Ionis Pharmaceuticals,Inc。(IONS) 首席执行官 Stanley Crooke 主持 2019年 股东年会 (成绩单)

Ionis Pharmaceuticals, Inc. (NASDAQ:IONS) 2019 Annual Meeting of Stockholders Conference Call June 6, 2019 5:10 PM ET

Ionis Pharmaceuticals,Inc。(纳斯达克股票代码:[IONS])2019年股东大会电话会议2019年6月6日美国东部时间下午5:10

公司参与者

Stanley Crooke - Founder, Chairman, CEO and President

  • Stanley Crooke - 创始人,董事长,首席执行官兼总裁

斯坦利·克鲁克

Good afternoon and welcome to 2019 Meeting of Ionis’ Shareholders. I will be making forward-looking statements that are associated with risks, so you're encouraged to consider both the risk and the opportunity as you think about Ionis.
This year at Ionis, we are celebrating our 30th anniversary, we opened new doors to our facility in March of 1989 and this actually is a picture of our first facility. We had a door, there it is. We also had a window and a sign and there they are. So for those of us who have participated, this has been a remarkable journey. But for me, what makes the journey extraordinary is that where we are today is simply the end of the beginning. And the most important thing we've accomplished is we've laid the foundation for an even more exciting future. And so today, of course, I'll present a solid summary of where the company stands today with a particular focus on what we've accomplished in the last -- since the last annual meeting. And then I'll put it in context, where we are today, a historical context, how we took a blank piece of paper and moved to the position the company enjoys today. And then the future, what does laying the foundation for that future actually mean for patients and shareholders in the coming years.
This actually is a picture I show to demonstrate conclusively that 30 years at the helm of Ionis has not aged me at all. I wish you hadn't laughed at that. This actually is a picture taken at the time we closed our initial round of financing. We raised a grand total of $5.2 million, not $52 million, not $152 million, $5.2 million. And Dave Ecker was one of my colleagues who helped me this company started. And so naturally here, I'm thanking him and I learned later what Dave was thinking. He was thinking, sure it's not like I'm signing up for 20 or 30 years, little did we know. In fact, Dave is still very much a part of the company. He's in the audience. And so you too can judge that 30 years of Ionis have not aged him either.
Ionis was formed to meet a very, very specific purpose. Prior to founding Ionis early, I in my career had the opportunity to occupy very senior positions in two different pharmaceutical companies. And it was a common knowledge to the industry at the time, that the productivity of our industry was declining and that that was going to continue for the foreseeable future, it certainly happened. And as I looked at our industry, I saw that we were still in 1989 entirely dependent on a technology that was more than a 100 years old. And that is still the case for the majority of the industry today. And as I looked out at other industries, it was just an absolute truism that quantum advances in productivity only happen when disruptive, more efficient new technologies were introduced. And so, Ionis was formed to respond to this decline in productivity, and it was formed to create an advance, a new platform for drug discovery that would be significantly more efficient.
We focused on creating a set of molecules that had never been made before and never been considered as possibly drug molecules or medicine molecule, and these molecules reduced the genetic code directly to bind to a set of targets inside the cell that had never been considered as targets for medicines until we did it, and we call that technology antisense. And though we knew nothing about the technology in 1989, I was confident that if we could be successful in creating this technology, it would be significantly more efficient than traditional technologies for drug discovery.

下午好,欢迎参加2019年Ionis股东大会。我将做出与风险相关的前瞻性陈述,因此在您考虑Ionis时,我们鼓励您考虑风险和机会。

今年在Ionis,我们庆祝成立30周年,我们在1989年3月为我们的工厂打开了新的大门,这实际上是我们第一家工厂的照片。我们有一扇门,就在那里。我们还有一个窗口和一个标志,他们在那里。所以对于我们这些参与过的人来说,这是一段非凡的旅程。但对我来说,让这次旅程变得与众不同的是,我们今天所处的位置只是开始的结束。我们所取得的最重要的事情就是为更加激动人心的未来奠定了基础。当然,今天,我将对今天公司所处的位置进行一个可靠的总结,特别关注我们在上一次年会之后所取得的成就。然后我会把它放在我们今天所处的背景中,这是一个历史背景,我们如何拿出一张白纸并转移到公司今天享有的位置。然后是未来,为未来奠定基础的实际意义在未来几年对患者和股东意味着什么。

这实际上是我展示的一张图片,最终证明了在离开Ionis的30年里根本没有让我老去。我希望你没有嘲笑那个。这实际上是我们结束第一轮融资时所拍摄的照片。我们总共筹集了520万美元,而不是5200万美元,而不是1.52亿美元,520万美元。 Dave Ecker是我帮助我这家公司的同事之一。在这里,我很自然地感谢他,后来我才知道戴夫在想什么。他在想,确定这不是我报名20或30年,我们知道的很少。事实上,戴夫仍然是公司的一部分。他在观众席上。所以你也可以判断出30年的Ionis也没有让他老去。

Ionis的成立是为了满足非常非常特殊的目的。在早期创立Ionis之前,我在职业生涯中有机会在两家不同的制药公司担任非常高级职位。当时这个行业的一个常识是,我们行业的生产力正在下降,而且在可预见的未来,这种情况将会持续下去,这肯定会发生。当我看到我们的行业时,我看到我们仍然在1989年完全依赖于一项超过100年的技术。对于当今的大多数行业来说,情况仍然如此。当我看到其他行业时,只有在引入颠覆性,更有效的新技术时才能实现生产力的量子进步,这是绝对不言而喻的。因此,Ionis的成立是为了应对生产率的下降,它的成立是为了创造一个先进的,一个新的药物发现平台,效率会大大提高。

我们专注于创造一组以前从未被制造过的分子,从未被视为可能的药物分子或药物分子,这些分子直接减少遗传密码以结合细胞内的一组从未被认为是药物的目标,直到我们这样做,我们称之为技术反义。虽然我们在1989年对这项技术一无所知,但我相信,如果我们能够成功地创造这项技术,它将比传统的药物发现技术更有效率。

If we were successful then, I wanted to couple the technology to a new business model and alternative to the fully integrated pharmaceutical company model that recognized that we are today as we were then absolutely dependent on new product, and new products are dependent on innovation. So, our business model focused on achieving two key goals; one, to create and preserve over the very long haul innovation. Innovation is the source of new product; and then second, to treat each medicine in our pipeline as the unique, special asset that it is. And to work to identify the optimal organization to commercialize each medicine not to force-feed as is the modeled in the fully integrated company, all of our medicines into a single development distribution and commercial channel, each medicine treated as a unique, special asset.
And then finally, to create a new environment, a new culture which focused on bringing the best of scientific leadership that I had experienced, myself and others are in academic medical science and couple that to the best practices of management that I'd learned in my experience in the larger companies. And today, I'm pleased to tell you that, I think each one of these endeavors has been successful and in next few minutes I'll describe that for you.
So, where is Ionis today? We have pioneered the creation, not just of the new technology for drug discovery, but a new sector in our industry. Today, there are seven RNA-targeted medicines that have been approved for commercial use, five of those by Ionis. There are scores and scores of RNA targeted medicines in development, more than 40 of them are from Ionis, and there are numerous companies in this space, therefore quite a little while was only Ionis. And those companies spanned the gamut from small to very large, and many of those larger companies represent partners of Ionis.
So, we have led the creation of this technology. We continue to be the leaders in this technology. We've also pioneered the creation of a novel business model and a new much more productive culture, of which we’re very proud. And most excitingly after 30 years of steady progress, the pace of progress, our advances in the technology has never been faster. Innovation is very much alive and well at Ionis. We’ve shown that we can take those innovations and rapidly incorporate them into the medicines in our pipeline and that has led steadily improving performance of our medicines which of course expands the opportunity and allows us to approach ever greater commercial potentials.
Today we have three new transformative medicines that have been commercially proved in the last two plus years. Two of those, TEGSEDI and WAYLIVRA are being commercialized by our majority owned commercial affiliate Akcea. And because it’s majority owned, of course we consolidate all revenues and expenses. So we’re investing very aggressively in the commercialization of the two transformative new medicines through Akcea.
We are investing in advancing our pipeline of more than 40 transformative medicines in our pipeline and we’re investing particularly aggressively in our late stage pipeline which includes 10 medicines at least that we believe can be in Phase 3 trials by the end of 2019. We continue to invest in the technology and we’re investing in our people. And yet we are sustainably profitable.

