们有充足的资金来完成PREVAIL试验。

As a small company, we were able to, knock on wood, even though we'd have the money to finish the trials, start the trials, get them completed, and then we raised money along the way to now we have plenty of cash to finish the trial, the PREVAIL trial.

所以我们觉得这对我们来说真的很顺利，因为三期试验的成功让我们有资金去完成其他试验，所以时间点对我们来说非常合适。

So we feel it really worked out well for us, because the success of the phase three trials allowed us to fund the finishing of the other trials, so it timed it extremely well for our efforts.

ROSE和ROSE 2试验都再次显示，单药治疗能降低45%到50%的LDL，而联合依折麦布的话，能降低55%左右，效果更好。

We had ROSE and ROSE two both showed, again, the forty five percent to fifty percent monotherapy benefit, and then in combination with ezetimibe, you know, in that fifty five percent range higher, better LDL lowering.

然后我们做了布鲁克林试验，那是一个家族性高胆固醇血症的试验。

We then did what was called Brooklyn, which is a familiar hypercholesterolemia trial.

你知道，你做过很多关于这种常染色体显性遗传病的播客，这种病会导致非常高的LDL，而我们的试验显示，一年内LDL降低了40%。

Know you've done multiple podcasts on this autosomal dominant genetic disorder, very high LDL, showed a 40% LDL lowering over a year.

所以这是一项为期一年的研究。

So it's a one year study.

给我讲讲那些患者的情况。

Tell me about those patients.

他们之前已经在用什么药了？

They were already on?

几乎所有患者都在服用高强度他汀类药物。

Almost all were on high intensity stands.

很多人已经在服用依折麦布或PCSK9抑制剂。

Many were on ezetimibe or PCSK9 inhibitors already.

这些患者治疗已经很到位了，但他们的低密度脂蛋白胆固醇仍然偏高。

These are very well treated but their LDLs were still too high.

高到什么程度？

How high?

嗯，平均低密度脂蛋白胆固醇大约在100左右，差不多这样。

Well, average LDL is roughly around 100, something like that.

所以换句话说，入组标准并不限定你具体用哪种药，只要你在接受最大剂量治疗，而低密度脂蛋白胆固醇仍然超过某个阈值就行。

So in other words, the inclusion criteria is not limited to exactly which drug you're on, it's just that you're on maximum therapy and your LDL is still above a certain threshold.

所以对于家族性高胆固醇血症患者，当你在任何联合用药方案下，低密度脂蛋白胆固醇达到100时，obicetrapib能额外降低40%。

So on the familial hypercholesterolemia patients, when you show up at a LDL C of 100 on whatever combination you're on, obicetrapib lowered it by an additional 4040%.

所以大约从100降到60毫克每分升，差不多是这样。

So lowered it from one hundred to sixty milligrams per deciliter About on approximately.

我觉得这些数字大概就是这样。

That was, I think, are approximate numbers.

十二个月结束时，相比安慰剂，降幅大约是40%。

About 40% was the reduction at the end of twelve months versus placebo.

然后是Broadway试验，这些患者都是动脉粥样硬化性心血管疾病患者。

And then the, Broadway trials, these are all atherosclerotic cardiovascular disease patients.

同样，所有人都用最大剂量的他汀，大多数用高强度他汀，大约70%的人用的是20或40毫克的瑞舒伐他汀，或者40或80毫克的阿托伐他汀。

Again, all on maximal statins, majority on high intensity statins, like seventy percent were on twenty or 40 of rosuvastatin, or forty or 80 of atorvastatin.

他们都得到了很好的治疗。

They're all very well treated.

我们得到了大约35%的LDL降低效果，调整安慰剂效应后，略低于这个数。

And we got roughly around a 35% LDL lowering benefit, and then adjusting for placebo, a little less than that.

但十二周时变化幅度差不多是这样，并且持续了五十二周。

But it was around that percent change at twelve weeks and then it continued for fifty two weeks.

这就是我们的两个关键三期试验。

And so that was our two pivotal phase three trials.

