Amgen Inc.(AMGN) 管理层出席高盛第 40 届全球医疗保健大会 (成绩单)

[机器翻译] 电话会议 · 2019年06月13日 · 14 次阅读

Amgen Inc. (NASDAQ:AMGN) Goldman Sachs 40th Annual Global Healthcare Conference June 12, 2019 2:20 PM ET

Amgen Inc.(纳斯达克股票代码:[AMGN])Goldman Sachs第40届全球医疗保健会议2019年6月12日美国东部时间下午2:20

公司参与者

David Reese - Executive Vice President of R&D

  • David Reese - 研发执行副总裁

电话会议参与者

Terence Flynn - Goldman Sachs

  • Terence Flynn - 高盛

特伦斯·弗林

Okay, great. I think we are going to get started. Thanks for joining us for our session with Amgen. I am Terence Flynn, and I am the Biotech Analyst here at Goldman and we are very pleased to have Dave Reese, who is Executive Vice President of R&D for Amgen.
And with that, I am going to turn it over to Dave for some opening remarks and then I will dive into questions.

好,太棒了。 我想我们将要开始。 感谢您加入我们与Amgen的会议。 我是特伦斯·弗林,我是高盛的生物技术分析师,我们很高兴能有安进研发执行副总裁戴夫·里斯。

有了这个,我将把它转交给Dave一些开场白,然后我会深入研究问题。

David Reese

Well, thanks, Terrence. So, and it’s pleasure to be here today. Let me just make a few comments about our approach to R&D. I’ve been the Head of R&D for just about a year now. And how do I conceptualize R&D in our industry as it exists now and projecting out ten or fifteen years.
So, to me, there are two core existential problems that we need to solve. One of them is, how do we improve the success rates. Currently, they still run around 8% and it’s been that way for some time that varies by therapeutic areas. But we must do better.
And then, two, how do we reduce cycle times and drug development. Still 12 to 14 years on average from idea in the laboratory to achieving marketing authorizations for a drug. And so, to tackle both of those problems, we are creating and have created, what I would call, sort of an integrated triple threat.
We believe, we strongly believe that genetics will be foundational for drug development going forward, particularly outside of oncology. We are not talking tumor genomics here, but everything else and we’ve made through the acquisition of deCODE genetics and then enhancement of their work in the last several years, huge investments in genetics.
And just this morning, in fact, we announced the large collaboration with Intermountain Health on integrated delivery network in the – of course, mountain region of the United States. They are about roughly 3 million patients in their system. We are hoping over the next five years or so to sequence 500,000 individuals.
This will be the largest single project, focused project of its kind in the United States and I think is a tremendous collaboration of the leadership that Intermountain was visionary and one thing to be able to, both on an individual patient level begin using genetics to guide how they deliver healthcare to learn across their populations. How they can improve the delivery of healthcare.
And then of course, from our end, to take these insights and say, can we make new highly effective medicines. So that genetics piece is critical. I think, we are indisputably the world’s leaders in that right now and I feel very good about where we are. But that’s a starting point and coupled with that, you need strength in biology.
Genetics gives you ultimately link to a target or a pathway. There is a lot unique to figure out. I think that’s Amgen’s historic strength and we continue to buttress that.
And then finally, you need to engineer molecules based on those insights and so, I think about R&D, we’ve created really an integrated unit that is thinking from, okay, we’ve identified a genetic target through, okay, what kind of molecule are we going to bring to bear here. And I feel very good about where we are in that respect.
And then finally, to touch briefly on speed of development, I led from that first within Amgen starting several years ago to really greatly accelerate our development timeline from early preclinical work through clinical development that AMG 510. KRAS program is an example of where we applied what we’ve learned and again in an integrated fashion across the spectrum of drug development.

好吧,谢谢,特伦斯。所以,今天很高兴来到这里。让我就我们的研发方法做一些评论。我一直担任研发主管仅一年左右。我如何概念化我们行业的研发,因为它现在存在并预测了十年或十五年。

所以,对我来说,我们需要解决两个核心存在问题。其中之一是,我们如何提高成功率。目前,它们的运行率仍然在8%左右,而且这种情况在某种程度上因治疗领域而异。但我们必须做得更好。

然后,二,我们如何减少周期时间和药物开发。从实验室的想法到实现药物的营销许可,平均需要12到14年。因此,为了解决这两个问题,我们正在创造并创造出我称之为综合三重威胁的东西。

我们相信,我们坚信遗传学将成为未来药物开发的基础,特别是在肿瘤学之外。我们不是在谈论肿瘤基因组学,而是我们通过收购deCODE遗传学,然后在过去几年中加强他们的工作,在遗传学方面的大量投资,我们所做的一切。

事实上,就在今天早上,我们宣布与Intermountain Health就当时在美国山区的综合交付网络进行大规模合作。他们的系统约有300万患者。我们希望在接下来的五年左右的时间内对50万人进行排序。

这将是美国同类项目中规模最大的单一项目,我认为这是Intermountain具有远见卓识的领导力的巨大合作,并且能够在个体患者层面开始使用遗传学指导他们如何提供医疗保健,以了解他们的人口。他们如何改善医疗保健的提供。

然后,当然,从我们的最后,采取这些见解,并说,我们可以制作新的高效药物。因此,遗传学是至关重要的。我认为,我们现在无可争议地成为世界领导者,我对自己所处的位置感到非常满意。但这是一个起点,加上这一点,你需要生物学的力量。

遗传学为您提供最终与目标或途径的链接。弄清楚有很多独特之处。我认为这是Amgen的历史优势,我们继续支持这一点。

然后最后,你需要根据这些见解设计分子,所以,我考虑研发,我们创造了一个真正的综合单位,正在考虑,好吧,我们已经确定了一个遗传目标,好吧,什么样的我们要在这里承担分子。在这方面,我感觉非常好。

然后,最后,简要介绍一下开发速度,几年前我从Amgen开始的第一次领导,真正大大加快了我们从早期临床前工作到AMG 510临床开发的开发时间表.KRAS项目就是我们申请的地方的一个例子我们在整个药物开发领域以一体化的方式学到了什么。

I think we’ve probably taken on average three years off our development timelines right now and I think we can do better than that going forward.
So, I pause there and open it up for broader questions.