如果我们之所以成功,我想将这项技术与新的商业模式结合起来,以及完全整合的制药公司模式的替代方案,这种模式认识到我们现在已经完全依赖于新产品,新产品依赖于创新。因此,我们的业务模式专注于实现两个关键目标

In 2019 we’ll report our fourth consecutive year of operation profits and our third consecutive year of net profitability. We do that at a time when many of our peers with agendas that are far less exciting than our agenda, are losing hundreds and millions of dollars a year. The business model is delivering great value.
So now let’s focus on what we’ve accomplished since the last time annual meeting. And I'm only going to touch on the very highest of high points but what’s been accomplished I think is really exciting. This presentation will be posted and we encourage you to spend time with these slides and looking at -- have a look at what’s been achieved in just the last 12 months.
SPINRAZA is the first RNA-targeted medicine to be a blockbuster medicine and it has transformed the lives of patients and families with this terrible disease SMA. TEGSEDI is approved in the EU, the US and Canada and our commercial affiliate Akcea is launching that medicine in those markets. And WAYLIVRA has been approved in the EU and we continue conversations with the FDA toward a path to marketing in the US. And once again our commercial affiliate Akcea is now launching WAYLIVRA in the EU.
Our pipeline, although, last few years has delivered consistently, exceptionally, possibly performance, and [modification] in the last year. Based on initial clinical data, our partner Biogen has advanced our first medicine for severe neuromuscular degenerative disease ALS into pivotal trial. Time story so for the first medicine that actually reduces the cause of another neuro-degernative disease, Huntington’s Disease, our partner Roche has advanced that medicine into a broad Phase 3 reprogram. APO(a)-LRx, our medicine that we completed a very large Phase 2 trial in patients who have had already a heart attack or stroke is being prepared for an outcome study in cardiovascular medicine Phase 3 programs. This is potentially very large commercial opportunity for us. And despite the fact that TEGSEDI is just being launched our follow-on medicine which we think will be significantly better than TEGSEDI is being ready before Phase 3 program that we will begin in just a few months.
The technology continues to advance and I’m going to spend some time talking about those advances in the next little bit. So sufficed to say here that those advances continued to be broad advances that enhance the potential and versatility in value of our technology. And we’ve had an excellent financial year. And our first quarter of 2019 was the most successful financially quarter that we’ve had. We are on track to meet or much more likely exceed all of our financial guidance and as I said to continue to be profitable at the operating and the net line.
In our first quarter of 2019 we reported almost $300 million in revenue. We reported net profitability and operating profitability SPINRAZA, our flagship molecule reported growth in revenues of almost 50% and we ended the year -- ended the quarter with more than $2 billion in cash. And that gives us the wherewithal to invest aggressively at every element of business which we're certainly doing. Nevertheless we're on track to meet and much more likely exceed all of our financial guidance in 2019.

在2019年,我们将连续第四年报告营业利润和连续第三年的净利润率。我们这样做的时候,许多同事的议程远没有我们的议程那么令人兴奋,每年都会损失数亿美元。商业模式正在带来巨大价值。

所以现在让我们关注自上次年会以来我们所取得的成就。而且我只会触及最高点,但我认为已经完成了非常令人兴奋的事情。此演示文稿将发布,我们鼓励您花时间阅读这些幻灯片并查看 - 了解过去12个月内取得的成果。

SPINRAZA是第一种成为重磅炸弹药的RNA靶向药物,它通过这种可怕的疾病SMA改变了患者和家属的生活。 TEGSEDI在欧盟,美国和加拿大获得批准,我们的商业分支机构Akcea正在这些市场推出该药。 WAYLIVRA已在欧盟获得批准,我们将继续与FDA进行对话,以便在美国进行营销。我们的商业分支机构Akcea现在再次在欧盟推出WAYLIVRA。

尽管如此,我们的管道在过去几年中已经在去年提供了持续,特殊,可能的性能和[修改]。根据最初的临床数据,我们的合作伙伴Biogen已将我们的第一种严重神经肌肉退行性疾病ALS药物推进到关键试验中。时间故事对于实际上减少了另一种神经痴呆症,亨廷顿氏病的原因的第一种药物,我们的合作伙伴罗氏已将该药物推进到广泛的3期重新编程。 APO(a)-LRx,我们的药物,我们已经为已经心脏病发作或中风的患者完成了一项非常大的2期试验,正准备进行心血管医学第3阶段计划的结果研究。这对我们来说可能是一个非常大的商业机会。尽管TEGSEDI正在推出我们认为比TEGSEDI明显更好的后续药物,我们将在短短几个月内开始实施第3阶段计划。

这项技术不断发展,我将花一些时间在下一点谈论这些进展。这里足以说明这些进步仍然是广泛的进步,增强了我们技术的潜力和多样性。我们的财政年度非常好。我们2019年第一季度是我们拥有的最成功的财务季度。我们有望会见或更有可能超出我们的所有财务指导,正如我所说,继续在运营和网络上实现盈利。

在2019年的第一季度,我们报告了近3亿美元的收入。我们报告了净利润率和营业利润率SPINRAZA,我们的旗舰分子报告收入增长近50%,我们在本年度结束时以超过20亿美元现金结束。这使我们有足够的资金积极投资于我们当然正在做的每一项业务。尽管如此,我们仍有望在2019年达到并超出我们所有的财务指导。

Now let's spend just a little bit of time looking at the drivers of growth during the next year, the next two years and the next three to five years. In the next year of course, the commercial growth that we will report will be driven by our three recently commercialized transformative medicines SPINRAZA, TEGSEDI, WAYLIVRA and so we will spend a minute talking about those.
SPINRAZA is the standard-of-care for all forms of the disease SMA. It is a medicine that has transformed the lives of these patients and their families in almost -- in ways that are inconceivable before SPINRAZA and it is a blockbuster. In a little more than two years it’s delivered more than $3 billion in revenues and sale and we believe that it will have experienced about a $2 billion plus of sales year in 2019, it’s a blockbuster and it deserves to be.
Just consider the impact of SPINRAZA on these patients and their families with this disease. Before SPINRAZA, babies born with the most severe form of disease which tragically is also the most common, on average had life expectancy of six months. In six months half of the babies would be dead or require a machine to breath for them for the rest of their lives. Today we know that if we treat before these babies become symptomatic, any baby with SMA, the vast majority of these infants grow and develop like normal, healthy children. Ask any parent what's the most important thing in the world is and it would be a healthy child.
The other forms of the disease are aggressive and progressive and lead to being wheelchair fast and most of the patients become so weak that they can't brush the teeth or lift the pencil. We know today that the longer we treat these patients, the stronger they get. So the earlier we treat the better, the longer we treat to better. And our experience now is more than six years. And the safety and tolerability profile of SPINRAZA remains really remarkable and pristine, as SPINRAZA changed practice of medicine. Before SPINRAZA, there was no hope, there was no therapy, there was no reason to try to make a rapid diagnose. Today, because of SPINRAZA, genetic tests for this disease are being incorporated in newborn screening protocols around the world. And that means that we can treat every patient who has this disease before they become symptomatic, and change their future, and give them a future without limits.
And we're not done. We and Biogen are making solid progress in finding an even better medicine, a better SPINRAZA that may produce even greater benefit, and certainly will be more convenient for these patients to use because it would be administered much less frequently. We all of us here feel privileged to have been a part of this development of this medicine.
TEGSEDI is a transformative medicine to treat patients with the polyneuropathy form of a severe degenerative disease that lessens in this fatal TTR amyloidosis. TTR disease derived from mutations in the gene that produces protein TTR may deliver, and as a consequence this protein precipitates in tissues throughout the body. The folks with the polyneuropathy form of the disease, the dominant symptoms they have come because the protein precipitation sensory nerves and they lose the ability to feel, in motor nerves and in muscles. And so their muscles waste away, and eventually they become house fast and then dead fast, and then of course, they degenerate and succumb to the disease. They also have TTR that precipitates in their internal organs, and the nerves that manage internal life. So they have trouble managing their blood pressure, they have tremendous difficulty with managing their gastrointestinal and generally urinary tract. And so once again, they become house fast and dead fast and isolated. Most of these patients are unable to work.