我们还和依折麦布联合做了另一个叫Tandem的试验，LDL降幅非常接近50%。

And in combination with Ezetimibe, did another trial called Tandem, where the LDL lowering was very much 50%.

所以我们正在开发一种复方药，把这两种药合在一起。

So we have a combo pill we're developing the two drugs together.

不过，Broadway试验真正帮到我们的是，我们展示了在一年内主要不良心脏事件减少了21%。

What was important about Broadway though that really helped us a lot was we showed in that study a twenty one percent reduction in major adverse cardiac events at one year.

这个结果在统计学上并不显著，因为只有2500名患者，但方向是对的，而且相当有力。

It was not statistically significant, because this is two thousand five hundred patients, but it was the right direction, and it was pretty powerful.

如果看里程碑分析，我们把前六个月去掉，结果就开始变得显著了。

If you look at kind of a landmark analysis, we divide, take the first six months away, it starts to become significant.

而且记住，这些曲线需要时间才能分开。

And then remember, it takes time for these curves to separate.

大家都非常兴奋。

Everyone got excited.

我们显然想利用这一点来推进PREVAIL，因为PREVAIL的患者群体几乎相同，有9500名患者。

Again, we're trying to obviously leverage that with PREVAIL, because it's almost identical population in PREVAIL, which is nine thousand five hundred patients.

这是动脉粥样硬化性心血管疾病（ASCVD）人群。

It's an ASCVD, atherosclerotic cardiovascular disease population.

LDL还是偏高，这是关键，你得让LDL水平高一些，但又不能太高，否则降脂治疗的效果会太强，或者会带来伦理问题。

LDL, again, in the higher end, that's the key, you have to try to get higher LDL levels but not being too high where it becomes, you get too much drop into therapies or you get unethic issues, ethical issues.

所以这些患者都在接受最大耐受剂量的他汀治疗。

So these are all on max B tolerated stats.

这项研究叫PREVAIL，现在已经进行到第三年了。

That's called PREVAIL, and that study now is approaching, we're in the year three of the study now.

那这项研究什么时候出结果？

And this study will read out when?

我们有两个条件来决定试验结束。

We have two factors to stop the trial.

一个是至少随访两年半。

One is that we have a minimum fallback of two and a half years.

这又是从其他试验中学到的经验。

Again, the learnings from the other trials.

另一个也是由事件驱动的。

And the other is also event driven.

需要多少事件才能让研究有足够的统计效力，来评估我们所说的四终点MACE，也就是心脏病发作、中风、心血管死亡，还有冠状动脉血运重建，这就是四终点MACE。

How many events to power the study appropriately for what we call four point MACE, which is the heart attack, stroke, cardiovascular coronary death, and then revascularization, coronary, so those are the four point MACE.

所以我们需要足够的事件数才能停止试验。

So we have that events need to be adequate to stop the trial.

所以这可能会让我们比两年半的时间稍微长一点。

So that may take us into a little bit longer than the two and a half year.

但两年这个时间点，今年年底就到了，这是最短随访时间。

But the two and year mark ends this year, at the end of this year, for the minimum follow-up.

这项试验将在欧洲和美国进行评估。

That will be a trial evaluated in both Europe and The United States.

全世界范围内，是的。

All over the world, yeah.

中国、日本，到处都是，有400多个试验点，这是一项全球性研究。

China, Japan, everywhere, it's 400 plus sites and it's a global study.

如果这项研究结果是积极的，那是不是就能在欧洲和北美获批，用于二级预防的obicetrapib？

And the outcome of that study, should it be positive, would be approval in Europe and North America for obicetrapib in secondary prevention?

其实我们在欧洲获批并不需要这个结果。

We actually don't need it for approval in Europe.

为什么？

Why is that?

因为那边的体系不一样。

Well, it's a different system.

他们相信降低LDL就是降低LDL，所以不需要结局试验，他们需要结局研究来获批。

They believe in LDL lowering is LDL lowering, so you don't need They don't need the outcome trial, They need the outcome study for approval.