我认为我们现在平均可能比我们的开发时间表少了三年,我认为我们可以做得更好。

所以,我暂停一下,打开更广泛的问题。

特伦斯·弗林

Great. Well I think that’s a great framework to start with. Maybe the one question, just as you think about measuring productivity of the R&D organization, you mentioned the 8% rate is a cycle time. Are those the key metrics that you and management are looking at? Are there other metrics in terms of timeline?

非常好。 我认为这是一个很好的框架。 也许只有一个问题,正如您考虑测量研发组织的生产率一样,您提到8%的比率是一个周期时间。 这些是您和管理层正在关注的关键指标吗? 在时间表方面还有其他指标吗?

David Reese

We have intermediate metrics. To me the only important metric ultimately is, how many drugs are approved and are successful and by successful I mean, you have both access to the patients need them and reimbursement. So that there is an appropriate return on investment. Now of course, along the way, in research and development we have various metrics.
The number of new product teams that we form each year for example is a metric coming out of our discovery research lab. And when we form a product team, that means, we have a clinical candidate molecule that we are intending to take into human. In the last few years, we’ve had record numbers of product teams formed and I think we are reaching a new equilibrium in terms of productivity at Amgen.

我们有中间指标。 对我而言,最重要的唯一指标是,有多少药物被批准并且是成功的,而且我的意思是,您既可以获得患者需要也可以获得报销。 这样就可以获得适当的投资回报。 当然,在此过程中,在研究和开发过程中,我们有各种指标。

例如,我们每年组建的新产品团队数量来自我们的发现研究实验室。 当我们组建产品团队时,这意味着我们有一个临床候选分子,我们打算将其纳入人类。 在过去的几年里,我们已经创造了创纪录的产品团队数量,我认为我们在Amgen的生产力方面达到了新的平衡。

特伦斯·弗林

Okay. And in terms of the Intermountain Health collaboration, maybe just help us think about, what does that bring in that deCODE doesn’t have? Or what does that add to deCODE in terms of capabilities?

好的。 就Intermountain Health合作而言,也许只是帮助我们思考一下,deCODE没有带来什么? 或者,在功能方面,deCODE会增加什么?

David Reese

I think there are a couple things. One of the secrets which no secret in genetics is power of numbers. deCODE has roughly 1.6 million participants in its databases now. This will add another 0.5 million. That puts us almost a log ahead of where almost anyone else is.
So, sheer power of numbers is important as you are trying to associate genetic variations with disease states or protection from disease states. In addition, this is a more, when you want genetics that caused more the outbred population, so it’s a little more heterogeneous and allows us to then broaden a mix of populations that we are looking at.

我认为有几件事情。 遗传学中没有秘密的秘密之一就是数字的力量。 deCODE目前在其数据库中约有160万参与者。 这将再增加50万。 这使我们几乎领先于其他几乎所有人的日志。

因此,当您尝试将遗传变异与疾病状态或疾病状态保护联系起来时,数字的绝对权力非常重要。 此外,当你想要遗传因素导致更多的远交种群时,这是一个更多,所以它更加异质,并允许我们扩大我们正在考虑的人口组合。

特伦斯·弗林

Okay. And when do you think you can start seeing some efforts in terms of new targets, et cetera coming out of that collaboration?

好的。 你认为什么时候可以开始看到新目标方面的一些努力,等等呢?

David Reese

Yes, we started this more an – probably a little early to speculate on timelines. But our goal is to be pretty aggressive and ambitious and we have, again, I think the best genetics unit in the world, okay.

是的,我们更多地开始这个 - 可能有点早,以推测时间表。 但我们的目标是相当积极和雄心勃勃,我们再次,我认为世界上最好的遗传学单位,好吧。

特伦斯·弗林

Great. Maybe, we will move on to ASCO. I know this was an ASCO for you guys. A lot of new exciting data. Maybe we will start with 510. You mentioned that in your opening remarks. But maybe just give us a little bit of the background here around the target, why you decide – why did you decided to pursue KRAS? And then, kind of the genesis of your program? And then we can talk through some of the more detailed data.

非常好。 也许,我们将继续前往ASCO。 我知道这对你们来说是个ASCO。 很多新的令人兴奋的数据。 也许我们将从510开始。你在开场白中提到了这一点。 但也许只是给我们一些围绕目标的背景知识,为什么你决定 - 为什么你决定追求KRAS? 然后,你的程序的起源是什么? 然后我们可以通过一些更详细的数据进行讨论。

David Reese

Sure. And I am happy to talk about KRAS. So, let me start actually with our framework in oncology.

当然。 我很高兴谈到KRAS。 那么,让我开始实际使用我们的肿瘤学框架。

特伦斯·弗林

Sure.

当然。

David Reese

Because that’s what led us to KRAS and our oncology strategy is predicated on the belief that the future of oncology meaning the next 15, 20 years is the marriage of precision oncology or targeted therapy with immune oncology. You are starting to see a resurgence actually of precision oncology and targeted therapy which have been quiet for a little while.
Now, within Amgen, we said, okay, within those spaces, where are we going to make our strategic bet. Within on precision oncology, we said, we are going to go after very high value targets, KRAS, MCL-1, Holy Grail type targets. We are not a chemistry organization of 3,000 individuals, but we have, what I characterize as a – team there.
They are an international class group of chemists and I think the KRAS program is an example of that. So we said, okay, we are going after high value targets. The KRAS field opened up from a – with a paper from UCSF in the last three, four, five years that gave some structural clues about how you may go after that target or why do we care about KRAS, where RAS is one of the first oncogenes identified mutations in the different forms of RAS occurring up to 40% of all human cancers.
It is the most frequently mutated oncogene that’s often a driver. Oncogene occurs early in the pathogenesis of disease. But it has been undruggable for almost four decades and the reason it’s been undruggable is that, it’s – the RAS is a globular protein. I have likened it to a golf ball with little dimple.
So, when you design small molecule inhibitors that as a protein usually there is a pocket and you figure out a way to bind in that pocket and block the function of the protein.
Here, there wasn’t much about pocket. Now, we were able to understand building on some of that structural biology and through, I think some very elegant structural biology and then ultimately medicinal chemistry of our own way to slot into a shallow groove that’s created on the surface on the molecule attached to the assisting – that’s the C and the G12C mutation covalently, so, permanently.
And then, there is also another shallow groove that we figured out opens up and we could reach in and grab that, as well. So it was a tremendous feat of medicinal chemistry on the part of the team.