现在让我们花一点时间来看看明年,未来两年和未来三到五年的增长动力。在接下来的一年中,我们将报告的商业增长将由我们最近商业化的三种变革药物SPINRAZA,TEGSEDI,WAYLIVRA推动,因此我们将花一分钟时间谈论这些。

SPINRAZA是所有形式的SMA疾病的标准治疗方法。这种药物几乎已经改变了这些患者及其家人的生活 - 这种方式在SPINRAZA之前是不可想象的,而且它是一部重磅炸弹。在短短两年多的时间里,它的收入和销售额超过30亿美元,我们相信它在2019年将经历大约20亿美元的销售额,这是一部重磅炸弹,值得一试。

只考虑SPINRAZA对这些疾病患者及其家属的影响。在SPINRAZA之前,出生时患有最严重疾病的婴儿最不常见,平均预期寿命为6个月。在六个月内,一半的婴儿将会死亡,或者需要一台机器为他们的余生呼吸。今天我们知道,如果我们在这些婴儿出现症状之前治疗,任何患有SMA的婴儿,绝大多数婴儿会像正常健康的孩子一样成长和发育。问问任何一位家长,世界上最重要的是什么,这将是一个健康的孩子。

该疾病的其他形式是侵略性和进行性的并且导致轮椅快速并且大多数患者变得如此虚弱以至于他们不能刷牙或举起铅笔。我们今天知道,我们治疗这些患者的时间越长,他们就越强大。所以我们越早对待越好,我们对待的时间越长越好。我们现在的经验已经超过六年了。虽然SPINRAZA改变了医学实践,但SPINRAZA的安全性和耐受性仍然非常显着和纯净。在SPINRAZA之前,没有希望,没有治疗,没有理由尝试快速诊断。今天,由于SPINRAZA,这种疾病的基因检测正被纳入世界各地的新生儿筛查方案中。这意味着我们可以在患有症状之前治疗每一位患有这种疾病的患者,改变他们的未来,并给予他们一个没有限制的未来。

而我们还没有完成。我们和Biogen在寻找更好的药物方面取得了坚实的进展,更好的SPINRAZA可以产生更大的益处,并且这些患者肯定会更方便使用,因为它的使用频率要低得多。我们这里的所有人都很荣幸能够成为这种药物开发的一部分。

TEGSEDI是一种治疗患有多发性神经病变形式的严重退行性疾病患者的变革性药物,可减轻这种致命的TTR淀粉样变性。源自产生蛋白质TTR的基因突变的TTR疾病可以传递,并且因此该蛋白质在整个身体的组织中沉淀。患有多发性神经病的人患有这种疾病,他们的主要症状是因为蛋白质沉淀感觉神经并且他们失去了在运动神经和肌肉中感受到的能力。所以他们的肌肉就会浪费掉,最终他们快速成为房子,然后快死了,当然,他们退化并屈服于这种疾病。它们还具有在其内部器官中沉淀的TTR,以及管理内部生命的神经。因此,他们在管理血压方面遇到困难,他们在管理胃肠道和一般泌尿道方面遇到了巨大的困难。因此,他们再次变得快速,快速而孤立。大多数这些患者无法工作。

And, Chuck here is a patient who participated in our Phase 3 studies with TEGSEDI. And he's very typical of the patients that were in that study. By the time Chuck enrolled in the trial, he was desperately ill, he had prepared himself and his family to die. And as he said, he entered the trial simply with the hope that it might bring knowledge that would bring benefit to his children, who also have the disease, generation after generation of disease.
Today, Chuck has gained weight, he's energetic, he's alive, he's traveling around the world and he's looking forward to spending time with his grandchildren daily. And that is why we believe that TEGSEDI can be the medicine of choice for many patients with this disease because they can give it to themselves once-a-week themselves that frees them from the sense of the disease, allows them to be around the world traveling and doing what they need and our commercial affiliate, Akcea has reported about $9 million in sales in the first quarter post a few weeks of launch. And so, we're encouraged, it's still early but we're encouraged by the launch. We're also encouraged by what we are hearing from the field. Reimbursement conversations are going well and these patients are taking care by a wide range of specialists, physicians and we're seeing prescriptions come from essentially all of the physicians who take care of them.
Moreover, we're seeing very good compliance with the medicine, which is quite encouraging and as we gain pricing, our Akcea gains pricing, then they're advancing in new markets, so growth will come from.
WAYLIVRA is the first and only medicine to bring benefit to patients with the severe triglyceride disease and these patients have a severe disease. These patients have high triglycerides because they can't clear triglycerides from their blood. So they have triglycerides that are measured in thousands of milligrams per deciliter. If you had a triglyceride level of a 175, your physician or spouse, if you’ve got an active spouse like I do, would force you to go on a diet and get exercise and alike.
In contrast to some diseases, triglycerides in this disease are known to be the cause of the problem that these people have. They are not simply a biomarker, and these patients have substantial day-to-day difficulties, have significant GI distress and abdominal pain is fairly constant and in addition they have difficulty in thinking, they call it brain frog. They also have significant emotional issues that stem from this disease, so most of these people are unable to work and many of them are socially entirely isolated.
All of those problems are then punctuated by bouts of acute pancreatitis. Pancreatitis is an emergency that typically goes in the ICU and can kill you, and recurrent bouts of pancreatitis lead for loss of pancreatic function, which can lead to diabetes and other things. So, these people have significant issues. And Alvin is a very typical patient who was in our Phase 3 studies at all of these problems.

Chuck在这里是一名患者,他参加了我们与TEGSEDI的第三阶段研究。他是该研究中非常典型的患者。当Chuck参加审判时,他病得很重,他已经准备好了自己和他的家人去世。正如他所说,他进入试验只是希望它可以带来知识,这些知识将为他的孩子带来益处,他们也患有疾病,一代又一代的疾病。

今天,Chuck体重增加,他精力充沛,他还活着,他正在世界各地旅行,他期待着每天与孙子孙女共度时光。这就是为什么我们认为TEGSEDI可以成为许多患有这种疾病的患者的首选药物,因为他们可以每周给自己一次,让他们摆脱疾病​​的感觉,让他们在世界各地Akcea已经在发布几周后的第一季度报告了约900万美元的销售额。所以,我们受到了鼓励,现在还为时尚早,但我们对此次发布感到鼓舞。我们从现场听到的内容也让我们感到鼓舞。报销对话进展顺利,这些患者正在接受广泛的专家,医生的照顾,我们看到处方基本上都来自照顾他们的所有医生。

此外,我们看到非常好的药品合规,这是非常令人鼓舞的,随着我们获得定价,我们的Akcea获得定价,然后他们在新市场中进步,因此增长将来自。

WAYLIVRA是第一种也是唯一一种为患有严重甘油三酯疾病的患者带来益处的药物,这些患者患有严重疾病。这些患者的甘油三酯含量高,因为他们无法从血液中清除甘油三酯。因此,他们的甘油三酸酯的测量值为每分升数千毫克。如果您的甘油三酯水平为175,您的医生或配偶,如果您像我一样有一个活跃的配偶,会迫使您节食并进行锻炼等。

与某些疾病相反,已知这种疾病中的甘油三酯是这些人所具有的问题的原因。它们不仅仅是一种生物标志物,这些患者每天都有很大的困难,胃肠道疼痛严重,腹痛相当稳定,而且他们很难思考,他们称之为脑蛙。他们也有来自这种疾病的重大情绪问题,所以这些人中的大多数都无法工作,其中许多人在社会上完全孤立。

然后所有这些问题都被急性胰腺炎发作所打断。胰腺炎是一种紧急情况,通常发生在ICU,可以杀死你,并且反复发作的胰腺炎导致胰腺功能丧失,这可能导致糖尿病和其他事情。所以,这些人都有重大问题。 Alvin是一位非常典型的患者,他在所有这些问题上都参加了我们的3期研究。

In just three months of treatment, we demonstrated that WAYLIVRA can reduce triglycerides by the astonishing number of 1700 milligrams per deciliter and we demonstrated that the study is more powered demonstrated, these were the largest studies in this disease conducted that we had evidence of benefit in pancreatitis [TACs] and abdominal pain and had abdominal pain as a constant problem.
It's been now approved in the EU so our colleagues at Akcea are launching in the EU as we speak and we continue to have productive interactions with the FDA with regard to getting this medicine approved in the US. We also continue to learn about this medicine. We now are gaining substantial long-term experience in our open-label extension study and we see that we have solid long-term benefit that these patients are gaining.
We will also complete a study in a disease that's also a triglyceride disease that is triglyceride storage disease and we’ll be reporting results from that study later this year. So we have three medicines that are transformative in three different diseases that have been launched in the last two plus years and of course we’re investing in. We have four medicines that we expect to be in the Phase 3 trials by the end of the year, two already are in the Phase 3 trials and these two APO(a)-LRx and TTR-LRx will be in the Phase 3 trials by the end of this year.
And finally the pipeline is large and continues to advance and so we expect another year of quite significant moves from clinical studies in a range of medications that involve a wide range of health problem.
So now let’s just focus on this group of medicines that are in advanced development, these 10 medicines that could be in Phase 3 by the end of next year. This is the list of these 10 medicines and so it is a large base case pipeline as large as any I'm aware of in our industry.
It’s broad, yes we have a good many medicines for rare diseases so we have an even larger pipeline for the much more common disease and the much larger commercial activities and a centered base. Each of these medicines has the potential to transform the treatment of the disease that they’re focused on as has SPINRAZA, TEGSEDI, WAYLIVRA.
Today we’re going to simply focus on the medicines that will be in Phase 3 by the end of this year but these medicines are really important and we will be completing clinical trials and so stay tuned you’ll get a chance to hear a lot about these medicines in the coming months.
IONIS-HTTRx is the first medicine to reduce the cost of Huntington’s Disease, Huntington’s Disease is severe neuro-degenerative disease, it’s genetically borne with the potential but the disease doesn’t manifest itself until midlife. And so these patients know they may have the disease and know if they manifest themselves in the time of their life. And when that happens they lose the ability to control their muscle movements and so they have bunch of bizarre movement disorders, they deteriorate mentally and then they have severe emotional changes and so this is a very, very difficult disease for families to manage.

