Stanley Crooke:
These patients arrived at our door, hopeless, helpless, lost. The system is not working for them. And so among other things we provide is, first, realistic hope. And then of course, treatment. Not every patient is amenable to treatment with ASOs and not every patient we treat is going to benefit, but certainly we're seeing encouraging evidence of benefit in quite a number of patients we've treated.
And it's not just the patient. The patient is destroyed, literally, but the family is impoverished. It's robbed of hope. It's robbed of dreams. And if I can do something about that, then I am going to. It's really that simple.
Gina:
There are approximately 7,000 known rare diseases, 95% of which have no treatment. While some rare diseases are gaining attention from the pharmaceutical industry, there's a subset of conditions that is unlikely to ever be treated by traditional drug developers, and that's ultra-rare disease.
Ultra-rare diseases are defined as conditions that affect 30 or fewer people worldwide. Historically, patients of these uncommon conditions have had virtually no shot at seeing a cure in their lifetimes. That is, until now.
I'm Gina Mullane, and in this episode of Vital Science we'll speak with Dr. Stanley Crooke, CEO of the n-Lorem Foundation, about his organization's mission to treat ultra-rare disease patients for free for life. We'll discuss the antisense oligonucleotide, or ASO technology beyond these customized treatments, the economics of the special type of drug development, and what it could mean for ultra-rare disease patients worldwide.
Todd:
Welcome to Vital Science, Stan. We're honored to have you. Tell us about yourself and your role at the n-Lorem Foundation.
Stanley Crooke:
Well, my name is Stan Crooke. I received my MD and PhD degrees at Baylor College of Medicine, did my house staff training there as well, and have lived in both academia and industry for my entire career. I've been involved in discovering and developing a more than 23,24 drugs that are currently marketed and was a senior leader at Bristol Myers, which is now Bristol Myers Squibb. And then at I was head of R&D for SKB, which is now GSK.
And then in 1989, I founded the company that I'm very proud of, Ionis Pharmaceuticals. And there we invented and advanced a new platform for drug discovery called antisense technology or RNA-targeted drug discovery. And it's that technology and the unique efficiency of the technology and many other characteristics of the technology that enable, in January of 2020, the founding of n-Lorem.
n-Lorem is a nonprofit foundation that I founded. Our mission is to take advantage of the efficiency, versatility, and basic qualities of antisense technology to discover, develop, manufacture, and provide experimental ASO treatments to patients with what we call nano-rare mutations for free for life.
Nano-rare mutations are the rarest of diseases and the rarest of mutations. Many of our patients are unique, that is, there's a single patient that we know of today that have the mutation and the disease that patient has. Some of our patients are members of a very exclusive club of no more than 30 human beings around the world that have that mutation. And so it is a foundation that's been enabled by the work that I've led over the last more than three decades, and it's a foundation that's doing something that was literally inconceivable till we began doing it, which is the idea you could actually discover a medicine for a single patient and then give it away for life for free. And that's what we're doing.
Todd:
Man, what a story. I love that, and just to hear your three decades of experience in the drug development industry, it's inspiring. I'm curious, thinking about your mission of the n-Lorem Foundation, what are you most proud of?
Stanley Crooke:
Well, I'm proud of the fact that we're able to do it, the fact that we recognize... Probably the best way to tell it is a story.
In 2017, I had two parents who visited me at Ionis, the company I founded and led and was the chief scientist for, and these two parents had children with extremely rare mutations in a gene called SCN2A. SCN2A is an ion channel, and you have many different ion channels that move basically electrons charges around, and that's how you function. That's how your brain works, how our heart works and how your nerves work. And mutations in these kinds of diseases typically produce terrible seizures. These children have terrible seizures, but it's a set of mutations that is so rare that it's very difficult to imagine a commercial entity ever developing a drug for it because it would be very difficult to even mount the necessary clinical trials. And if you succeeded, you'd have to charge these families many millions of dollars a year for the drug.
I realized at that time that the technology we created could potentially do that. And I put together the rest of the pieces over the next three years, and ultimately, while it wasn't exactly what I planned at this stage in my career or my life, it really boiled down to a moral decision. Would I let these patients continue to progress and die without any hope, without any hope of any kind of treatment, or would I make the effort? And ultimately, I decided to do that. It's been a grand journey. We started in January of 2020.
Gina:
At that time, when n-Lorem was just getting off the ground, Dr. Crooke expected to receive a handful of applications. Today, the company has received nearly 200 applications for treatment and has been able to approve 80. Last year, in a single month, they filed four INDs for treatment of fewer than 20 patients, a move never before seen in the pharmaceutical industry. This begs the question, how has n-Lorem found the funds to do this at no cost to the patient?