因为这是导致我们进入KRAS的原因,我们的肿瘤学战略是基于这样一种信念,即肿瘤学的未来意味着未来15年,20年是精确肿瘤学或靶向治疗与免疫肿瘤学的结合。你开始看到精确的肿瘤学和靶向治疗的复苏已经安静了一段时间。

现在,在Amgen内,我们说,好的,在这些空间内,我们将在哪里进行战略性投注。在精确肿瘤学中,我们说,我们将追求非常高价值的目标,KRAS,MCL-1,圣杯型目标。我们不是一个拥有3000个人的化学组织,但我们拥有,我在那里的团队特征。

他们是国际一流的化学家,我认为KRAS计划就是一个例子。所以我们说,好吧,我们正在追求高价值目标。 KRAS领域从过去三年,四年,五年的UCSF论文开始,提供了一些关于如何追求目标的结构线索,或者我们为什么关心KRAS,其中RAS是第一个致癌基因鉴定出不同形式的RAS中的突变,其发生高达所有人类癌症的40%。

它是经常变异的致癌基因,通常是驱动因素。癌基因发生在疾病的发病机制的早期。但近四十年来它一直不可挽回,而且它不可挽回的原因在于,RAS是一种球状蛋白质。我把它比作一个带有小凹坑的高尔夫球。

所以,当你设计小分子抑制剂时,作为一种蛋白质,通常会有一个口袋,你想出了一种结合在口袋里并阻断蛋白质功能的方法。

口袋里没有太多东西。现在,我们能够理解一些结构生物学的基础,通过,我认为一些非常优雅的结构生物学,然后最终药物化学,我们自己的方式插入一个浅沟槽,在分子表面上创建的附加到协助 - 这是C和G12C突变的共价,所以,永久。

然后,还有另一个我们想到的浅槽,我们可以进入并抓住它。所以这是团队中药物化学的巨大成就。

特伦斯·弗林

Okay, great. Maybe as we talk through the data, there are couple of key takeaways. The first was just obviously activity in a number of tumor types. But maybe a little bit more striking in non-small cell lung cancer relative to colorectal which are the two predominant types where G12C is seen.
So, maybe one of the debates is again, dose versus biology and gain, maybe help us think about the relative efficacy in those different populations?

好,太棒了。 也许在我们谈论数据时,有几个关键的要点。 第一个显然是许多肿瘤类型的活动。 但是相对于结肠直肠而言,非小细胞肺癌可能有点引人注目,这是看到G12C的两种主要类型。

那么,也许其中一个辩论是,剂量与生物学和收益,也许可以帮助我们思考这些不同人群的相对疗效?

David Reese

Yes. So, in – what Terence is alluding to is that, in non-small cell lung cancer, five of ten patients for whom we had data as of nine days ago, I think when it was presented had responses. We hadn’t seen any formal responses in colorectal cancer although roughly half the patients it had some shrinkage in their tumors on scans.
And so, one question is why is there this differential response? I’d say a few things. Number one, we had only treated one patient with colorectal cancer at the top target dose. And so, we are enrolling a number of patients very rapidly at that dose. And so, I think in the coming months, we’ll actually have much deeper insight into that particular question.
A second question is, these tumors are complex in terms of their molecular wiring. And so, one thing that we are working very hard to understand as we accumulate data is, are there other suites of mutations that help predict response in resistance. Does that drive you towards specific combination therapies? And how does that make you position this drug as part of the sort of broader pallet of therapies that’s going to offer for these patients.
So, I feel very good about where we are. I can report that, we just very recently opened the expansion phase of that first in human study and we expect to complete enrollment within the next few weeks give or take. It’s a reflection of the tremendous interest of our investigators and what they are seeing in the clinics.

是。因此,Terence所暗示的是,在非小细胞肺癌中,我们在9天前获得数据的10名患者中有5名,我认为当它出现时有反应。我们在结直肠癌中没有看到任何正式的反应,尽管大约一半的患者在扫描时肿瘤有一些收缩。

所以,有一个问题是为什么会出现这种差异反应?我会说几件事。第一,我们只用最高目标剂量治疗了一名结直肠癌患者。因此,我们在该剂量下非常快速地招募了许多患者。因此,我认为在接下来的几个月里,我们实际上会对这个特定问题有更深入的了解。

第二个问题是,这些肿瘤的分子布线很复杂。因此,当我们积累数据时,我们正在努力理解的一件事是,是否有其他一组突变可以帮助预测抗性反应。这是否会促使您采用特定的联合疗法?这又是如何使您将这种药物定位为为这些患者提供更广泛的治疗方法的一部分。

所以,我对自己所处的位置感到非常满意。我可以报告,我们最近刚刚在人类研究中开启了第一个扩展阶段,我们希望在接下来的几周内完成注册。这反映了我们调查人员的巨大兴趣以及他们在诊所看到的内容。

特伦斯·弗林

And that’s both for the lung and colorectal in terms of the expansion?

就扩张而言,这对于肺部和结直肠都是如此?

David Reese

Yes, it’s open and then we are moving on to open combination trials as well we presented data at AACR suggesting and we got the manuscript under review now. But we’ll report these data more completely, but suggesting that KRAS in addition can inflame tumors impart probably through up regulations class 1 and may see expression.
And so the – it was quite a potent interaction between checkpoint inhibitors and the AMG 510. So we are opening in days – that was going to matter of days or so of the first patients in that combination.

