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#141 Stan Crooke on Ultra Rare Disease Drugs

by Kira Dineen
February 19th 2021

Biotech titan Dr. Stan Crooke joins host Kira Dineen to celebrate rare disease month! Dr. Crooke was the Founder of IONIS Pharmaceuticals, with extensive expe... More

How is it that we find ourselves surrounded by such complexity? Such elements, genes of you and me are all made of DNA. Were all made of the same. Hello, you're listening to DNA today, a genetics podcast and radio show. I'm your host card nine. I'm also a certified genetic counselor practicing in the prenatal space. On this show. We explore genetics impact on our health through conversations with leaders in genetics experts like genetic counselors, researchers, doctors and patient advocates. My guest today is biotech tightened dr stan crook. He was the founder of Iona's pharmaceuticals with extensive experience in the pharmaceutical industry developing more than 20 marketed drugs recently, he founded another pharmaceutical company and Laura um which we are diving into on this episode is part of our rare disease month celebration. So thank you so much Dr cook for coming on the show.

I'm excited too. Talk about rare diseases today. Well, I'm glad glad to be joining you. Thanks. So I thought we could educate people that may not be familiar with rare diseases that it affects less than 200,000 people in the us. But taking this a step further, what is an ultra rare disease? Well there's no generally accepted definition but at in more um um If we uh we we define it as having 1 to 30 patients in the world who have precisely the same mutation. And so this is much different than just like one and 200,000. You're talking about just a handful or 30 people in the world. So that is where we're setting the scene for an ultra rare disease. That's exactly right. And it is exactly the number that matters because it's the numbers that caused the challenges that are unique to this patient group. And what are some of those challenges and treating patients with ultra rare diseases that have ultra rare genetic mutations? Well, of course it all stems from the numbers.

Um Typically these mutations produce severe manifestations of the mutation, sometimes very rapidly fatal. And if a patient is lucky enough to survive, typically they'll spend many years seeking a diagnosis and then if they're lucky, they'll get to a facility that can genetically characteristic the mutation. And even in that case, then typically what they have to be told is there's no treatment and it's very unlikely there ever will be the treatment. And it's that aspect of lack of treatment then laura um was founded to try to try to manage and for people to better understanding what is the standard process for drug development so that we can compare it to how yours differs so vastly. Uh The standard process for drug discovery and development of course is highly regulated, requires a great many studies and animals and then numerous proofs of value in human beings And a commercial entity also has to advertise all the failures against a few successes.

And that's why uh the typical time for drug drug discovery to commercialization is more than 17 years And they cost for drug that's successful is over $2 billion. Now, if you focus on rare diseases Again, the requirements are quite stringent still. And so typically it's going to be maybe 10 years and and $1-$500 million dollars worth of investment. Uh, the problem with the ultra rare patient is even meeting those those requirements becomes impossible. How does one do a trial with a single patient and prove that benefit and risk or appropriate? So, certainly a lot of differences when we're comparing a more common condition where you have, You know, thousands, hundreds of thousands, millions of patients that you can work with. But for this, the population is so small and talking about just the cost of developing a drug.

And you're saying it takes like 17 years on average to develop a drug that is a long time. And just how much money has to go into this. So it's just remarkable what you're able to do for the rare disease community. I mean, tell people what and Lori um is about and how you differ from this standard drug development process. An alarm is a charitable foundation. It's actually not a pharmaceutical company, it's a charitable foundation and I found it in laura to take advantage of the technology that we created at Iona is called Antisense Technology. That technology is vastly more efficient than other drug discovery technologies especially done at Iona's because we pioneered it. We have all sorts of systems that facilitate the identification of the right S. O. And um and so our process at end Warum recognizes that we can't spend enormous amounts of time or money uh in animal studies and it's essentially impossible to perform a clinical trial that would meet requirements for approval.

And so we have no intention of trying to achieve a commercial approval. And our plan is to provide these experimental S. O. S. For life for free to these patients. And the reason we can do it is just the extraordinary efficiency and versatility of the technology that we created at Ioannis. So and laura um is basically a bridge from the need which is the patient and in research investigator who's taking care of that patient and who has characteristic genetics of that patients to the engine we build and Ioannis which then can for some of these patients create an esso manufacturing and get it to them and provide that S. O. For free for life. And so it is a remarkable new dimension to the idea of drug discovery development. It's never even been dreamt of before, it's never been tried. But it's very clear that a commercial model can't meet the needs of these patients.