在短短三个月的治疗中,我们证明了WAYLIVRA能够以每分升1700毫克的惊人数量减少甘油三酯,我们证明该研究更有力量证明,这些是本病最大的研究,我们有证据表明有益于胰腺炎[TACs]和腹痛并将腹痛作为一个常见问题。

它现已在欧盟获得批准,因此我们在Akcea的同事正在我们发言时在欧盟推出,我们将继续与美国食品和药物管理局进行富有成效的互动,以便在美国批准该药物。我们还继续了解这种药。我们现在在开放标签扩展研究中获得了长期的丰富经验,我们发现这些患者正在获得可靠的长期益处。

我们还将完成一项疾病的研究,该疾病也是一种甘油三酯疾病,即甘油三酯储存疾病,我们将在今年晚些时候报告该研究的结果。因此,我们有三种药物在三种不同的疾病中具有变异性,这些疾病已经在过去的两年多时间内推出,当然我们正在进行投资。我们有四种药物,我们期望在第三阶段试验结束时使用。一年,两个已经进入第三阶段试验,这两个APO(a)-LRx和TTR-LRx将在今年年底前进入第三阶段试验。

最后,管道很大并且继续发展,因此我们期待在一系列涉及广泛健康问题的药物的临床研究中再过一年相当重要的举措。

所以现在让我们只关注那些正处于高级开发阶段的药物,这些药物可能会在明年年底进入第3阶段。这是这10种药物的清单,因此它是一个大型基础案例管道,与我所知道的行业一样大。

这是广泛的,是的,我们有许多罕见疾病的药物,所以我们有更大的管道,更常见的疾病和更大的商业活动和中心基地。这些药物中的每一种都有可能改变他们所关注的疾病的治疗方法,如SPINRAZA,TEGSEDI,WAYLIVRA。

今天我们将只关注到今年年底将进入第3阶段的药物,但这些药物非常重要,我们将完成临床试验,所以请继续关注,你将有机会听到很多关于这些药物在未来几个月。

IONIS-HTTRx是第一种降低亨廷顿病成本的药物,亨廷顿氏病是一种严重的神经退行性疾病,它具有潜在的基因,但直到中年才会出现这种疾病。因此,这些患者知道他们可能患有这种疾病,并知道他们是否在生命中表现出来。当发生这种情况时,他们失去了控制肌肉运动的能力,因此他们有一堆奇怪的运动障碍,他们在精神上恶化,然后他们有严重的情绪变化,所以这是一个非常非常困难的疾病,家庭管理。

But it is a rare disease but it’s a fairly frequent rare disease so we’ve about 30,000 patients in the United States that are symptomatic with this disease to say and another 30,000 in the rest of the world. What we’ve shown in our initial short-term clinical trial is quite significant reductions in the cause of the disease that are quite durable and preliminary evidence of benefit despite the fact that Huntington’s Disease is fairly slowly progressing even in the short study we have encouraging evidence, benefit and an excellent safety tolerability profile.
Based on all of that our partner Roche initiated a very broad Phase 3 program and added a new every four month dosing regimen to its Phase 3 study that will certainly be more convenient for these patients. Roche has announced that it will be chatting with regulatory agencies to consider and accelerate the path to commercializing this medicine to them.
Tofersen is the first medicine in our program that we’re conducting with Biogen that’s focus on the treatment of another severe neuro degenerative disorder ALS. ALS is the disease that reduces muscle function throughout the body so these patients who become paralyzed, they become wheelchair fast and eventually there has to come typically the respiratory failure.
ALS genetics are actually rather complex. There are a number of known genetic causes that happen over and over again and then there are sporadic cases that happen because of mutations in the variety of genes. SOD1 our first medicine focuses on a group of patients that we know have the disease caused by this target SOD1. Many of these patients will have a particularly aggressive form of the disease, they mostly come with the disease with issues.
In the initial trial that we did which is only three months long, we demonstrated robust reductions in the cause of the disease and then very excitingly a statistically significant benefit in measures of the disease in just three months. And the benefit was greatest in the patients with the most aggressive disease.
And so we're very excited about this medicine, our partner Biogen is moving it along and again plans to discuss accelerated approval for this medicine with regulatory agency. As I said, ALS is a complex genetic disease and this is just a first step in our broad program. Our intention is to create medicines that can bring benefit across the board to patients with ALS. The next medicine in our pipeline is already in clinical trials and C9ORF as you can see C9ORF’s spot is for about 10% of the cases of ALS. So which is a larger opportunity to benefit and it’s a larger commercial opportunity and then we certainly expect additional medicines to treat the rest of this pie.
APO(a)-LRx is a very important medicine in our late stage pipeline. And Michael here is a prototypic patient with this problem. He was in his mid 30s healthy, active, fit. All of his risk factors that were known like bad cholesterol were well-controlled; everything was fine until he had a nearly fatal heart attack. He ended up with a number of events and required a heart transplant. His only problem was that he had very highly elevated APO(a). APO(a) is sometimes called LP(a) and it’s a lipo protein made in the liver. So it’s like bad cholesterol. It’s different from bad cholesterol and that is entire genetically defined so you can't fix it with diet or exercise and there has never been a treatment for it until now.

但这是一种罕见的疾病,但它是一种相当常见的罕见疾病,所以我们在美国有大约30,000名患有这种疾病症状的患者,而在世界其他地方则有30,000名患者。我们在最初的短期临床试验中所显示的是相当持久的疾病原因的显着减少和尽管亨廷顿氏病即使在我们鼓励的简短研究中进展缓慢的事实也是有益的初步证据证据,益处和出色的安全耐受性。

基于这一切,我们的合作伙伴罗氏开展了一项非常广泛的3期计划,并在其第3阶段研究中增加了新的每4个月给药方案,这对于这些患者来说肯定会更方便。罗氏宣布将与监管机构聊天,以考虑并加快向他们商业化这种药物的道路。

Tofersen是我们计划中的第一种用Biogen进行治疗的药物,专注于治疗另一种严重的神经退行性疾病ALS。肌萎缩侧索硬化症是一种降低全身肌肉功能的疾病,因此这些患者瘫痪,轮椅变得快速,最终通常会出现呼吸衰竭。

ALS遗传学实际上相当复杂。有许多已知的遗传原因一次又一次地发生,然后由于各种基因的突变而发生散发病例。 SOD1我们的第一种药物专注于我们知道患有该目标SOD1引起的疾病的一组患者。这些患者中的许多患者将具有特别侵袭性的疾病形式,他们大多数患有疾病。

在我们进行的仅为期三个月的初步试验中,我们证实了疾病原因的显着减少,然后在短短三个月内非常令人兴奋地在疾病的测量中获得统计学显着的益处。在患有最具侵袭性疾病的患者中,益处最大。

因此我们对这种药非常兴奋,我们的合作伙伴Biogen正在推动它,并再次计划与监管机构讨论加速批准该药。正如我所说,ALS是一种复杂的遗传性疾病,这只是我们广泛计划的第一步。我们的目的是创造可以为ALS患者带来全面益处的药物。我们管道中的下一种药物已经进入临床试验和C9ORF,因为你可以看到C9ORF的现场约占ALS病例的10%。因此,这是一个更大的受益机会,这是一个更大的商业机会,然后我们当然希望有更多的药物来治疗这个馅饼的其余部分。

APO(a)-LRx是我们后期管道中非常重要的药物。迈克尔在这里是一个解决这个问题的原型病人。他30多岁时健康,活跃,健康。他所有的坏胆固醇风险因素都得到了很好的控制