是的,它是公开的,然后我们继续开放组合试验,我们在AACR提出的数据显示,我们现在正在审查手稿。 但是我们会更完整地报告这些数据,但是建议KRAS可能会通过第1类法规可能引发肿瘤,并且可能会看到表达。

所以 - 它是检查点抑制剂和AMG 510之间非常有效的相互作用。因此我们在几天内开放 - 这对于该组合中的第一批患者来说将是几天左右。

特伦斯·弗林

Okay. And is that by tumor type or that all tumor types in terms of combination?

好的。 并且是按肿瘤类型还是所有肿瘤类型组合而言?

David Reese

We’ll share a little more later in the year as we move that along.

我们将在今年晚些时候分享更多内容。

特伦斯·弗林

Okay. And then, one – in terms of thinking about other tumor types, were there any other patients that were enrolled? Can you just remind us what did you see in terms of activity?

好的。 然后,一个 - 在考虑其他肿瘤类型方面,是否还有其他患者入组? 你能提醒我们你在活动方面看到了什么吗?

David Reese

There were just – there was less than a handful of patients and you will tend to see endometrial cancer. One of our real focus is going forward will be to make sure we look at pancreatic cancer where KRAS G12C mutations occur in couple percent of patients, endometrial cancer, appendiceal carcinomas, that’s strangely enough have a relatively high prevalence of this particular mutation.
And then, there are other handful of others. So, you know we put a lot of emphasis on determining safety and efficacy in those populations.

只有 - 只有不到几个患者,你会倾向于看到子宫内膜癌。 我们真正关注的一个重点是确保我们研究胰腺癌,其中KRAS G12C突变发生在几个百分比的患者,子宫内膜癌,阑尾癌中,奇怪的是这种特定突变的患病率相对较高。

然后,还有其他一些其他人。 因此,您知道我们非常重视确定这些人群的安全性和有效性。

特伦斯·弗林

Okay. And I think the other question was, I mean, any of these targeted therapies, whether it was EGFR, ALC or RET, now KRAS’s durability of response. And so, as you think through that, is there anything unique about KRAS that we should consider as we think about how durable some of these responses might be over the longer term?

好的。 而且我认为另一个问题是,我的意思是,这些靶向治疗中的任何一种,无论是EGFR,ALC还是RET,现在都是KRAS的反应耐久性。 因此,正如您所想的那样,当我们考虑长期来看这些响应中的持久性时,我们应该考虑KRAS的任何独特之处吗?

David Reese

Yes, it’s a challenging question. One way, and that’s – it’s a great question and I am asked at all the time and I point out that it took 40 years to get a molecule that’s only been in the clinic seven months. So there is still couple unanswered questions that we need to broach.
But, as I said, RAS mutations are often occur relatively early in the genesis of many of these tumors in adolescents as various clones develop. They will generally harbor those mutations and that gives you some optimism that you could see real duration of response. But, I think in this case, when you are sailing near the edge of the years, some, the clinical data will be determinative, I think the correlative signs in the biomarker it will also be critical here.

是的,这是一个具有挑战性的问题。 一种方式,那就是 - 这是一个很好的问题,我一直被问到,我指出,需要40年的时间才能得到一个只在诊所里呆七个月的分子。 因此,我们还需要提出几个尚未解决的问题。

但是,正如我所说的,随着各种克隆的发展,RAS突变通常发生在青少年中许多这些肿瘤发生的相对较早的时期。 他们通常会怀有这些突变,这让你有一种乐观的态度,你可以看到真正的反应持续时间。 但是,我认为在这种情况下,当你在近年来的航行中,有些时候,临床数据将具有决定性,我认为生物标志物中的相关标志在这里也是至关重要的。

特伦斯·弗林

Okay. And then, one more just obviously people are highly focused on kind of past the market here. We’ve seen other companies employ kind of, Phase 2 single-arm studies. It would seem like that’s a probably a pathway that you guys could follow. Have you had any conversations yet with regulators in terms of how many patients kind of duration that you could address that?

好的。 然后,还有一个显然人们高度关注这里的市场。 我们已经看到其他公司采用了第二阶段的单臂研究。 看起来这可能是你们可以遵循的途径。 您是否与监管机构就可以解决的持续时间有多少患者进行过任何对话?

David Reese

Yes, what I can say about that, we normally don’t comment in detail on regulatory interactions. But I would say, we’ve had very positive interactions and as the program moves along, we’ll talk more about that.
As you pointed out, in these settings where there really is no standard therapy available or patients who have exhausted all standard therapies or can be expedited ways towards registration and that’s certainly something we are keenly interested in.

是的,我可以说的是,我们通常不会详细评论监管互动。 但我想说,我们已经进行了非常积极的互动,随着计划的进展,我们将更多地讨论这个问题。

正如您所指出的那样,在这些环境中,确实没有标准治疗方法,或者已经用尽所有标准治疗方法或者可以加快注册方式的患者,这当然是我们非常感兴趣的事情。

特伦斯·弗林

Okay. And you guys, I think you mentioned that you feel like you have an optimized dose here at the 960 for both the colorectal and lung?

好的。 而且你们,我想你们提到过,你觉得你们在结肠直肠和肺部都有960的优化剂量吗?

David Reese

We did very extensive modeling pre-clinically. And I think there are couple things to keep in mind here. So this is a covalent inhibitor. This is not a traditional kinase inhibitor where you want to shut it down for 24 hours and in fact, RAS itself, like the kinetics of RAS production it’s half life is about a day.
And we have , I think a very extensive preclinical evidence that if you achieve the appropriate exposure for a couple hours, two to four hours, you basically poison RAS for the duration of that dosing interval and in fact the exposures we are achieving in the clinics are well beyond what we were required for tumor regression. So, I feel good about the dosing and we feel quite good about the quite benign adverse event profile we are seeing so far.