Even if one could get approval For a patient population save 10. Uh the cost of doing that would mean that you'd have to charge these poor families tens of millions of dollars a year probably. I think that's wrong. And I think it would also be very bad for our industry and so in alarm is designed to meet that very specific need um in the patients that we can design S. O. S. To to treat. So let's talk about A. S. O. S. What our S. O. S. And how are they different than other approaches to drug development? Well I'm sure your audience knows that that that genes are transcribed into RNA. And that RNA then is used to produce the proteins that do the work of the body. Most drug discovery technologies focused on making molecules that bind to proteins. Aniston's technology takes an entirely new approach and designs small bits of jean like material heavily chemically modified.

So they have good drug properties to bind the target RNA. S. And cause that RNA to either be used more effectively to make more protein or to be degraded or prevented from making a disease causing protein. What makes it so much more efficient as we know the rules the very rules that are used by your body to manage genetic information are the rules that we follow when we want to design an S. O. To take advantage of that target RNA. So being able to take it so differently as you were saying a lot of drugs are targeting proteins to either fix them or make them work better. Whereas this is kind of taking a step earlier in the process and saying well let's let's change those instructions and what's being used in the cell. Exactly right. So you can think of it as we engage in altering the information management system of the cell. Whereas the typical drugs try to alter the way work is done in the cell.

And since we know the rules then it becomes a much more efficient process for how to do that. And of course I say that like it's simple, it's only taken 30 years and several billion dollars to get to this place, right. It wasn't like it was an overnight, let's start this company. There's so much science behind that. So what do a ESoS target in the body we're talking about? M. R. N. A. But what are the specific organs that are targeted is different for every type of drug? Are there similar organs that are usually targeted? One of the beauties of the technology is that within a particular chemical class all the agents are basically the same. They just differ in terms of genetic zip code so that we can take tremendous advantage of that consistent performance. And with the medicines that we use uh we know they distribute very broadly uh They can be administered by essentially all routes of administration including local for long and local for I and of course interest secretly for for administration of central nervous system disorders.

So within more um what we've done is focus on five organs where we really understand the performance of these medicines. We we know the doses are low. We know the routes are correct so that we can minimize the risk that the patient might be exposed to. And those are liver, kidney, lung I and the central nervous system, liver and kidney. We administer subcutaneous li uh the drugs distribute very broadly and then in the eye, lung and central nervous system we administer locally, which makes it even safer so that you're only targeting the organs that you really need to for those certain disorders then. Um so you know, we talked about and lori um taking a charitable approach to this, which is so different than what I hear from other companies of, you know, you're looking to raise money and then you're paying a pharmaceutical company to start developing and look at molecules that might work for a drug. I mean, this is so different and interesting. How can you fund all of this?

Where is the money coming from? How is this? Uh, scalable approach? Well, let's answer the last question first. It's very scalable. That is if we have sufficient funds, the technology is versatile enough that we can treat many many patients. We can't treat all and obviously our limitations today of these organs and there are mutations that we can't address. So it is eminently scalable and my focus is not on the patients. We can't help. My focus is on helping the patients we can and changing the futures of these families because they're really desperate. Now, The opportunity that we have really just began with the technology and once I realized that technology could do this, then then we had to put the rest of it together. The founding donors where I own this pharmaceuticals, Ioannis has donated about $2.8 million dollars Biogen, our partner in the central nervous system and in the same range they don't want us to give specific numbers.

And my wife and I have donated $3.2 million. And our plan this year was not, that is 2020 was not to raise money because I wanted to prove that the concept could work. But in fact just word of mouth and and interest, uh, several other additional millions of dollars in new new donations have come in And we certainly have proven that the system can work in 2020. So we're very excited about the progress we made. That is remarkable just to here and just that you've given some of your own money to be having this as to start the company and for all of these families that it's going to be impacting. I mean that's just huge. I'm imagining all of the rare disease parents that are listening to this and just hearing that, you know, we always hear, oh, there's new developments and new technology, but it's it's inspiring to hear that this is a specific one that's not just working for one rare disease, but you're focused on, you know a variety of rare diseases that are in this ultra rare space.

