Ionis Pharmaceuticals, Inc. (NASDAQ:IONS) 2019 Annual Meeting of Stockholders Conference Call June 6, 2019 5:10 PM ET
Stanley Crooke - Founder, Chairman, CEO and President
- Stanley Crooke - 创始人，董事长，首席执行官兼总裁
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.
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。
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.
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.
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。
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.
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。
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.
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.
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.
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.
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.
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.
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。
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.
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。
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.
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