我们在临床前进行了非常广泛的建模。 我认为这里有几点要记住。 所以这是一种共价抑制剂。 这不是传统的激酶抑制剂,你想要将其关闭24小时,事实上,RAS本身,就像RAS生产的动力学一样,它的半衰期大约是一天。

而且我们有一个非常广泛的临床前证据表明,如果您在两到四个小时内达到适当的暴露时间,那么您在给药间隔期间基本上会毒害RAS,事实上我们在诊所中实现的暴露 远远超出我们肿瘤消退所需的范围。 所以,我对给药感觉很好,我们对目前为止看到的相当良性的不良事件情况感到非常满意。

特伦斯·弗林

Okay. Maybe, just last question on this front, before I move to the bispecific platform is, just talk to us about differentiation versus the competitor program already that’s out there. I know there are some questions in terms of how similar or different these programs are. And then anything at this point in terms of how to think about resistance, overlapping resistance?

好的。 也许,就在这方面的最后一个问题,在我转移到双特异性平台之前,只是谈谈差异化与竞争对手计划已经存在的问题。 我知道这些程序的相似或不同有一些问题。 那么在这一点上如何考虑阻力,重叠阻力?

David Reese

Sure. What – so, I can't comment on other programs, because we haven't seen any data.

当然。 什么 - 所以,我不能评论其他程序,因为我们还没有看到任何数据。

特伦斯·弗林

Okay.

好的。

David Reese

And so I am sort of repeatedly asked to comment on the mirage which is difficult.

所以我一再被要求评论很难的海市蜃楼。

特伦斯·弗林

Okay.

好的。

David Reese

And so, in the fullness of time, we will see the data as they unfold in the field. Might resistance develop, of course, I mean, I wouldn’t be so naïve to think that after everything we’ve learned about targeted therapy oncology that resistance will not emerge at least in some tumors, that’s a – I think a critical question that we need to address in terms of development going forward.
It’s one reason I actually like very much the combination of the checkpoint inhibitors to really bring an orthogonal immunologic approach to bear on the tumor at the same time and try to prevent that sort of escape.

因此,在充足的时间内,我们将看到数据在现场展开。 当然,可能会产生阻力,我的意思是,我不会那么天真地认为,在我们所了解的有关靶向治疗肿瘤学的所有内容之后,至少在某些肿瘤中不会出现阻力,这是一个 - 我认为这是一个关键问题 我们需要在未来的发展方面加以解决。

这也是我非常喜欢检查点抑制剂的组合,同时真正带来正交免疫方法同时对肿瘤产生影响并试图阻止这种逃避的原因之一。

特伦斯·弗林

Okay, great. Well, the other program, you had a couple of updates on your BiTE platform at ASCO with respect to BCMA and the PSMA specifically, and so maybe first on the BCMA, we’d just be curious, kind of, how to think about that data in the context of the competitive landscape and then where does your half life extended version really fit in and it seems like, to me, that’s probably the more commercially viable of the two approaches.

好,太棒了。 好吧,另一个程序,你在ASCO的BiTE平台上有一些关于BCMA和PSMA的更新,所以也许首先在BCMA,我们只是好奇,有点,怎么想这个 在竞争格局的背景下的数据,然后你的半衰期扩展版本在哪里真正适合,对我来说,似乎这两种方法可能更具商业可行性。

David Reese

So, we presented, as you know, it’s an update of the first in human study from AMG 420, the first-generation continuous infusion BiTE at ASCO. And there – it was a sort of a natural extension, longer follow-up in these patients. I think, the takeaway was that the response rate was enhanced a little bit with longer duration of exposure in these – in some of these patients.
A number of them are continuing to receive therapy. So those data will evolve as we go forward. I would say the adverse event profile, there were no real changes from what we had reported at ASH. And our investigators remain incredibly enthusiastic. As you know that the BCMA landscape is incredibly dense and with multiple molecules and mechanisms of action at last, kind of for 38 something give or take.
Our approach to development here will be to say, okay, where do we believe the BiTE can really have the biggest impact and so we will be looking to move to earlier lines of therapy. For example, where you’ve got a lower tumor burden, where our goal really will be to drive patients into a minimal residual disease remission that hopefully in the last four years.
I think that, one of our goals with the BiTE programs is also to be able to deliver an attractive economic package for molecules that are dosed in micrograms, at microgram levels and that we think, in terms of things like cost of goods, we’ll be extremely competitive. So, we like where we sit there. Are we going to certainly blanket the entire landscape, I am not sure.
But, we want to focus our resources where we think we can deliver the most value for patients and again generating appropriate return on investments.

因此,正如您所知,我们提出了ASCO第一代连续输液BiTE AMG 420人体研究的第一次更新。而且 - 这是一种自然延伸,对这些患者进行更长时间的随访。我认为,最重要的是,在这些患者中,这些患者的接触时间延长,反应率略有提高。

其中一些人继续接受治疗。因此,这些数据将随着我们的发展而演变。我会说不良事件情况,我们在ASH报道的情况没有真正的变化。我们的调查人员仍然非常热情。如你所知,BCMA景观非常密集,最后有多种分子和作用机制,有38种东西给予或带走。

我们在这里的发展方法就是说,好吧,我们相信BiTE在哪里可以产生最大的影响,因此我们将寻求转向更早的治疗方案。例如,在肿瘤负担较低的情况下,我们的目标实际上是将患者纳入最小残留疾病缓解期,这有望在过去四年中有所改善。

我认为,我们的BiTE计划的目标之一也是能够为微克级以微克级给药的分子提供有吸引力的经济方案,我们认为,就商品成本而言,我们'会非常有竞争力。所以,我们喜欢我们坐在那里的地方。我不确定是否会覆盖整个景观。

但是,我们希望将资源集中在我们认为可以为患者提供最大价值并再次产生适当的投资回报的地方。

特伦斯·弗林

And is it, I know you guys have previously said that, the half-life extended version is about a year behind.

是的,我知道你们之前已经说过,半衰期扩展版本落后了大约一年。

David Reese

Yes, so, that – so, AMG 701 is a half-life extended version of BCMA BiTE. It is moving through dose escalation. I think we’ll have our initial clinical data either later this year, first part of next year from that program.