Once you know the mutation the name of the jesus doesn't really matter once you know the cause of a disease. Now you have a name for that disease. It is mutation X. Cause problem. And and that's very interesting is important to get people over that hump. We're agnostic as to the name of the disease. Once we know the mutation and uh and once we do that then of course we can move rapidly. And so what we offer which is very different is immediate hope and very near term treatment. Um Now that treatment is experimental and and our job is to minimize the risk, make the risk uh prudent while maximizing the benefit. And so we've put in important systems that assure high quality decision making, high quality discovery of the wright S. O. And high quality development to that patient. And then finally our intention is to evaluate the performance of these S.

O. S. And we've developed some novel systems to do that and publish those results every year in summary so that the world will have an opportunity to understand how much good we're doing what the risks are and what the challenges are when there are certainly many challenges that we have to face just for people to know that you are a resource and for your name to get out there so that people can find you So to understand the process a little bit more. How does it start if there's a rare disease parent listening to this and says wow this seems like it could be a fit. Like my child has a rare disease. We don't know exactly or we found the mutation but there isn't a treatment yet. What is that first step with starting this process? Well the the first step is to go to the website with a research investigator who is caring for the patient. It requires vote because we require a great deal of information. We need to know essentially a whole genome sequencing already done.

We need to know the nature of the mutation. We need to know the function of the gene. Uh that application then is completed. Its then blinded for patient confidentiality and we evaluated initially within an alarm. And then we present the case typically with the investigator uh present to a committee, we call the access to treatment committee and that committee is made up of all the different types of expertise. We feel we need to be sure that these decisions are well considered. If the committee agrees, then we move forward and we initiate discovery development of the A. S. O. And I own as in the meantime while that probably takes anywhere from nine months to a year. During that time we asked that the investigator in the patient documented disease thoroughly during that year so that we have a recent natural history to compare to when we add the treatment to it.

And that's how we're going to evaluate these patients. So it's complex as is necessary and it does require that the patient be at a tertiary care center where there's a research investigator who's capable of genomic sequencing. And so for parents that know of a couple other Children that have the same disorder, so the same mutation or that's the same gene that's involved. Can they approach and laura and say you know, there's a small group of us with this disorder. Can we all be treated together? Yeah let me just think an item very very clear because a disease has the same name or even the same gene does not mean that the patient has the same mutation. So um if the mutation is exactly the same then we can use the same A. S. O. That we used to treat that first patient. And in fact we've already helped investigators get several S.

O. S. To treat a group of patients that we now know is somewhat larger than we thought. And these are fuss mutation LS patients. The first mutation a less produces a very aggressive form of ALS from symptom onset to death is on average about six months. And and so that's an example of a single A. So being able to be used for a number of patients. Much more common is the mutations that what unique to that patient And in that case every new mutation that comes our way requires a new discovery exercise. So the short answer which I should have given you to begin with is asked still out the application and let us see what we can do. Yeah definitely. That's a great example and you know, encouraging to hear that you know, for those cases for those you know severe form of A. L. S. That you're able to develop an A. S. O. And have something that is um you know, certainly helping with treatment there, is there other conditions and disorders our other genes that you've been able to develop A.

S. O. S. For um within this new company or new organization I should say. Yeah a foundation. It's important to separate it from companies because we are charitable. Uh there are and and and as you might imagine a good many of the cases that were receiving are from this have to do with central nervous system disorders. And a lot of them are mutations in channels, iron channels and the iron channels of course manage electrical activity in your brain and your heart and everywhere else. And so many of these patients have epilepsy severe. And then obviously if that begins in infancy they usually will have some sort of developmental delay. Uh And and so those are good examples of of patients for whom we're making esos to treat right now. Uh And then the first mutations are good examples of actually older patients that we've already helped get experimentally associate.