美国的情况就不同了。

The US is different story.

然后他们有一年的时间来建立他们的支付方组合。

Then they have a year to set up their payer mix.

所以他们有一年的时间让结局研究的结果进入支付方的报销体系。

So they have the year for the outcome study to kind of come into the payer reimbursement.

在美国就不一样了，因为你希望在上市时就能搞定报销，所以我们希望上市时就有结局研究的数据。

For US, it's different because you want to line up your reimbursement at launch and so we want to have the outcome study when we launch.

所以实际上欧洲会先上市。

So actually Europe will be first.

我前几天看了ROSE-two试验，发现一个有趣的点，我们会把那些研究链接放出来让大家看，就是LDL-C的降幅，还有NMR测的LDL-P降幅，以及APO B，这几个指标之间存在相当大的不一致。

I went through the ROSE-two trial the other day and one of the things that I found interesting was, and we'll link to those studies so folks can see it, but the LDL C lowering, there was also an NMR for LDL P lowering and then there was APO B and there was quite a discordance between those.

APO B的降幅，我记得大概是16%。

The APO B lowering, I don't remember, was maybe 16%.

但比其他指标要温和得多。

But it was much more modest than the others.

你觉得这是什么原因？

What do you think accounts for that?

这是我们正在研究的问题。

It's something we're looking at.

我知道我们很多好朋友，像Tom、Allen，他们都是apoB的坚定支持者。

I know a lot of our good friends, Tom, Allen, they're all apoB.

我比较倾向于用LDL P，有几个原因。

I'm more of an LDL P person for a couple reasons.

第一，在我们实验室更容易拿到。

One, it's easier to get in our lab.

真的吗？

Really?

对，确实更容易。

Yeah, easier actually.

APOB其实也挺容易的。

APOB is still pretty easy.

我觉得APOB是最容易的，但LDL P对我来说比APOB更容易出现不一致。

I mean, I feel like APOB is the easiest thing to Yeah, the LDL P, but also LDL P to me is more commonly discordant than APOB.

你更容易看出来，因为APOB，LDL是80，APOB回来是85。

You can see it more easily because APOB, LDL's 80, APOB comes back 85.

真的是这样吗？

Is that really that kind of thing?

通常LDL是70的时候，LDL颗粒数会是1500。

Usually what typically have with LDL P of LDL 70, LDL particles 1,500.

这样很容易就能看出不一致，容易多了。

It's very easy to see the discordance a lot easier.

你做NMR用的是哪种检测方法？

Which assay did you use for NMR?

用的是那个，LipoScience的。

This was the This is the Liposcience.

LipoScience的那个，现在被LabCorp收购了，对吧？

Liposcience one, which is owned by LabCorp now?

对，现在归LabCorp所有。

It's owned by LabCorp, yes.

但我们用的是Jim Cromwell以前的检测方法，你说得对。

But we used This is Jim Cromwell's old assay You're right.

其实不是，以前用的不是那个。

From used actually no.

我们用的是，我们用的是Liposcience。

We used the we used the Liposcience.

是的。

Yes.

那就是我们用的那个检测方法。

That was the assay that we used.

好的。

Okay.

据我所知，那是最可靠的一个。

So that is the most reliable one to my knowledge.

对，完全正确。

Right, exactly right.

所以我们正在做很多工作来确认这一点。

And so we're doing a lot of work confirming that.

汤姆实际上发表了一篇论文，当LDL P和APOB不一致时，是什么在驱动这种不一致？

Tom actually published a paper, when LDL P and APOB are discordant, what is driving that?

这种情况不太常见，但确实会遇到。

Which is not very common, but you do see it.

原因是胰岛素抵抗和大量小颗粒。

And it's insulin resistance and a lot of small particles.

这样apoB和LDL P之间就会出现不一致。

You get discordance between apoB and LDL P.

然后有一项关于CETP的研究。抱歉，你刚说的是apoB和LDL P。

And then there's a study done at the CETP Sorry, you said apoB and LDL P.