Developing these drugs commercially would have resulted in exorbitant out-of-pocket costs for patients as most drug platform technologies are not well suited for creating individualized medicines. n-Lorem has been able to produce these treatments through funds from founding donors, including the organization Dr. Crooke created, Ionis, and n-Lorem's partner in neuroscience, Biogen, as well as many other individual and corporate donors.
Let's hear more from Dr. Crooke on how, and Lauren has found so many partners in this cause.
Stanley Crooke:
We are the only thing that's available to help them today. We are. These patients arrive at our door, hopeless, helpless, lost. The system is not working for them, and so among other things we provide is, first, realistic hope. And then of course, treatment.
Not every patient is amenable to treatment with ASOs, and not every patient we treat is going to benefit, but certainly we're seeing encouraging evidence of benefit in quite a number of patients we've treated. And it's not just the patient. The patient is destroyed, literally, but the family is impoverished. It's robbed of hope. It's robbed of dreams. And if I can do something about that, then I am going to. It's really that simple.
Todd:
It's quite clear that your philosophy that you just laid out is driving the mission, not just for you, but for anyone associated with n-Lorem or anyone that decides to contribute and help support. And I think that's the great thing about rare disease research is that while these rare diseases may be n of a handful, the plurality together as an industry is so powerful and so inspiring.
It seems to me that your mission as a non-for-profit organization, as you're creating these individual treatments for patients for nano-rare diseases. And I love how you framed this, that the principle that the individual is the indivisible unit of human value. And I just think that's so well said.
Stanley Crooke:
Well, it's the way I've lived my life, and for almost five decades now, I've been a senior leader in this industry, and every day I've worked, I've known absolutely that I work for the patient. We have to make money to pay the bills, but I work for the patient.
When you're developing drugs commercially, you're not allowed to know the patient. You're fully blinded. In our case, most of the patients unblind us because they're on the internet looking for help, trying to find out what's wrong with them. I think the heart of our industry is about the patient, and so often it's obscured by the abstractions of science and medicine and business. There are no abstractions here. Every application that comes in is a desperate patient and a needy family. Then we get to know them and we get to help them. And when we are unable to get an ASO to a patient in time to save their lives, those are bad days too. And so we do have our bad days, but the net of it is wonderful.
Todd:
I'd like to talk about nano-rare disease. For our listeners, what classifies the disease as being nano-rare?
Stanley Crooke:
Yes. Well, first of all, it's a term I coined and I do believe that it's essential that we begin to parse patient populations more precisely, especially down at the very rare end of the spectrum because the patients are different and potential solutions may need to be different. Now, the nano-rare patient is defined as patients with a mutation that's expressed in no more than 30 patients in the world. Keyword, mutation. Not disease, mutation.
Gina:
The patients n-Lorem is able to treat each have very different conditions, but they do have one thing in common. They all have an understandable, definable, single gene mutation. When there is only one patient of a given genetic condition, it takes an average of five to eight years from symptom onset to be diagnosed, if you are diagnosed at all. Many patients are directed to n-Lorem by the Undiagnosed Disease Network, a consortium of tertiary care institutions, but there are millions of patients who fit this category. The more that are sequenced, the more mutations will be able to be treated.
n-Lorem's role is to understand exactly what the mutation is, the function of the gene, the primary and secondary manifestations of the disease, the organs involved, and what's important to the patients. Then, the organization can determine if an ASO can be developed for treatment.
Let's hear more from Dr. Crooke on how the industry can better support these patients.
Stanley Crooke:
If someone were able to achieve commercial approval, which I strongly hope doesn't happen, then patients would have to be charged millions and millions of dollars a year. I think that surely this industry can do better than that. It would be a disaster for patients and far worse for the industry. And so they're a unique patient population, unserved by the current systems, and one of our goals is to derive genomic sequencing into newborn screening protocols. Only then will we know the prevalence of these extraordinarily rare mutations. Only then will we know what fraction are of these mutations cause disease, what genes are involved, and only then will we be able to get to the patients before they become so sick that they're very difficult to treat in the first place.
And you think about the potential that's unlocked by taking a patient who's trying, as a child, to die, not all of our patients are children, but let's focus on infants, and provide a life to that. What you do is you enable that child to grow and produce and become a full human being, and you free that family up from the catastrophic limitations that a child with a terrible disease imposes on a family.
So yes, there are patients we can't treat, but I look at it as my job is to treat the patients I can today. And I think that's a very good way to change the world. One patient, one family at a time, always about that person and that family, doing our best by them. And that's what we do. And I would say if you talk to anybody at n-Lorem, you'd hear the same story. It's a privilege. It's a great privilege to be doing what we're doing, and we couldn't do it without organizations like CRL.