是的,所以,所以,AMG 701是BCMA BiTE的半衰期扩展版本。 它正在通过剂量递增。 我想我们将在今年晚些时候,明年的第一部分,从该计划获得我们的初步临床数据。

特伦斯·弗林

Okay. And do you think it’s reasonable to assume that, based on pre-clinical efficacy, we should see a comparable level of efficacy between the half-life extended and the continuous infusion?

好的。 你认为根据临床前疗效,我们应该看到延长半衰期和连续输液之间的疗效水平相当,这是否合理?

David Reese

Based on everything that we’ve seen pre-clinically, we are quite optimistic about the half-life extended program. Of course, we have to demonstrate that.

根据我们在临床前看到的所有内容,我们对半衰期扩展计划非常乐观。 当然,我们必须证明这一点。

特伦斯·弗林

And then the infection rates, again, that’s the other thing that to me, it looks like maybe be able to optimize with the half-life extended version. Is that, all assumptions?

然后感染率再次,这对我来说是另一回事,看起来可能能够使用半衰期扩展版本进行优化。 那是所有的假设吗?

David Reese

I think there is a potential advantage in that domain, because the patients don’t require an intraputaminal catheter.

我认为该领域存在潜在的优势,因为患者不需要输精管内导管。

特伦斯·弗林

Yes. Okay.

是。 好的。

David Reese

And these patients are profoundly immune-suppressed. The background infection rate in patients with myeloma who had multiple prior lines of therapy are actually quite high.

并且这些患者具有极强的免疫抑制能力。 具有多个先前治疗线的骨髓瘤患者的背景感染率实际上相当高。

特伦斯·弗林

Okay. And then the other program was the PSMA BiTE for prostate cancer. And again I think that was the first solid tumor data that you guys have shown with the BiTE platform. And I guess, one of the takeaways was, because of the way that trial transitioned the trial, you didn’t reach really top dose. So, maybe just kind of help us frame what you saw and the confidence in again the half-life extended version that I think is again already in the clinic?

好的。 然后另一个项目是前列腺癌的PSMA BiTE。 我再次认为这是你们在BiTE平台上展示的第一个可靠的肿瘤数据。 我猜,其中一个要点是,由于试验转变试验的方式,你没有达到真正的最高剂量。 那么,也许只是帮助我们构建您所看到的内容以及我认为再次出现在诊所的半衰期扩展版本的信心?

David Reese

Yes, that is a great question. So, these programs target PSMA, which is prostate-specific membraning – a perfectly misnamed proteins target in certain ways. But nevertheless a very good target in prostate cancer and there is evidence that PSMA expression actually tends to go up as the disease progresses. So, another sponsor initially had this program that was through Micromet collaboration that preexisted our acquisition of Micromet. We reobtained the rights to the program.
And as you were noting presented from somewhat truncated first in human trial data at ASCO that reached the top dose of 80 micrograms. There were no dose-limiting toxicities when the other sponsor for strategic reasons decided not to move forward. I think what was notable in that program were a couple of things, one it was extremely well tolerated.
Number two, there were a number of patients who had PSA declines and then there were a couple patients who had what we characterize is real clinical responses and single one patient in particular who had dramatic decline in all of the tumor markers and a new resolution of skeletal lesions which were dense on various scans, PET scans and bone scans.
That patient also had quite significant symptomatic improvement and went from filling up paperwork for hospice before entering the trial to actually skiing five or six months later and had quite a prolonged response. So I think that gives us proof of principle and now we need to broaden that experience and as you noted, we’ve introduced a half-life extended PSMA targeting BiTE into the clinic and that molecule marching through dose escalation actions pretty quickly.
And so, we will see, whether it’s later this year or more likely sometime next year we will have initial clinical data from that program.

是的,这是一个很好的问题。因此,这些程序针对PSMA,这是前列腺特异性膜 - 一种完全错误的蛋白质靶标,在某些方面。但是,前列腺癌是一个非常好的目标,并且有证据表明PSMA表达实际上随着疾病的进展而趋于上升。因此,另一个赞助商最初通过Micromet合作开展了这项计划,该计划预先存在我们对Micromet的收购。我们重新获得了该计划的权利。

正如您在ASCO的人体试验数据中首先略微截断的那样,达到最高剂量80微克。当其他赞助商因战略原因决定不继续前进时,没有剂量限制性毒性。我认为在该计划中值得注意的是一些事情,一个是非常好的容忍。

第二,有一些患者PSA下降,然后有一些患者具有我们所描述的真实临床反应,特别是一名患者,其中所有肿瘤标志物的显着下降和新的分辨率在各种扫描,PET扫描和骨扫描中密集的骨骼病变。

该患者也有相当显着的症状改善,并在进入试验之前填写临终关怀的文书工作,实际上在五六个月后滑雪并且有相当长的反应。因此,我认为这给了我们原理的证据,现在我们需要拓宽这种经验,正如您所指出的,我们已经将针对BiTE的半衰期扩展PSMA引入临床,并且该分子很快就通过剂量递增动作进行。

因此,我们将看到,无论是今年晚些时候还是更有可能在明年的某个时候,我们将从该计划获得初步临床数据。

特伦斯·弗林

Okay. What – and then in terms of any of the other BiTEs that you wanted to highlight that you are looking for to the, call it, 12 to 18 months in terms of some of the key readouts, because I know it’s been a big push for you guys that’s giving some of the BiTE data out there?

好的。 什么 - 然后就你想要突出显示的任何其他BiTE而言,在一些关键的读数方面称之为12到18个月,因为我知道它是一个很大的推动力 那些给那些BiTE数据的人呢?

David Reese

No, no, no, that’s a great question. We have roughly a dozen either in the clinic or just about to be in the clinic across hematologic malignancies and solid tumors. So we’ve got several BiTEs targeting acute leukemia AML. And so, those are ones that we are looking for over the next year or 18 months as you pointed out in terms of the timeline.
And then, in solid tumors, we’ve discussed a couple of the programs. Another I would highlight is DLL3, AMG 757 which is a target that is expressed in small cell lung carcinoma widely in other neuro endocrine tumors in which small cell lung cancer is a form of neuro endocrine tumor.
And that actually we believe in terms of solid tumors is one of our best targets, because the differential expression between that, the target in tumor cells and in normal cells is quite extreme and that’s what you want for a BiTE target. So, that’s marching through dose escalation as well and that’s one we’ll be looking for read out for the coming years.