It’s estimated that there are 8 million people in the world who had a heart attack or stroke and the cause of their heart attack and stroke and what will happen to the next is up to the APO(a). So this is a very large opportunity. This is the patient population we studied in our 286 patient Phase 2 study and it is the patient population that will be studied in the outcome study of the Phase 3 program that Novartis is getting ready to start like this year.
In this study of 286 patients we look at different doses and dose schedules. And if you just look at the yellow line, that's the dose that we will likely use in our Phase 3 program, 80 milligrams once a month, very low dose just administered by the patient themselves every month. At that dose we lowered APO(a) by more than 85% or thereabouts. And we were able to take almost 100% of these patients and get them below the level where they needed to get so that the risk of cardiovascular disease caused right away is now not elevated.
And so these were exciting data. The study was all patients enrolled treated for six months, many were treated for a year. And the other thing that made it exciting because this drug is a part of our LICA group of chemical medicines, it was extremely potent and extremely well tolerated and safe. In fact, compliance in this study was greater than 90% and side effects were higher, they were minor, but they were higher in the placebo group than the APO(a) treated group. And compliance was actually higher in APO(a) more people finished the trial taking our medicine than on placebo dose. So it’s a very, very effective agent, and that profile once a month, high side potency well tolerated is a profile we're seeing over and over again in all of our LICA medicine, our liver LICA.
So, to get an outcome study started, of course, takes quite a bit of time and planning. We're very pleased that our partner the largest is well along, we certainly expect this study underway by the end of the year with enrollment of the first patient either late this year or very early next year.
Now the final medicine that we'll talk about is our follow-on to TEGSEDI. Once again, this is a liver LICA medicine. So we are seeing exactly what we expect, substantial potency, excellent tolerability, excellent safety. So it's a medicine that can be useful, people would have any form of this TTR disease. TTR disease occurs because TTR settles out in various organs in the body. And so the symptoms can defect all of those events. And it can happen with mutations, but there are also some patients who appear to have normal TTR protein but also settle out in various tissues. These patients were grouped into two broad groups. One group is the polyneuropathy form, the patients who we treated with TEGSEDI and are treating with TEGSEDI, and the other group is broadly called the cardiac involvement disease. In these patients, their symptoms derived primarily because they accumulate this protein in the walls of their heart.

据估计,世界上有800万人心脏病发作或中风,心脏病发作和中风的原因以及接下来发生的事情取决于APO(a)。所以这是一个非常大的机会。这是我们在286名患者的2期研究中研究的患者人群,将在今年诺华公司准备开始的第3阶段计划的结果研究中研究患者人群。

在这项针对286名患者的研究中,我们研究了不同的剂量和剂量时间表。如果您只看黄线,那就是我们可能在我们的第3阶段计划中使用的剂量,每月80毫克,非常低的剂量,每个月由患者自己管理。在该剂量下,我们将APO(a)降低了85%以上。我们能够接受几乎100%的这些患者并使他们低于他们需要的水平,以便立即引起心血管疾病的风险现在不会升高。

所以这些都是令人兴奋的数据。该研究是所有患者入组治疗6个月,许多患者接受治疗一年。另一件令人兴奋的事情是因为这种药物是我们LICA化学药物组的一部分,它非常有效,耐受性极好且安全。事实上,本研究中的依从性大于90%,副作用较高,较轻微,但安慰剂组较APO(a)治疗组高。 APO的合规性实际上更高(a)更多人完成了服用我们药物的试验而不是安慰剂剂量。因此,它是一种非常非常有效的药剂,并且每月一次,高效耐受性是我们在LICA所有药物LICA中一遍又一遍地看到的。

因此,要开始进行结果研究,需要花费大量时间和计划。我们非常高兴我们的合作伙伴是最好的合作伙伴,我们当然希望这项研究能够在年底进行,第一名患者将在今年年底或明年初入组。

现在我们谈到的最后一种药是我们对TEGSEDI的后续行动。再一次,这是一种肝脏LICA药物。因此,我们正在看到我们所期望的,实质性效力,优异的耐受性,出色的安全性。所以它是一种有用的药物,人们会患有任何形式的这种TTR疾病。 TTR疾病的发生是因为TTR在体内各种器官中沉淀下来。因此症状可能会破坏所有这些事件。并且它可能发生突变,但也有一些患者似乎具有正常的TTR蛋白,但也在各种组织中沉淀。这些患者分为两大类。一组是多发性神经病变形式,我们用TEGSEDI治疗并用TEGSEDI治疗的患者,另一组广泛称为心脏受累疾病。在这些患者中,他们的症状主要是因为他们在心脏壁上积聚了这种蛋白质。

As a consequence, the walls of their heart thicken, and then the heart isn't compliant as it need to be and so it can't pump. So these people have cardiac dysfunction that’s easily measured and thickening of the cardiac walls that are easily measured. And of course, eventually they succumb come because of congestive heart failure. And while we haven't studied TTR-LRx in these patients, we do have data that gives us a lot of optimism that it will work and actually come from TEGSEDI. TEGSEDI, which is the parent drug here was studied by Dr. Benson at his clinic in the Indiana University , he studied 33 patients who've been treated for about three years many of them and compared them to patients who were untreated in his own practice, and he gave them all 300 milligrams subconsciously throughout the study. And here is some data that he recently presented.
And so on the left here in black are patients in Dr. Benson's practice that were untreated and on the top his measuring how thick the ventricle walls are. And you can see that they get thicker pretty quickly in 12 months, very big increase, and then translates to an inability to exercise, which is easily measured on the treadmill. In this case it’s called a 6-minute-walk test, how far you can walk in 6 minutes.
Now, over here are the patients treated with TEGSEDI, and remarkably it didn't just slow the thickening of the heart, it reduced the thickening of heart and it actually improved the number of how long how far these patients could walk in 6 minutes. And so, that's very encouraging as well as the safety tolerability profile witnessed.
Next steps, we are just finishing the initial trial. We have already reported that we see really very dramatic reductions in the cause of the disease and that we will complete and we will initiate a Phase 3 program. We have productive interactions with regulators in the US and the EU. So, we know the design of the Phase 3 study. We will be initiating a polyneuropathy study that will go very rapidly we believe, and then the cardiac study will be a cardiovascular outcome study that will take a little long, both of those will get underway this year.
So, now let's just focus on the pipeline, it’s the broader pipeline. Here is the pipeline. I know you can't read that, that's because it's large. I think that's a good thing. And the points that I want to make here are first it is large. It is large and mature as any pipeline of any company that I am aware of in our industry. It is broad. Large pipeline for severe disease and even larger pipeline for the many major health problems and very large commercial opportunities and it's innovative.
Each of these is first-in-class having the potential to be as transformative for the treatment of rare disease as SPINRAZA was for SMA. So, that to us is an extraordinarily exciting present, and now I'd like to spend some time walking you through how we got here, how we started with a blank piece of paper and end up where we are today 30 years later. This actually is a picture of a group of us, loading up our first NDA back when we used to file NDAs with paper. This was a small one, so we're really glad that we don't have to fill all those trees to file electronically anymore. It's also a lot heavier.

结果,他们的心脏壁增厚,然后心脏不符合它需要,因此它不能泵。因此,这些人的心脏功能障碍很容易测量,心脏壁增厚很容易测量。当然,最终他们因为充血性心力衰竭而屈服。虽然我们没有在这些患者中研究TTR-LRx,但我们确实有数据让我们很乐观,它会起作用,实际上来自TEGSEDI。 TEGSEDI是这里的母体药物,由Benson博士在印第安纳大学的诊所进行研究,他研究了33名接受过大约三年治疗的患者,并将他们与未经治疗的患者进行了比较。他在整个研究过程中潜意识地给了他们300毫克。以下是他最近提供的一些数据。

在左边这里是黑色的,Benson博士的实践中没有接受过治疗的患者在顶部测量了心室壁的厚度。而且你可以看到它们在12个月内变得越来越厚,非常大的增加,然后转化为无法运动,这很容易在跑步机上测量。在这种情况下,它被称为6分钟步行测试,你可以在6分钟内走多远。

现在,在这里接受TEGSEDI治疗的患者,显而易见的是,它不仅减缓了心脏的增厚,还减少了心脏的增厚,实际上改善了这些患者在6分钟内行走多长时间。因此,这非常令人鼓舞,同时也见证了安全耐受性。

接下来的步骤,我们刚刚完成初步试验。我们已经报告过,我们看到疾病的原因非常显着减少,我们将完成,我们将启动第3阶段计划。我们与美国和欧盟的监管机构进行了富有成效的互动。因此,我们知道第3阶段研究的设计。我们将开始一项多神经病变研究,我们相信这项研究会非常迅速,然后心脏病研究将是一项需要一段时间的心血管预后研究,这两项研究将在今年开始。