Todd:
That's well said. I do want to spend a little bit of time talking about antisense therapies, or ASOs, which is the key to treating the untreatable, really. What is antisense technology?
Stanley Crooke:
So an antisense drug is a genetic medicine, that is, we take the genetic code and we design an oligonucleotide, a few nucleotides, antisense oligonucleotide, and oligo just means few. And as you know, your DNA and RNA are polynucleotide. So we're just a little hunk of genetic-type material that is heavily chemically modified so that it has good drug properties. And then we administer the ASO to the patient and then alter the target RNA. These are drugs targeting RNA to either prevent the production of a disease-causing protein or to enhance the production of a protein that is needed for health. And we can do both today.
That little simple statement took about three decades of my life and thousands and thousands of publications and a couple of decades when most of the world scoffed at what we were doing to achieve that. Today, there are now 14 RNA-targeted drugs that have been approved commercially, there are hundreds of RNA-targeted drugs for diseases that range from the single patient to millions in development, and there are scores and scores of companies that are being founded to do this. And we're proud the fact that we drove it, that we created this space, and the fact that this technology now enables the ultimate step to the rarest of patients.
To create this seemingly impossible model to give drugs away is something I never dreamt of in 1989 when I founded the company. But I dreamt of most of the other stuff, and to see it as a reality is, once again, I keep using the word because I keep feeling the way I feel, and that's privilege. I have had the privilege of doing this.
Gina:
For rare disease, ASOs open a new door to treatment. Antisense therapies are designed to seek out, bind to, and destroy mRNA in a specific way so that the amount of disease-causing protein is dramatically decreased. Antisense therapies can also treat diseases caused by too little protein by increasing the production of the protein, thereby restoring the protein to normal levels.
As Dr. Crooke describes it, ASO is not gene therapy. It is genetic therapy. The distinction being that ASO cannot treat a null mutation as it does not involve replacing genes. ASO therapies exist for cardiovascular disease, Alzheimer's, Parkinson's, and metabolic diseases, but its broad application has been particularly life-changing for rare diseases like spinal muscular atrophy.
Previously the most common genetic cause of infant death, spinal muscular atrophy can now be treated with antisense therapy, and, if done early enough, can lead to a normal healthy life for these children. Biogen's novel ASO treatment for the SOD1 mutation of ASL, Toferson, is currently with the FDA for review, and Dr. Crooke expects the future to be bright for additional ASO applications.
Let's hear more on what it takes to bring these treatments to market.
Todd:
So I'd like to talk a little bit about collaboration as a strategy and partnerships in general. Collaboration really is the key to rare disease drug development. Walk me through your approach to experimental ASO drug development that n-Lorem Foundation focuses on.
Stanley Crooke:
Well, we know we can't do it alone. We're a tiny little organization and while we've raised a lot of money, we still have to raise a lot more and we still have to prove that this idea is sustainable. I'm heartened by the progress that we've made and I'm very confident we can do that. I started Ionis with $5.2 million total in a garage, and over the 30 years, I think we raised about $10 billion. So this seemed pretty easy to me, really.
But we can't do it alone. We have to have collaborators that are clinical investigators and institutions that work the patients up, to give us the patients and the information we need to make the drug. We have to have investigators of those institutions who are willing to treat those patients with an experimental medicine. Essentially every vendor to the industry, the oligonucleotide side of the industry, is a supporter, and that goes from small-scale synthesis to large-scale synthesis and toxicology studies, such as we do at CRL, our clinical partners, Parexel.
So all of the industry has stepped up and a good many biotech and pharma companies have contributed dollars and other things. So our approach to collaboration is if it's good for our patients, we do it. If it can help a patient and there's a collaborator willing to help us, they're our friends. And everything gets very simple when you think of it patient by patient and, "Who can help me the next patient?" That's the only question I ever ask. And then figuring out a way that we can work together. Every collaboration is different. Every partner is different. Once again, I don't think it has a single thing to do with me or n-Lorem, it has to do with the tangibility and poetry of the mission.
Todd:
Well, Stan, I don't know if you know this, but you're one of the few great stories that start in garages. I love that you called out your garage.
Stanley Crooke:
Well, our first facility, we had four chemical hoods in the garage and we learned the hard way that if we ran all four hoods, we created such a vacuum that a couple of chemists passed out. It came to me pretty quickly that productivity declined if we had that happen, so we had to open the garage door when we ran all four chemical hoods. So that's a true story, and I have pictures of it to prove.