你是指apoB和LDL C吗？

Did you mean apoB and LDL C?

不，是LDL P，当它们不一致的时候。

No, LDL P, when they're discordant.

换句话说，当apoB不高而LDL P高时，是什么原因导致的？

In other words, when apoB is not high and LDL P is high, what explains that?

为什么会出现APOB正常但LDL P非常高的情况？

What is the reason why you have a normal APOB and a very high LDL P?

但我不明白为什么小颗粒能解释这种不一致，因为每个颗粒上仍然有一个apoB。

But I don't understand why small particles would explain that discordance because each particle still has one apoB on it.

如果事实证明apoB的质量因颗粒大小而略有不同，我们认为这就是原因。

If it turns out the mass of apoB is different by the size, slightly different from each particle, and that we believe is the explanation.

为什么会这样？

Why is that?

这是因为当颗粒表面较小时，质量不仅仅是蛋白质，还有其他糖分子附着在上面，这会影响测量时的质量。

It's because when you have the smaller surface, the mass is not just the protein, there's also other sugar molecules that attach to that that make the mass of when you measure them.

所以apoB是一个质量测定。

And so apoB is a mass assay.

而LDL P是核磁共振测定的。

The LDL P is the NMR, the nuclear magnetic resonance.

CETP抑制就是一个例子，会出现不同的结果。

So CTP inhibition is the one example where you get different results.

LDL P会显著下降。

LDL P goes down very much dramatically.

小颗粒下降了90%。

Small particles go down by 90%.

小颗粒几乎被清除了。

You wipe out small particles.

APOE的下降幅度没有预期的那么大。

APOE doesn't go down as much as you'd expect.

所以我们正在努力更好地理解这一点。

And so we're trying to understand that better.

实际上，我们正在英国生物银行做大量工作，试图弄清楚这种情况发生时，风险会如何变化。

We're doing, actually, we're doing a lot of work on the UK Biobank trying to see when that happens, where does risk follow?

当你拿到结果数据时，那将会非常有趣，假设这两种生物标志物之间的不一致仍然存在。

That's actually going to be very interesting when you get your outcome data, assuming that the discordance continues between those two biomarkers.

因为你可以回头说，根据LDL C或LDL P的降低，我们预测事件减少应该是多少，但这可能与APO B降低所预测的不同。

Because you'll be able to go back and say, well, we would predict based on this LDL C or LDL P lowering what the event reduction should have been, but that might be different than what's predicted by the APO B reduction.

有人提出了这个问题，但约翰和我都很有信心，结果会一样好。

People have brought that up as an issue, but John and I both feel very confident that it's gonna be as good.

我觉得我们可能会看一个叫做非高密度脂蛋白胆固醇的指标，它跟APOB非常接近，就是低密度脂蛋白加上极低密度脂蛋白胆固醇。

One thing I think that we'd look at it, what's called non HDL cholesterol, which is very close to APOB, it's LDL plus VLDL cholesterol.

我们回到默克的那个试验，也就是REVEAL试验，那个试验显示，获益主要是由非高密度脂蛋白胆固醇驱动的，跟它的相关性比APOB还要高。

We go back to the Merck trial, the REVEAL trial, that showed the benefit there was driven, it was really highly correlated with non HDL cholesterol, more so than APO B.

不过大概六年前，在《美国医学会杂志》或者《新英格兰医学杂志》上有一篇论文，比较了APOB和非高密度脂蛋白胆固醇，结果APOB表现更好。

Although there was that paper in either JAMA or New England Journal of Medicine about six years ago that compared APO B to non HDL C and APO B performed better.

但也有其他人的研究结果正好相反。

Others have shown the opposite though.

两种说法都有。

It goes both ways.

听着，我一直很喜欢APOB，就像低密度脂蛋白一样，但重要的是要理解不一致性是什么意思。

Listen, I love APO B, I always have, like LDL, it's important to understand what discordance means.

不一致性，你可以通过非高密度脂蛋白、APOB或者低密度脂蛋白颗粒数来观察到。

And discordance, you can get discordance with using non HDL, apoB, or LDL P.