那么,现在让我们只关注管道,它是更广泛的管道。这是管道。我知道你读不懂,那是因为它很大。我认为这是件好事。我想在这里提出的要点首先是它很大。与我所知道的任何公司的任何管道一样,它是庞大而成熟的。它很广泛。严重疾病的大型管道,甚至更大的管道,为许多重大的健康问题和非常大的商业机会,它的创新。

当SPINRAZA用于SMA时,这些中的每一种都具有作为转化用于治疗罕见疾病的潜力的一流。所以,对我们来说,这是一个非常令人兴奋的礼物,现在我想花点时间告诉你我们如何到达这里,我们如何从一张白纸开始,最终在30年后的今天。这实际上是我们一群人的照片,当我们用纸张申请NDAs时,加载了我们的第一个NDA。这是一个小的,所以我们真的很高兴我们不再需要填写所有这些树以便以电子方式提交。它也更重了。

You heard about companies that began in garages. I almost began in garage. This was our first chemistry lab and it had four chemical hoods and we quickly learned largely because our chemist passed out, that if we ran all four hoods at the same time, we sucked all the air out of garage. And so if you came to visit us, you knew we're going chemistry because the garage door head to deal with. So, to talk about what we've done and how we've done it, I'm going to divide it into three things. One, how did we advance the technology. Two, how did we create the business model. And three, what we have done to establish a uniquely productive innovative environment.
I think the first and most important point was we were committed to advancing this technology so long as we saw path forward so long as the data supported advancing the technology we would persevere. That separated us from most companies immediately. We had a very detailed strategic plan that we have implemented step by step.
At its simplest the plan was to invest broadly, deeply and consistently in all elements of the technology. And there were nothing -- there was no part of this technology that existed. We didn’t know how to make them, we had to learn how to manufacture them. We didn’t know how to analyze them and test, we had to create new means to analyze them and then we had to create means to analyzing blood and tissues and so on. And we persisted in this endeavor despite the advice that became very loud at times such as stop wasting your money advancing the technology focus on the single drug and then the advice that became much more prominent for quite a number of years, this technology is never going to work, give it up and do something that’s productive.
We ignored all that. And we persevered in investing in the technology good times and bad times. We continued to invest even when we were not sure that we’ll be able to fund the company to continue, that’s required. And then once we laid out the strategy and once we made the tip we met, really all we did was advances step by step. There’s no shortcut I wish there were, there was no shortcut. It’s just hard day to day blocking and tackling, we’ll move forward every day. Nothing more.
We also identified potential problems and then solved them. And presented our data as we have presented now many papers from our integrated safety database and because we were creating new knowledge, we unequivocally couldn’t have the innovators lead the company and so we had a very active effort to retain people or leaders long time. Of the original 30 people who ran Ionis in 1989, more than half are still with the company or have retired from the company. This echoes a critical element of why we’ve been successful.
We had advanced new medicinal chemistry, medicinal chemistry is the chemistry where you take a chemical and modify it so it has good drug profit. There had been no medicinal chemistry for making these molecules and the RNA targeted RNA technology is chemically based. In the first 20 plus years we focused exclusively really on enhancing the interaction of our medicines with their targets RNA and it was really tremendously successful. We steadily increased potency, today the most potent chemical test that we have in development we think we can treat patients for a year with 50 or 100 milligram of medicine, imagine that.

你听说过从车库开始的公司。我几乎开始在车库里。这是我们的第一个化学实验室,它有四个化学罩,我们很快就学会了很多,因为我们的化学家昏倒了,如果我们同时运行所有四个罩子,我们将所有的空气从车库吸走。因此,如果你来拜访我们,你知道我们正在化学,因为车库门要处理。所以,谈谈我们做了什么以及我们是如何做到的,我将把它分成三件事。一,我们是如何推进这项技术的。二,我们是如何创建商业模式的。第三,我们为建立独特的生产创新环境所做的工作。

我认为第一个也是最重要的一点是,只要我们看到前进的道路,我们就致力于推进这项技术,只要数据支持我们将坚持不懈地推进技术发展。这使我们立刻与大多数公司分离。我们有一个非常详细的战略计划,我们已经逐步实施。

最简单的计划是在技术的所有要素上进行广泛,深入和一致的投资。没有什么 - 这项技术的任何部分都不存在。我们不知道如何制作它们,我们必须学习如何制造它们。我们不知道如何分析和测试,我们必须创建新的方法来分析它们,然后我们必须创建分析血液和组织等的方法。我们坚持这一努力,尽管有时建议变得非常响亮,例如停止浪费你的钱将技术专注于单一药物,然后提出的建议在很多年里变得更加突出,这项技术永远不会发生工作,放弃,做一些有成效的事情。

我们忽略了这一切。我们坚持不懈地投资技术。即使我们不确定我们是否能够继续为公司提供资金,我们仍继续投资,这是必需的。然后,一旦我们制定了策略,一旦我们完成了我们遇到的提示,我们所做的一切都是一步一步的进步。没有我希望的捷径,没有捷径。这只是日常的阻挡和攻击,我们每天都会前进。而已。

我们还发现了潜在的问题然后解决了它们。并提供了我们的数据,因为我们现在已经从我们的综合安全数据库中提供了许多论文,并且因为我们正在创造新的知识,我们明确地无法让创新者领导公司,因此我们积极努力长期留住人员或领导者。在1989年运营Ionis的最初30人中,超过一半人仍在公司工作或已从公司退休。这与我们成功的原因相呼应。

我们有先进的新药物化学,药物化学是化学物质,你采取化学品,并修改它,因此它具有良好的药物利润。制造这些分子没有药物化学,RNA靶向RNA技术是基于化学的。在最初的20多年里,我们专注于增强我们的药物与其靶RNA的相互作用,并且它确实非常成功。我们稳步提高效力,今天我们开发的最有效的化学测试我们认为我们可以用50或100毫克的药物治疗患者一年,想象一下。

And as we increased potency we also reduced side effects that meant we increased therapeutic margins, we increased convenience, we then supported -- the potency supported advancing in the tissues that accumulate less drug like cancer and we enabled essentially all reach of administration except commercially affordable oral administration, I will come back to that. So this program was very successful.
Over the last decade or so we’ve added new focal points to our medicinal chemistry. And where we have focused is to enhance productive delivery to specific tissues and cell. The first major success was to enhance the amount of medicine delivered to liver cells and we call this program the generic term LICA which just means adding a chemical that is a ligand to our ASO, our medicines to deliver more of the drug in a good way to the right person. And this slide comes from the first paper of a composite performance of the first 10 of these medicines in clinical trials and they come from matched studies in normal volunteers four weeks treatment, various dose levels and then measuring the targeting blood.
And on the right are very potent parent molecules, which are important and consistent and then on the left are the new molecules that are more potent and also consistent. That consistency is very important because it facilitates rapid and efficient drug development. We know how the next drug has been because we just saw with the last slide. We've also reported the integrated safety database from this. What we can say is that we're almost, we're probably approaching nearly 1,000 subjects treated now. We have seen pristine safety, tolerability and convenience profile for this medicine.
This actually looks at the 14 liver LICA medicines that are in development today. I just want to emphasize that these medicines are all targeted to very large categories of disease, very common disease, enormous commercial opportunity, that's what this advance has facilitated us to do.
Here are the first two of the generation 25 liver LICA medicines. We think that the potency we these agents have we will be able to achieve commercially acceptable oral administration, medicines in a pill. And that really is the late frontier for the technology we’ve been able to [indiscernible] with that situation. We will be talking about that in the coming months, hopefully it will be exciting.
Having been successful in the liver we moved on working with our colleagues at AstraZeneca we found a ligand that we could attach that accumulates medicine in a productive way to the beta cells of the pancreas. Beta cells of the pancreas manage metabolic diabetes, obesity that sort of thing. We've never been able to work in the pancreas and this assay just measures the amount of the target RNA. In a flip of here, you can see that pancreas LICA Generation 2.5 medicine, essentially got rid of all the target. That opens up the pancreas for us, we began to see medicines come that are focused on pancreatic disease in coming years. We continue in this endeavor and we continue to see progress in other organs as well.