Todd:
That's great.
Stanley Crooke:
A lot of people claim to have started in the garage, but I have pictures.
Todd:
Yeah, you got pictures to prove it. I love it.
Stanley Crooke:
Yeah.
Gina:
And today, more and more missions are being carried out in the drug development world. New therapies previously needed to meet a higher threshold for commercialization, but today, the growth of contract research organizations has allowed even startups within the pharmaceutical industry to take an idea from discovery through to safety testing and manufacturing.
We are also seeing greater collaborations between patient advocacy organizations and agents of the pharmaceutical industry, creating a feedback loop for drug developers to recognize the needs of patients and how to meet them.
Let's hear more from Dr. Crooke on how awareness of these needs is driving innovation within drug development.
Todd:
When it comes to ultra-rare disease, especially those that drug developers may be unaware of, advocacy and awareness is just so important to treatment being developed. As a nonprofit, how does awareness play into your mission and funding these therapies?
Stanley Crooke:
Well, I do think we benefit from a good many patient advocacy groups, and there I think we have to go back to the AIDS activist to thank them for the voice that is so prominent now, both in regulatory processes and everything else. And so we have the benefit of these patient advocacy groups that have matured so effectively and the internet that enables.
My job, our job over the last three years, is to make people aware that in n-Lorem exists, that we are available to try to help some of these patients. And we're taking advantage of all the modern communication devices. Podcasts are really pretty cool, and it seems to be the way that most people are learning these days. And so this podcast, which goes to folks at CRL and others, is a step in the process of informing people that n-Lorem is available. And if we can help, we want to. I don't think there's any magic formula. I wish there were.
Todd:
Thinking about the future, future aspirations, what does the future hold for rare disease research and drug discovery?
Stanley Crooke:
Well, I'll just talk about n-Lorem. That's a big enough topic for me. Our intention is to demonstrate that this is a sustainable model, that it's a model of quality, that our patients are only exposed to prudent risk, and we intend to treat thousands of patients and create a path, blaze a path that others can follow with other technologies.
And I look at it very much like what I did with Ionis. There was nothing but skepticism about the technology for most of the time that we were at Ionis, and we were the only voice in the wilderness saying, "Hey, we're making progress." And now there are just literally scores and scores of companies in the space. So I want to repeat that. I want to show that this is possible. I want to blaze a path of quality and professional management of patients exposed to experimental medicines that others can follow as their technologies mature to the place that they can help these patients.
And I think that's the leverage we'll get to move from treating thousands of patients, that's all we're going to be able to do, to treating the millions of patients and be the tip of the spear that drives genomic sequencing into newborn screening protocols.
And the other thing that we've tried to do is create a community for these patients. It's our patient empowerment program. And the Centerpieces podcast series that I've been doing lots of interviews with patients and experts and also just basic lessons on what is a chemical. Many of these patients and families have done amazing work and they don't even have the basics. They have to go back and try to learn high school chemistry. And so providing that, I think, is another big thing that we're doing, and I think it's going well. To reduce the isolation of these patients and families in a meaningful way and to educate, I think is another big test that we are trying our best to take part in.
Todd:
So Stan, this was great. So how can our listeners help you and n-Lorem get there?
Stanley Crooke:
Well, first thank you, Todd, for the opportunity to make my pitch. We need your help, and we need help of all denominations and all types from all people. We don't, our patients do. Our patients need your help. And you can certainly go to the n-Lorem website. All kinds of cool stuff there.
So if you're interested in learning more about n-Lorem or feel that you might be able to help us, simply go to our website, nlorem.org. Failing that, you can call us at any time. You can call me and we'll either put you to work or put your dollars to use. I guarantee it will be used for helping a patient.
Todd:
Well, Stan, this was great. We really are grateful for you joining the Vital Science Podcast, and it's great to see how it all started in the garage to now really impacting and creating awareness for nano-rare disease research. So thank you so much for your mission and what you're doing for patients all around the world.
Stanley Crooke:
Well, thank you. I appreciate the opportunity to talk about what I care about.
Gina:
Dr. Stanley T. Crooke is the founder, chief executive officer, and chairman of the board of the n-Lorem Foundation.
Looking ahead to our next episode of Vital Science. In May we'll talk with Jennifer Panagoulias from the Foundation for Angelman Syndrome Therapeutics, or FAST, about how the organization's collaborative multidisciplinary approach is accelerating the development of treatment. Until then, thanks for listening.
These patients arrived at our door, hopeless, helpless, lost. The system is not working for them. And so among other things we provide is, first, realistic hope. And then of course, treatment. Not every patient is amenable to treatment with ASOs and not every patient we treat is going to benefit, but certainly we're seeing encouraging evidence of benefit in quite a number of patients we've treated.