我觉得总的来说，它们告诉你的信息是一样的，大体上。

I think by and large they tell you the same thing, by and large.

对，这是一个三阶项。

Yeah, this is a third order term.

便宜的方法是测非高密度脂蛋白，而APO B和LDL颗粒数会更精确一些，但需要额外的实验室检测。

The cheap way is non HDL, then APO B and LDL P are a little bit more precise, but another lab test involved.

我们知道在PREVAIL试验中降低APO B，我们仍然表现不错。

We know that in our APO B lowering with PREVAIL, we still do okay.

我们达到了想要的心血管获益。

We do okay with the outcome benefit that we want to achieve.

如果使用非高密度脂蛋白，我们甚至做得更好。

We even do better if we use non HDL.

但当然，我们同样对奥塞曲匹带来的Lp(a)降低效果感到兴奋。

But of course, what ocetrapib has that we're also excited about is the Lp lowering benefit.

降了多少？

How much was that?

大约50%。

It's about 50%.

这比PCSK9抑制剂的效果还要好。

Which is more than a PCSK9 inhibitor.

在50到150的范围内。

In the 50 to 150 range.

你得根据Lp的范围来界定它。

You have to bracket it by the range of Lp.

你觉得这个作用机制怎么解释？

What do you think explains that mechanism of action?

我们也不确定，因为我们一直在尝试，我们不知道为什么p六千九百和LpLA，我们不知道原因，不知道那些药物为什么能把LpLA降低15%到20%，但我们一直在研究这个，我们做了一个清除研究，确实能减少LpLA的产生。

We don't know for sure because we've been trying again, we don't know why p-six thousand nine hundred and LpLA, we don't know the reasons, all the reasons why those drugs lower LpLA about 15 to 20% but we were looking into this, we have done a clearance study, it does reduce production of LpLA.

我们做了一个实际的检测，那是一个标记LpLA的研究，结果显示它确实减少了合成。

We've done an actual assay looking at, it's a study labeling LpLA and seeing that it does reduce synthesis in that study.

那是个小规模研究，所以我们想再试试，但并不是所有原因都清楚。

It was a small study, so we want to try it, but we don't necessarily have all the reasons.

但其他C2抑制剂也能降低Lp，但效果远没有这么大。

But Lp lowering with the other C2 inhibitors as well, but not nearly as much.

其实也是一样的，你知道，我们有一种更有效的C2抑制剂。

It was the same thing, you know, we have a much more potent C2 inhibitor.

那我们现在用反义寡核苷酸降低Lp的进展如何？

And where are we right now with the antisense oligonucleotide that lowers Lp?

那个还在三期临床试验阶段吗？

That is still in a phase three trial?

对，今年就会有结果。

Yeah, it's coming out this year.

这个试验叫Horizon。

It's called Horizon.

这是一个非常重要的研究。

It's a really important study.

虽然它被延长了。

Although it was extended.

它本来可能因为无效而提前终止，对吧？

It could have been stopped for futility, right?

它本来可能因为无效而提前终止。

It could have been stopped for futility.

而且它的实际事件发生率比预期的要低，这很可能引出一个重要的讨论：今天我们应该如何治疗高Lp的患者？

And it has a lower than expected event rate, which probably brings us to another important discussion about how do you treat a high Lp today?

机制是什么？

What is the mechanism?

所以你想把LDL降下来。

So you want to bring the LDL down.

在Horizon试验中，他们想把LDL降到60，结果事件发生率比预期的要低。

So they want the LDL down to 60 in Horizon, and so they had a lower event rate than expected.

所以我认为这证明了我们目前的做法是正确的。

And so I think that proves our what we're doing today.

我相信你也经常听到这种情况，当患者有高Lp(a)时，他们会说，我不想吃他汀类药物，因为它会升高Lp(a)。

I'm sure you hear it too, but when you have a patient who has high LpLA, they go, I don't want to be on a statin because it raises LpLA.

那我们该怎么办呢？

And so what do we do?