不,不,不,这是一个很好的问题。我们在诊所或临近血液系统恶性肿瘤和实体瘤的诊所中大约有十几个。因此,我们有几种针对急性白血病AML的BiTE。因此,正如您在时间表方面指出的那样,那些是我们在未来一年或18个月内寻找的那些。

然后,在实体肿瘤中,我们讨论了几个程序。我要强调的另一个是DLL3,AMG 757,它是在小细胞肺癌中广泛表达的其他神经内分泌肿瘤中表达的靶标,其中小细胞肺癌是神经内分泌肿瘤的一种形式。

实际上我们相信实体肿瘤是我们最好的目标之一,因为肿瘤细胞和正常细胞中的靶标之间的差异表达非常极端,这就是你想要的BiTE靶标。因此,这也是通过剂量升级进行的,这是我们将要寻找的未来几年的读物。

特伦斯·弗林

And so, that one even you are still optimistic even given the Rova-T data. So the ADC DLL3?

因此,即使您使用Rova-T数据,即使您仍然乐观。 那么ADC DLL3?

David Reese

So, what I would say is that, based on what we know on the Rova-T program, I think the challenges there were related to the modality in the warhead and I haven’t seen anything that that tells me that there is an issue with the target. And so, I would say, we remain quite optimistic for DLL3 as a BiTE target.

那么,我想说的是,根据我们在Rova-T计划中所知道的,我认为那里的挑战与弹头的形态有关,我没有看到任何告诉我有问题的东西 与目标。 所以,我想说,我们对DLL3作为BiTE目标保持相当乐观。

特伦斯·弗林

Okay, great. Well, maybe if I am going to pass to breast cancer just in interest of time, Tezepelumab is another late-stage program that you guys have talked a lot about in Phase III for asthma. Maybe just walk us through kind of where we stand with enrollment, potential timelines on data and then the other big question I would get is just differentiation versus whether it’s depicts into the I/O five, so where so where we will talk to tell you that kind of ultimately fit in the landscape given the number of new biologics?

好,太棒了。 好吧,也许如果我只是为了节省时间而转移到乳腺癌,Tezepelumab是另一个晚期计划,你们已经在哮喘第三阶段谈了很多。 也许只是让我们了解一下我们的注册方式,数据的潜在时间表,然后我会得到的另一个重要问题就是区分它是否描述为I / O五,所以我们将在哪里谈论告诉你 考虑到新的生物制剂的数量,这种最终适合在景观中?

David Reese

And so, Tezepelumab is one of my favorite molecules. I have some biases there, because I was running our early development programs and we put that into humans and we helped design the inhaled allergen challenge study that was ultimately published in the New England Journal of Medicine. And that really gave us the sense that – it’s something interesting here. The Phase III program is moving along with our partners AstraZeneca on track.
We will complete enrollment on schedule in the coming months with the data readout next year. So I think it’s all systems go in the Phase III program. And, one of the reasons we really like the molecule is that in the Phase II program and based on the underlying and immunology of the target, we believe that this could have a role in both high eosinophilic or the allergic forms of asthma, as well as the non-eosinophilic or non-allergic forms of asthma.
For the latter, there are not any real biologic therapies or good therapies now for patients with severe disease. So this will potentially enable you to go across a very broad population. And in the target TSLP, is an upstream modulator or instigator of the inflammatory cascade. It’s also released from the epithelial side.
So it’s not – so we are not attacking the immune side here, but actually one of the nodes that we believe really is at the crux of the inflammatory response that occurs in asthma.

因此,Tezepelumab是我最喜欢的分子之一。我有一些偏见,因为我正在运行我们的早期开发计划,我们将其纳入人类,我们帮助设计吸入过敏原挑战研究,最终发表在新英格兰医学杂志上。这真的让我们觉得 - 这里有点有趣。第三阶段计划正在与我们的合作伙伴AstraZeneca一起走上正轨。

我们将在未来几个月按计划完成注册,明年将公布数据。所以我认为所有系统都进入了第三阶段计划。而且,我们真正喜欢这种分子的原因之一是,在II期计划中,基于靶标的潜在和免疫学,我们认为这可能在高嗜酸性粒细胞或哮喘的过敏形式中发挥作用,作为非嗜酸性或非过敏性哮喘的形式。

对于后者,现在对于患有严重疾病的患者没有任何真正的生物疗法或良好疗法。因此,这可能会让您遇到非常广泛的人群。并且在靶TSLP中,是炎症级联的上游调节剂或发起者。它也从上皮侧释放。

所以它不是 - 所以我们不是在这里攻击免疫方面,但实际上我们认为其中一个节点确实是哮喘发生的炎症反应的关键。

特伦斯·弗林

Okay. And given it is more upstream, are there any safety concerns we should think about an infection risk, things like that?

好的。 鉴于它更上游,是否有任何安全问题我们应该考虑感染风险,这样的事情?

David Reese

One of the – our hope would actually be the reverse.

其中一个 - 我们的希望实际上是相反的。

特伦斯·弗林

Okay.

好的。

David Reese

Because TSLP is not really present in non-inflammatory. So it’s not like a cytokine, which is part of the normal balance that your immune system carries forward. It’s really released in inflammation setting and in fact, TSLP levels in tissues or that you can measure systemically are quite, quite low in a in non-inflammatory state. So, the Phase II data was quite good in terms of the adverse event profile and we’ll see what the Phase III data shows.