And I think suggestive information that they did receive benefit is already being developed. Yeah, definitely. And and you've had such an extensive career in the pharmaceutical industry. I'm just like before this, I was just reading about so much of what you've done. I mean marketing 20 drugs including spin raza. Um, can you share about just that experience over the years and just seeing so many, you know, drugs come to market and I'm sure there's a lot of other drugs that, you know, you're involved with that didn't quite make it to that point because as we said, that's so involved. Um, and it takes a lot, you know, really put through drugs, put them through the wringer to to end up being an FDA approved. I mean, can you share some of that experience of, you know, maybe with spin rosa? Yes. Well, you know, um, I'm an MD PhD. And while I was finishing my training, I came to the conclusion that I could be the greatest scientist educator of all times and I couldn't possibly medicine leverage that I would get from making one good new medicine.

And that's why I went to the industry. I worked for the patient. We are special industry patients. First investors make their money if we're successful. And I've been involved in good many drugs that changed the lives of patients. But spin browser is a really special medicine that comes along once in a lifetime here you have a disease spinal muscular atrophy where prior to spin rosa no patient whoever had spinal muscular atrophy ever got better. The only course was down and the most common form of the disease, the type one Um caused on average death in infants at six months and they suffocate uh, and spin rods has changed all of that. We now know that if we treat patients before they become symptomatic, the vast majority of these patients grow and develop like normal healthy Children continue.

It astonishes me and I've been doing this for a lifetime and and no significant side effects. And that technology which allowed us to do that is the technology that we have available to us at any more. Um, and that's power, that's power for good. And I've had the opportunity to exercise it commercially and now I have the extraordinary opportunity to exercise it in this charitable fashion. And for me it's just go sort of the right way to take the next step and my long efforts in this in this area. Yeah, definitely. Well, I just want to thank you on behalf of the rare disease community because I think so many people are going to hear this interview and just it's gonna give them so much hope and just something to invest in and something to do because you know from what I hear of rare disease parents and people in the community that it can be really challenging to be on that diagnostic odyssey and getting an answer.

And even when you get an answer, oftentimes there isn't a treatment and you're able to say, you know what, let's let's change that and let's change that for the ultra rare disease people and people that are affected by these conditions. So I just want to thank you so much for starting this and it's very exciting. I'm really looking forward to seeing all of the new developments from this. Is there anything you'd like to leave with our audience today? Well, first, thank you. One of my tasks right now is to make as many physician communities and patient communities aware of in alarm as possible. Uh it feels terrible to imagine that there's a patient who we might help, who goes on help because they don't know. So thank you for that and I would just say, mhm, that hope is a tremendously powerful asset to give patients and families hope and then be able to deliver help. Too many of them is a joyous, wonderful experience.

One that I wish everyone could have. But I'm lucky enough to have it. And so cross your fingers for us and we've got plenty of challenges ahead, but I feel we're off to a great start look forward to telling you more about our progress in the coming years. Yeah, definitely. And for people that are listening do your part by sharing about and Lauren you can share this episode, we're gonna have things on social media on our website. DNA podcast dot com. And we're gonna have links to and Lauren dot org. And so more information there. But I think a way that for people that are involved in the rare disease community, I mean social media and word of mouth has a huge impact. The rare disease community is very tight. So, um, that is certainly a way that, you know, we can be contributing to your efforts and really passing that along. Um, is there any other websites to plug? Oh and laura that'll do the job. Just come see us. And if you are listening to this on the podcast or radio, you can also check it out on youtube. All of our 2021 episodes are available on there and search social media for DNA.

Today again, we're gonna be posting a lot of information about this episode which you can share. And if you have any questions for myself or doctor crook, you can email into info at DNA podcast dot com and I'll make sure those are forwarded on appropriately. And I also just wanted to mention that later this month. Um, U. N. Is hosting a podcast symposium. So be sure to check out our social media for more information on that. Uh thank you so much for coming on the show. Dr cook again. It was such a pleasure to have you on. And for all of your years of experience. I mean, this could have been like a whole series. So you know, just tip of the iceberg. So thank you so much. Thanks carol. All right, thanks for listening and join us next time to learn, discover new advances in the world of genetic DNA.

#141 Stan Crooke on Ultra Rare Disease Drugs
#141 Stan Crooke on Ultra Rare Disease Drugs
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