随着我们增加效力,我们也减少了副作用,这意味着我们增加了治疗利润,我们增加了便利性,然后我们支持 - 支持在组织中推进的效力,积累较少的药物,如癌症,除了商业上,我们实现了基本的所有管理范围口服,我会回来的。所以这个计划非常成功。

在过去十年左右的时间里,我们为药物化学增添了新的焦点。我们关注的重点是提高对特定组织和细胞的生产性。第一个重大成功是增加了输送到肝细胞的药物数量,我们称这个程序为通用术语LICA,这意味着添加一种化学物质作为我们ASO的配体,我们的药物以更好的方式提供更多的药物对合适的人。本幻灯片来自临床试验中前10种这些药物的复合性能的第一篇论文,它们来自正常志愿者4周治疗,不同剂量水平的匹配研究,然后测量靶向血液。

在右边是非常有效的母体分子,它们是重要且一致的,然后在左边是更有效且一致的新分子。这种一致性非常重要,因为它有助于快速有效的药物开发。我们知道下一种药物是如何产生的,因为我们刚看到最后一张幻灯片。我们还从中报告了集成安全数据库。我们可以说的是,我们差不多,我们现在可能接近近1000名接受治疗的受试者。我们已经看到该药的原始安全性,耐受性和便利性。

这实际上是关注今天正在开发的14种肝脏LICA药物。我只想强调,这些药物都针对非常大的疾病类别,非常常见的疾病,巨大的商业机会,这就是这一进步促使我们做的事情。

这是25代肝脏LICA药物中的前两种。我们认为,这些药物具有的效力,我们将能够实现商业上可接受的口服给药,药丸中的药物。对于我们在这种情况下已经[音频不清晰]的技术而言,这确实是后期的前沿。我们将在接下来的几个月里讨论这个问题,希望它会令人兴奋。

在肝脏上取得成功后,我们继续与阿斯利康的同事一起工作,我们发现了一种可以附着的配体,可以有效地将药物积聚到胰腺的β细胞中。胰腺β细胞管理代谢性糖尿病,肥胖就是这样。我们从来没有能够在胰腺中工作,这种测定只是测量目标RNA的量。在这里,您可以看到胰腺LICA Generation 2.5药物,基本上摆脱了所有目标。这为我们开辟了胰腺,我们开始看到未来几年专注于胰腺疾病的药物。我们继续这一努力,我们继续看到其他机构的进展。

We hadn't just focused on chemistry, we have also start to understand at an almost second by second level, what are the molecular mechanisms that cause the effects that we observe with our medicine and then use that information to make better medicine. In 1990 I think, I divided potential mechanisms in two big groups, those that would cause the degradation of the RNA and those that were bind to the RNA but causes to change its shape or function.
And we understand the degradation methods, mechanisms at a wonderful level of detail and we use that information and made better and better medicine and of course we had many examples of RNAse H1 and of course SPINRAZA is an example of this lower mechanism. What we've attempted to do over the years is to expand the [rapid-fire] of mechanisms for which we know how to design ASOs to do. And the reason for that is it increases the versatility. And that allows us to think about creating all kinds of other problems. This is just a partial list of the mechanisms that we now know how to design ASOs for and one area of very intense effort was to develop means that we can use to selectively increase the level of proteins. And we've made great progress. That means we not only can fix things that are problem, because you have too much. But we can work on diseases where you need a little more. All of that then adds to the value of the technology.
We have enabled, essentially, all the major organs of the body or almost all the major organs of the body. And we can deliver by essentially any route, and we're on track to be able to report that we can put our medicines in a pill and deliver it by now.
This has a look at the timelines and it's really pretty simple. We laid the foundation in beginning, we laid out the strategy, step by step we followed it, we executed. And we had some early successes, and now of course, the momentum as you would hope in the technology is even more, all that accumulated information informs the next steps. And that is how you create a new sector in an industry.
Creating a new sector in an industry is not easy. If it were easy, everybody would do it. And so of course, we had disappointments, of course, we had failures. But here's the thing. When we had a disappointment, we asked why did it happen? We learned why, then we applied that information to do better the next time. Disappointments provide informed us, they never defined us. And we're proud of that.
The other way to look at what the advances in the technology have done and I'll just get through this very quickly. We’ve expanded the opportunities are enormous. And that sets us up for a future in which we bring benefit to patients with a wide range of problems. So we are in possession of the most direct route from the gene to the patient, it is by far the most efficient platform that I'm aware of. And it's getting more efficient and that of course then leads to competitive advantage.
Now, very recently, in the last couple of three years, we've added a new focus to our medicinal chemistry program. These two papers are the first two papers from a large group of papers that demonstrate that, that we know how to with simple chemical modifications, straightforward modifications, drive our medicines to do what we want them to do and next to nothing what we don't want them to do and we're learning how to move our medicines inside cells, so we get them where we want them. And that means that we're on the cusp of actually achieving the goal of designer medicine. And that excites us tremendously about our future. Another giant step forward, we hope for the technology and the efficiency of it. That's technology.

我们不仅仅专注于化学,我们也开始在几乎二度的水平上理解,导致我们用药物观察到的效果的分子机制是什么,然后利用这些信息来制造更好的药物。在1990年,我认为,我将潜在的机制划分为两大类,即导致RNA降解的那些和那些与RNA结合但导致改变其形状或功能的小组。

我们理解降解方法,机制处于非常精细的细节水平,我们使用这些信息并制造出更好更好的药物,当然我们有很多RNAse H1的例子,当然SPINRAZA就是这种较低机制的一个例子。多年来我们试图做的是扩大我们知道如何设计ASO的机制的[快速发展]。其原因是它增加了多功能性。这使我们能够考虑创造各种其他问题。这只是我们现在知道如何设计ASO的机制的部分列表,并且一个非常激烈的工作领域是开发可以用于选择性地增加蛋白质水平的方法。我们取得了很大进步。这意味着我们不仅可以修复有问题的东西,因为你有太多东西。但是我们可以针对需要更多的疾病进行治疗。所有这些都增加了技术的价值。

基本上,我们已经使身体的所有主要器官或几乎所有身体的主要器官成为可能。我们可以提供基本上任何途径,我们正在按计划报告我们可以将药物放入药丸并立即交付。

这看一下时间轴,它非常简单。我们在开始奠定了基础,我们制定了战略,我们一步一步地遵循它,我们执行了。我们有一些早期的成功,现在,当然,你希望技术的动力更大,所有积累的信息都会告知接下来的步骤。这就是你如何在一个行业中创造一个新的部门。

在一个行业中创建一个新的部门并不容易。如果这很容易,那么每个人都会这样做。当然,当然,我们有失望,当然,我们失败了。但这就是事情。当我们失望时,我们问为什么会这样?我们了解了为什么,然后我们应用这些信息,以便下次做得更好。失望告诉我们,他们从未定义过我们。我们为此感到自豪。

另一种看待技术进步的方法,我将很快解决这个问题。我们扩大了机会是巨大的。这为我们的未来奠定了基础,我们为患有各种问题的患者带来了益处。因此,我们拥有从基因到患者的最直接途径,它是迄今为止我所知道的最有效的平台。而且效率越来越高,当然也会带来竞争优势。

现在,最近,在过去的三年里,我们为我们的药物化学计划增加了一个新的焦点。这两篇论文是来自大量论文的前两篇论文,这些论文证明,我们知道如何通过简单的化学修饰,直接的修改,推动我们的药物去做我们想要他们做的事情,并且几乎没有我们做什么我希望他们这样做,我们正在学习如何在细胞内移动我们的药物,所以我们将它们送到我们想要的地方。这意味着我们正处于实际实现设计医学目标的尖端。这激发了我们对未来的巨大兴趣。另一个巨大的进步,我们希望它的技术和效率。这是技术。

The business model was really straightforward. We focused on innovation and our goal was to create and preserve innovation over the very long haul. And then to focus on treating each of our medicines as a precious asset and find the very best organization to commercialize on. That then of course partnering was a critical part of our strategy, and we have been very successful in corporate partnering. I think we had more as many partnerships and diverse partnerships as any company in our sector or any company in biotech and a plus of that it’s given us multiple source of revenue. This just looks at the business model, we laid that out. In the early days -- and we have evolved in our strategy as one would hope from partnering. In the early days, since we started with $5.2 million, we did partnerships for money, and we also did partnerships to validate that we were doing something worth doing, and to access resources.
As the technologies matured and we matured, of course that strategy changed entirely. Today, we partner for strategic reasons. We partner late, and we have achieved our goal of retaining a much greater fraction of commercial revenue. And then very recently, we formed our first commercial affiliate that's majority owned and that's Akcea and that of course achieves a very highest level of retention of commercial revenues, as we consolidate all of the revenues as they break. And we think Akcea is off to a very good start, in fact their valuation is now $2 billion plus and again we look at that as a great step. We fully intend to repeat this with additional commercial affiliates in the future.
As the technology has matured and as recognition has matured, price of entry has gone up. This is a perfect example, 2013 we did Biogen strategic transaction started with $100 million, 2018 we did same thing started with $1 billion. Every number on this table has gone up and most importantly royalties have gone up. And I can tell you that, the price of entry is now hire than this by quite a little bit.
And all of that the combination of the technology and the business model gives us this picture. Today we have one medicine in development for every 11 people at Ionis, compare that to any other company, any other business model, any other technical approach and you're going to get thousands of people per molecule per development candidate, and that leads to competitive advantage.
Now, I'll talk about the culture. We knew that, we wanted to create a very different environment, and so we created absolutely every system, every HR system, every motivational system, every administrative de novo, specifically to reinforce the behaviors that we wanted. All of that was created at Ionis for Ionis. We've implemented that. We then strengthened our organization and continued to emphasize our unique approaches. And then over the last 10 years we solely we focused on teaching, why we do the things we do the way we do them, strengthening the organization and building a really robust succession plan. We've done it and we're excited about it. And so today, Ionis absolutely is a culture of yes, yes to patients, yes to experiment, yes to the innovation, yes to new medicines, yes to prudent risks and yes to our people, our innovative people.