因为TSLP并非真正存在于非炎症中。 所以它不像细胞因子,它是免疫系统发展的正常平衡的一部分。 它确实在炎症环境中释放,事实上,组织中的TSLP水平或者你可以全身测量的TSLP水平非常低,处于非炎症状态。 因此,就不良事件概况而言,第二阶段数据非常好,我们将看到第三阶段数据显示的内容。

特伦斯·弗林

Great. And I know you guys, atopic dermatitis is kind of the other indication that you are focused on. You had run a previous trial there. You may had some learnings from that, you made some changes conducting a new Phase II trial. But maybe just give us a little bit more detail on kind of the key changes why you are confident in atopic dermatitis you have given the prior readout?

非常好。 我知道你们,特应性皮炎是你关注的另一种迹象。 你曾在那里进行过一次试验。 您可能从中获得了一些经验,您在进行新的II期试验时做了一些更改。 但是,或许只是给我们更详细的一些关键变化,为什么你对先前读数的特应性皮炎有信心?

David Reese

Yes, I would say a couple things. So, number one the evidence preclinical and translational evidence linking TSLP to the disease stage is actually a stronger, stronger in atopic dermatitis as it is in asthma. I think we have learned – and the first Phase II trial was launched sometime ago. And I think that’s a field that’s rapidly evolving.
We’ve learned a lot about background therapies, how to control for them, the natural history of the disease which naturally waxes and wanes in the absence of therapy. And I think we’ve designed what quite comfortable is a quite rigorous Phase II trial to really test the hypothesis in atopic dermatitis.

是的,我会说几件事。 因此,将TSLP与疾病阶段联系起来的临床前和转化证据的第一名实际上是特应性皮炎中比哮喘更强,更强的证据。 我想我们已经学会了 - 第一期II期试验是在不久前推出的。 而且我认为这是一个快速发展的领域。

我们已经学到了很多关于背景疗法,如何控制它们的知识,这种疾病的自然历史在没有治疗的情况下会自然地变蜡和减弱。 而且我认为我们已经设计了一个非常舒适的相当严格的II期试验来真正检验特应性皮炎的假设。

特伦斯·弗林

And would we – could we also see data next year from that study?

我们能不能从明年的研究中看到明年的数据?

David Reese

I am probably not ready to speculate on what the timelines might be for that trial.

我可能还没准备好推测该试验的时间表可能是什么。

David Reese

Okay. Maybe Omecamtiv and other late-stage programs, I guess, for heart failure here. You did start a new Phase III trial. Maybe just help us think about the rationale behind that study and how you think about kind of the what’s the differentiated feature of this drug? What are the risks in that?

好的。 也许Omecamtiv和其他后期计划,我想,这里的心脏衰竭。 您确实开始了一项新的III期试验。 也许只是帮助我们思考一下这项研究的基本原理,以及您如何思考这种药物的差异化特征? 那有什么风险?

David Reese

So, Omecamtiv is a novel mechanism of action. The heart failure field hasn’t really seen a novel mechanism of action going on two decades now. So I think, that’s one thing that makes us optimistic. The second thing is the mechanism of action by really enhancing the contractility apparatus in the heart is orthogonal. So, almost all of the other therapies that currently exists which in one way or another affect the afterload that the heart sees or the preload burden that the heart sees.
So that it can be used in combination with therapies or layered on therapies and in fact, that’s the design of the Phase III trial. The Phase III program itself is also on track with our partners, cytokinetics and we anticipate wrapping up enrollment in that Phase III program within the next coming weeks to few months on schedule.
That is over 8,000 patients trial. So it will be one of the largest studies ever conducted in heart failure and we hope also one of the most rigorously conducted trials in heart failure.

因此,Omecamtiv是一种新颖的作用机制。二十年来,心力衰竭领域还没有真正看到一种新的作用机制。所以我认为,这是让我们乐观的一件事。第二件事是通过真正增强心脏收缩性装置的作用机制是正交的。因此,几乎所有目前存在的其他治疗方法都会以某种方式影响心脏所看到的后负荷或心脏所看到的预负荷。

因此它可以与治疗组合使用或分层治疗,事实上,这是III期试验的设计。第三阶段计划本身也与我们的合作伙伴,细胞动力学一起走上正轨,我们预计在未来几周到几个月内如期完成第三阶段计划的注册。

这是超过8,000名患者的试验。因此,这将是有史以来在心力衰竭方面进行的最大规模的研究之一,我们也希望这也是最严重的心力衰竭试验之一。

David Reese

Okay. Great. Maybe just in the last couple minutes, as we talk through your different therapeutic areas, cancer, immunology, cardio, we did dip in CNS, you obviously have aim a big anywhere that you feel like you have a need to kind of build out your early mid-stage pipeline in terms of thinking about other areas that you maybe need to bolster up a little better. Do you feel like you’ve got a pretty adequate opportunity set?

好的。 大。 也许只是在最后几分钟,当我们谈论你的不同治疗领域,癌症,免疫学,有氧运动,我们确实浸泡在CNS,你显然有一个很大的目标,你觉得你有必要建立你的 在思考其他领域的早期中期管道,你可能需要加强一点。 你觉得你有一个非常充足的机会吗?

David Reese

Yes, we like the strategic focus in the four therapeutic areas that we’ve got right now. Of course, we are always open to scientific serendipity. But our largest emphasis by far will be on those therapeutic areas which are large.
When you think about our aspiration to really affect diseases that have a large effect on the public health, cardiovascular disease, cancer, neuro degeneration, these constitute 80% of the public health burden going forward and I would anticipate that in most of those areas we will have a significant focus going forward.

是的,我们喜欢我们现在所拥有的四个治疗领域的战略重点。 当然,我们总是乐于接受科学的意外发现。 但到目前为止,我们最大的重点是那些大的治疗领域。

当你想到我们真正影响对公共健康,心血管疾病,癌症,神经退化产生重大影响的疾病的愿望时,这些疾病构成了公共卫生负担的80%,我预计在大多数这些领域我们 将有一个重点关注未来。

David Reese

Okay. Great. Well, I think we are out of time. Thank you, very much Dave.

好的。 大。 好吧,我想我们没时间了。 非常感谢Dave。

David Reese

Thank you. It’s been a pleasure.

谢谢。 这是我的荣幸。

David Reese

Thanks.

谢谢。

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