其实，把低密度脂蛋白降下来，确实能大幅降低风险。

Well, the truth of the matter is you bring the LDL down, really mitigate risk substantially.

Horizon研究，你觉得问题在于他们的低密度脂蛋白胆固醇降得太低，导致事件数不够。

Horizon So you think that the issue with that study was their LDL C was so low that you didn't get enough events.

所以用ASO药物清除Lp，并没有起到作用。

So abolishing Lp with the drug, the ASO, didn't matter.

不，不，我觉得会有作用的。

No, no, I think it will matter.

只是在他们观察的时间范围内没体现出来。

We just don't Well, it didn't matter in the timeframe that they looked.

事件数收集得不够。

Didn't need to collect enough events.

我是说，很可能会有作用。

I mean, could well matter.

我是说，结果应该会在今年某个时候出来，已经有报道了。

I mean, it's gonna come out, we believe, sometime this year, has been reported.

所以这有望把Lp(a)和我们最开始讨论的因果关系联系起来。

So that'll hopefully convert the LpLA to our very opening discussion about causality.

这样一来，我们就知道它是一个重要的风险标志物，我们相信它是因果性的，有很多理由相信这一点，而现在我们有了一个研究证明降低它是有益的。

That becomes then, we know it's an important risk marker, we believe it's causal, lot of reasons to believe it's causal, and now we have a study that proves that lowering it has benefit.

这将是一个巨大的成就。

It'll be a great achievement.

不过，这远不是最好的降低Lp(a)的疗法。

Now, this may not be the best Lp lowering therapy by far.

我的意思是，还有其他看起来更好的疗法也在进入大型试验，所以Lp(a)的时代正在开启。

Mean, there's others that are look a lot better that are moving into big trials as well, and so it's the Lp era is getting started.

我们正在接近另一个有望非常重要的因果因素，可以通过治疗积极干预。

I mean, we're getting to another hopefully very important causal factor that can be treated aggressively with therapy.

我们希望obicetrapib能成为这种治疗模式的一部分。

We hope obicetrapib can be part of that treatment paradigm.

从纯粹的心血管角度来看，你认为obicetrapib会如何被使用？

From a purely cardiovascular standpoint, how do you see obicetrapib being used?

如果结局试验的结果符合你的预期，那会怎样？

Should the outcome trial end in the fashion that you would expect?

你觉得它在目前我们用来降低LDL的药物组合中，应该处于什么位置？

Where do you think it fits into the current toolkit we have with respect to pharmacologically lowering LDL?

我想再说一遍，你的问题问得对，应该这样来思考。

I want to say, again, your question is the right way to frame it.

我们必须要有PREVAIL试验的阳性结果，并且要证明这种药物在他汀类药物基础上的额外益处。

We have to have a positive PREVAIL trial and we have to show the benefits of the drug on top of statins.

不过，想想他汀类药物擅长什么，不擅长什么。他汀能降低LDL，耐受性好，能减少心血管事件，而且是仿制药，开起来很方便。

However, when you think about what statins do well and what they don't do so well so statins lower LDL, they're well tolerated, and they reduce cardiovascular events, they're generic, and they're very easy to prescribe.

这些都是它的优点。

That's all the good things.

那他汀类药物有什么不足呢？

What does statins not do so well?

它会稍微增加患糖尿病的风险。

It raises the risk of diabetes slightly.

它会升高LpLA，而且对降低小颗粒的效果不太好。

It raises the LpLA, and it does not lower small particles very well.

它主要降低的是非小颗粒。

It lowers mostly the non small particles.

那obicetrapib有什么优势呢？

What does obicetrapib do well?

根据我们的Broadway试验数据以及其他CT抑制剂的结果，它能降低患糖尿病的风险。

It lowers the risk of diabetes based on our Broadway trial data, as well as other CT inhibitors.

它能把Lp降低大约百分之五十，处于中等水平。

It lowers Lp in that fifty percent range, in that moderate band.

它能降低糖尿病风险，降低Lp，还能把90%的小颗粒降下来。

It lowers the risk of diabetes, lowers Lp and lowers the small particles by 90%.