商业模式非常简单。我们专注于创新,我们的目标是在很长一段时间内创造和保持创新。然后专注于将我们的每种药物视为宝贵的资产,并找到最好的商业化组织。当然,伙伴关系是我们战略的重要组成部分,我们在企业合作方面非常成功。我认为我们拥有的合作伙伴关系和合作伙伴关系多于我们行业中的任何公司或生物技术公司中的任何公司,而且我们拥有多种收入来源。这只是看商业模式,我们就这样说了出来。在早期 - 我们已经在我们的战略中发展,因为人们希望通过合作来实现。在早期,自从我们从520万美元开始,我们就是为了钱而建立合作伙伴关系,我们还建立了合作伙伴关系,以验证我们正在做一些值得做的事情,以及获取资源。

随着技术的成熟和我们的成熟,当然这种策略完全改变了。今天,我们出于战略原因合作。我们合作伙伴很晚,我们已经实现了保留更多商业收入的目标。然后在最近,我们成立了我们的第一个商业子公司,这是大多数人拥有的,而Akcea当然实现了最高水平的商业收入保留,因为我们将所有收入整合在一起。而且我们认为Akcea有一个非常好的开端,事实上他们的估值现在已经超过20亿美元,我们再次认为这是一个很好的一步。我们完全打算在未来与其他商业分支机构重复这一点。

随着技术的成熟和认可的成熟,进入价格已经上涨。这是一个完美的例子,2013年我们做了Biogen战略交易以1亿美元开始,2018年我们以10亿美元的价格开始做同样的事情。这张桌子上的每个号码都涨了,最重要的是版税增加了。而且我可以告诉你,入门的价格现在已经超过了这一点。

所有这些技术和商业模式的结合为我们提供了这样的图景。今天,我们为Ionis的每11个人开发一种药物,将其与任何其他公司,任何其他商业模式,任何其他技术方法进行比较,并且每个开发候选人每分子将获得数千人,这导致竞争优势。

现在,我将谈论文化。我们知道,我们想创造一个非常不同的环境,因此我们创造了绝对的每个系统,每个人力资源系统,每个激励系统,每个行政重新,特别是为了强化我们想要的行为。所有这些都是在Ionis为Ionis创造的。我们已经实现了这一点。然后,我们加强了我们的组织,并继续强调我们独特的方法。然后在过去的十年里,我们只专注于教学,为什么我们按照我们的方式做我们做的事情,加强组织并建立一个非常强大的继任计划。我们已经做到了,我们对此感到很兴奋。所以今天,Ionis绝对是一种肯定的文化,对患者是肯定的,对实验是肯定的,对创新是肯定的,对新药是肯定的,对谨慎的风险是肯定的,对我们的人,我们的创新人是肯定的。

In our industry, there are tremendous challenges. Most of the time we fail in other technologies, the costs are enormous, the time is enormous. There is just so many opportunities to say no. Now let me ask you this can you imagine that any patient ever got better because of CEO of some company said no? Many of them said yes. We say yes. And all of that then translates to competitive advantage that we’ll continue to grow.
So now on to the future. This is an interesting picture of course it’s written on your knee and we’re standing in front of what we call the patent wall. Every one of these plaque represents a patent that has been issued and invention that we made. So about 15 years ago we stopped getting these plaques because we ran out of room. But inventions are continuing. What that means is that as we invent our control of the technology continues into the future.
Innovation, value, benefit. The other way to look at this is as transition. In January I assume the role of a very active Executive Chairman and Brett becomes CEO. I'm confident that that’s the right choice, he is a 30 year veteran at Ionis. Brett and I have been friends and colleagues for almost 40 years. I'm also confident that the organization is ready for this transition and Brett inherits a really strong vibrant organization.
This is a look at the senior team, it is deep. Ionis has always been our strength, it’s astonishing how deep and exciting we are. When I see the young scientists who are here, their energy, excitement and just how smart they are, it amazes me. And it’s not just science, we’re deep and talented in every element of the business. We have long tenure of leadership but we welcome new people and new ideas and so it’s working. And the commitment to patients has never been higher. Walk out ask anybody we have seen why do you come to work today, every single one of them will tell these people depend on me. What better motivation could we have than sit people within the Ionis.
So now I want to finish by letting SPINRAZA speak. Introducing to the family Lee, I want to thank them for letting us share this video. The Lee family has had five children, two healthy boys and three siblings born just in May. One baby died, the other child is fully paralyzed and needs machine to breathe for it, and the fifth child [Keira] was treated with SPINRAZA before she became symptomatic. These were these. I'm sorry I am ahead myself but I do think this is important. This is our view of the world these days, this is us with the technology in this center, in this circle our patients are benefiting today and then there’s the rest of the world out there. That’s where we hope to go.
That’s [Keira], that’s her first dose, walking, everybody seeing, running out of her diaper, many of us are familiar with that one. All of her milestones. And our closure parents. She has a future without limits, she has a future, and she got her brother. We wanted to do AGM.
Thank you very much. Thank you, buy more stock and of course you can tie it.

在我们的行业中,存在巨大的挑战。大部分时间我们在其他技术上都失败了,成本巨大,时间巨大。有很多机会说不。现在让我问你,你可以想象,因为某公司的首席执行官说不,所有病人都变得更好了吗?他们中的许多人都说是的。我们说是的。所有这些都转化为我们将继续增长的竞争优势。

所以现在走向未来。这是一张有趣的图片,当然它写在你的膝盖上,我们站在我们称之为专利墙的前面。这些牌匾中的每一个都代表了我们发布的专利和发明。因此,大约15年前,我们停止了这些斑块,因为我们没有房间了。但发明仍在继续。这意味着,随着我们发明我们对技术的控制将持续到未来。

创新,价值,效益。另一种看待这种情况的方式是过渡。 1月份,我担任一位非常活跃的执行主席和布雷特担任首席执行官。我相信这是正确的选择,他在Ionis有30年的经验。近40年来,布雷特和我一直是朋友和同事。我也相信组织已经为这种转变做好了准备,而Brett继承了一个非常强大的组织。

这是一个高级团队,它很深。 Ionis一直是我们的力量,令人惊讶的是我们是多么深刻和令人兴奋。当我看到这里的年轻科学家,他们的精力,兴奋以及他们多么聪明时,我感到惊讶。这不仅仅是科学,我们在业务的每个方面都很有才华。我们有很长的领导权,但我们欢迎新人和新想法,所以它正在发挥作用。对患者的承诺从未如此高涨。走出去问任何我们看到你为什么今天来上班的人,他们中的每一个都会告诉这些人依赖我。我们有更好的动力,而不是坐在Ionis内的人。

所以现在我想通过让SPINRAZA发言来完成。向李家人介绍,我要感谢他们让我们分享这个视频。李家有五个孩子,两个健康的男孩和三个兄弟姐妹刚出生在五月。一个婴儿死亡,另一个孩子完全瘫痪,需要机器呼吸,第五个孩子[凯拉]在出现症状之前接受了SPINRAZA治疗。这些就是这些。对不起,我自己领先,但我觉得这很重要。这是我们对世界的看法,这就是我们在这个中心的技术,在这个圈子里,我们的患者今天受益,然后世界其他地方就在那里。这就是我们希望去的地方。

那是[凯拉],这是她的第一剂,走路,每个人都看到,尿布用完了,我们很多人都熟悉那个。她所有的里程碑。而我们关闭父母。她有一个没有限制的未来,她有一个未来,她有她的兄弟。我们想做AGM。

非常感谢你。谢谢你,买更多的股票,当然你可以绑它。

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