所以它会是和他汀类药物很好的搭配。

And so it would be a great companion drug to statins.

基于这些原因，我们认为它会是继他汀之后的首选药物。

We believe it becomes the go to drug after statins for those reasons.

它基本上解决了他汀类药物带来的那些问题，因此确实是他汀类药物的好搭档。

It makes the statin liability issues mostly go away and it really is a good companion drug to a statin for that reason.

现在我们有了与依折麦布的复方制剂，这让我们达到了与PCSK9抑制剂，甚至即将上市的口服PCSK9抑制剂相同的水平。

Now we have the combo pill with ezetimibe, which puts us in the same range as the PCSK9 inhibitors or even the upcoming oral PCSK9 inhibitors.

约翰，关于他汀类药物还有另一个问题，我觉得没有得到足够的重视，因为我知道它还没有显示出临床上的危害。

There is another issue, John, with statins that I don't think gets enough attention because I realize it hasn't demonstrated a clinical harm.

但有些事情，我想我们只是出于谨慎，会去关注它，那就是它可能对转氨酶产生相当大的影响，尤其是与依折麦布合用时。

But there's something that always, I guess we just out of an abundance of caution, pay attention to it, which is it can have a pretty significant impact on transaminases, especially when combined with ezetimibe.

说实话，我们看到这种情况的频率远高于文献报道的。

And we see that, honestly, think we see that far more than it's reported in the literature.

所以，我理解指南是怎么说的。

So, I understand what the guidance says.

指南说，如果AST和ALT升高不到3倍，可以忽略不计。

The guidance says if the AST and the ALT rise by less than 3X, you can ignore it.

这在临床上没有意义。

It's not clinically significant.

但那就意味着你得让服用可定和益适纯的患者，AST和ALT都到80了，还继续让他们这样。

But that means you're going to be tolerating patients on Crestor and Zetia walking around with AST and ALT of 80.

而实际情况是，我真的很难相信这样做是合理的。

And the reality of it is I just have a hard time believing that that makes sense.

你怎么看这个问题？

What's your view on that?

你觉得我是不是太较真了？

Do you think I'm being too much of a puritan?

也不是，我也有同感。

Not really, I kind of feel the same way.

我是那种把‘首先不伤害’放在第一位的人。

I'm a first do no harm kind of guy.

你知道吗，你提的这一点在我的临床实践中非常重要。

I mean, you bring up a very big point for me in my clinical practices.

我不喜欢高剂量的他汀类药物。

I don't like high dose statins.

我尤其不喜欢八十毫克的阿托伐他汀。

I don't like eighty milligrams of atorvastatin in particular.

我也不喜欢四十毫克的瑞舒伐他汀。

I don't like forty milligrams of rosuvastatin.

你见过汤姆·戴斯普林发布的那张漂亮的图表吗？

Have you seen Tom Dayspring put out a beautiful figure?

那是汤姆从所有文献中整理出来的经典图表之一，展示了每种他汀的剂量反应关系。

It's one of like your classic Tom figures that he pulled out of all the literature and it shows the dose response of every statin.

我们现在会把它展示给患者，尤其是那些服用高剂量他汀的患者。

And we now show it to our patients, especially those that come in on high dose statins.

我敢肯定它正好说明了你要说的，就是在最低剂量下你几乎就能获得全部的效果。

I'm sure it demonstrates exactly what you're about to say, which is you're getting virtually all the bang for your buck at that lowest dose.

那条曲线下降得那么厉害，以至于服用超过最大剂量一半的他汀几乎是不合理的。

And that curve is so concave down that it's almost unjustifiable to be on a statin above fifty percent of its max dose.

是的，就是说，需要伤害的人数与需要治疗获益的人数相比，实在不划算。

Yeah, mean, it's like the number needed to harm versus the number needed to treat benefit is just not desirable.

我尽量把他汀剂量降下来。

I try to cut the statin.

顺便说一句，患者们也不想要高剂量的他汀。

Patients, by the way, they don't want high dose statins either.

整个高剂量他汀指南的范式是错的。

The whole high dose statin guideline paradigm is off.

它根本行不通。

It doesn't work.

为它辩护一下，我想对每个人都宽容一点。

And in defense of it, look, I want to be charitable to everybody.

二十五年前，这还说得通。

It made sense twenty five years ago.

因为二十五年前，没有瑞百安，没有波立达，没有依折麦布，没有贝派地酸，什么都没有。

Because twenty five years ago, you didn't have Repatha, you didn't have Praluent, you didn't have Ezetimibe, you didn't have bempedoic acid, you had nothing.

他汀就是唯一的药。

This was your drug.

当时我们也没有证据表明这些药叠加使用有额外的好处。

We didn't have evidence of benefit either on top of these drugs.

现在有很多研究证明了这些好处。

Now we have many studies showing the benefits.

趋势正在转变。

The tide is turning.

现在人们开始提倡指南。

People are now advocating guideline.

欧洲已经在推广早期联合治疗，就是为了尽早使用联合疗法。

Europe is already on board with more combo therapy early just to get combo therapy.

所以我认为，根据我们的数据，obicetrapib应该成为下一个首选药物，如果你需要更强的效果，可以加上依折麦布复方药。

So I think obicetrapib then becomes, in my view, based on our data, should become the next go to drug, and if you need even more potent, you can add the ezetimibe combo pill.

所以我们相信，单用OB或者OB加依折麦布，百分之九十的患者就能完成他们的降脂治疗。

So we believe that with OB alone and OB with ezetimibe, ninety percent of patients are done with their lipid treatment.

这就是我们的想法。

And so that's how we think.

对于初级保健医生来说，这正是他们想要的。

For primary care doctors, that's what they're looking for.

他们想要的是能直接加到他汀类药物上，然后就能完事的东西。

They're looking for something they can just add to a statin and then they can call it a day.

给我解释一下。

Explain something to me.

如果你今天去买品牌药Zetia，其实并不贵。

So if you go and buy branded Zetia today, it's not that expensive.

如果你去买品牌药Nexletol，那价格跟注射用的单克隆抗体差不多，对吧。

If you go and buy branded Nexletol, I mean, it's as expensive as an injectable monoclonal Right.

是的。

Yes.

所以，你……也许你不想谈这个，但我必须问一下。

So, do you And maybe you don't want to talk about this, but I have to ask.

我的意思是，你觉得obicetrapib在美国会怎么定价？是会像Zetia那样，还是更像Nexletol那样？

I mean, when you think about how obicetrapib will be priced in The United States, is it going to be priced more like Zetia or is it going to be priced more like Nexletol?

不幸的是，关键不在于价格，而在于能否获得。

Unfortunately, it's all about access, not about price.

这就是最大的区别。

That's the big difference.

所以我们还没决定定价，通常要到上市时才会定，但说实话，系统就是这样运作的。

So we haven't decided on pricing, you don't do that till you launch, but it's really, fortunately how the system works.

如果你定价太低，药品福利管理机构就没有返利利润可赚，所以他们不会把它列入处方集。

If you price too low, the PBMs don't have any rebating profits to make, so they don't put it on formulary.

所以你必须得玩得起返利游戏，相应地定价。

And so you gotta be able to play the rebate game and price it accordingly.

我们也开始看到这种情况在莉莉直销等渠道被打破，我们很高兴看到这个系统随着时间推移变得更好。

We're starting to see that breakdown also with Lilly Direct and all these We love to see that system get better as time goes on.

这样人们如果想的话，就可以自掏腰包支付合理的价格，然后拿到药。

And so people can just pay a reasonable price out of pocket if they want to and they get the drug.

听着，你不需要从一个做播客的傻瓜那里得到建议，但我必须告诉你，我真的认为这些药定价过高是一个巨大的错误。

Look, you don't need advice from a bonehead with a podcast, but I have to tell you, I really think it is a terrible mistake when these drugs are priced outrageously.