And it's not just the patient. The patient is destroyed, literally, but the family is impoverished. It's robbed of hope. It's robbed of dreams. And if I can do something about that, then I am going to. It's really that simple.
Gina:
There are approximately 7,000 known rare diseases, 95% of which have no treatment. While some rare diseases are gaining attention from the pharmaceutical industry, there's a subset of conditions that is unlikely to ever be treated by traditional drug developers, and that's ultra-rare disease.
Ultra-rare diseases are defined as conditions that affect 30 or fewer people worldwide. Historically, patients of these uncommon conditions have had virtually no shot at seeing a cure in their lifetimes. That is, until now.
I'm Gina Mullane, and in this episode of Vital Science we'll speak with Dr. Stanley Crooke, CEO of the n-Lorem Foundation, about his organization's mission to treat ultra-rare disease patients for free for life. We'll discuss the antisense oligonucleotide, or ASO technology beyond these customized treatments, the economics of the special type of drug development, and what it could mean for ultra-rare disease patients worldwide.
Todd:
Welcome to Vital Science, Stan. We're honored to have you. Tell us about yourself and your role at the n-Lorem Foundation.
Stanley Crooke:
Well, my name is Stan Crooke. I received my MD and PhD degrees at Baylor College of Medicine, did my house staff training there as well, and have lived in both academia and industry for my entire career. I've been involved in discovering and developing a more than 23,24 drugs that are currently marketed and was a senior leader at Bristol Myers, which is now Bristol Myers Squibb. And then at I was head of R&D for SKB, which is now GSK.
And then in 1989, I founded the company that I'm very proud of, Ionis Pharmaceuticals. And there we invented and advanced a new platform for drug discovery called antisense technology or RNA-targeted drug discovery. And it's that technology and the unique efficiency of the technology and many other characteristics of the technology that enable, in January of 2020, the founding of n-Lorem.
n-Lorem is a nonprofit foundation that I founded. Our mission is to take advantage of the efficiency, versatility, and basic qualities of antisense technology to discover, develop, manufacture, and provide experimental ASO treatments to patients with what we call nano-rare mutations for free for life.
Nano-rare mutations are the rarest of diseases and the rarest of mutations. Many of our patients are unique, that is, there's a single patient that we know of today that have the mutation and the disease that patient has. Some of our patients are members of a very exclusive club of no more than 30 human beings around the world that have that mutation. And so it is a foundation that's been enabled by the work that I've led over the last more than three decades, and it's a foundation that's doing something that was literally inconceivable till we began doing it, which is the idea you could actually discover a medicine for a single patient and then give it away for life for free. And that's what we're doing.
Todd:
Man, what a story. I love that, and just to hear your three decades of experience in the drug development industry, it's inspiring. I'm curious, thinking about your mission of the n-Lorem Foundation, what are you most proud of?
Stanley Crooke:
Well, I'm proud of the fact that we're able to do it, the fact that we recognize... Probably the best way to tell it is a story.
In 2017, I had two parents who visited me at Ionis, the company I founded and led and was the chief scientist for, and these two parents had children with extremely rare mutations in a gene called SCN2A. SCN2A is an ion channel, and you have many different ion channels that move basically electrons charges around, and that's how you function. That's how your brain works, how our heart works and how your nerves work. And mutations in these kinds of diseases typically produce terrible seizures. These children have terrible seizures, but it's a set of mutations that is so rare that it's very difficult to imagine a commercial entity ever developing a drug for it because it would be very difficult to even mount the necessary clinical trials. And if you succeeded, you'd have to charge these families many millions of dollars a year for the drug.
I realized at that time that the technology we created could potentially do that. And I put together the rest of the pieces over the next three years, and ultimately, while it wasn't exactly what I planned at this stage in my career or my life, it really boiled down to a moral decision. Would I let these patients continue to progress and die without any hope, without any hope of any kind of treatment, or would I make the effort? And ultimately, I decided to do that. It's been a grand journey. We started in January of 2020.
Gina:
At that time, when n-Lorem was just getting off the ground, Dr. Crooke expected to receive a handful of applications. Today, the company has received nearly 200 applications for treatment and has been able to approve 80. Last year, in a single month, they filed four INDs for treatment of fewer than 20 patients, a move never before seen in the pharmaceutical industry. This begs the question, how has n-Lorem found the funds to do this at no cost to the patient?
Developing these drugs commercially would have resulted in exorbitant out-of-pocket costs for patients as most drug platform technologies are not well suited for creating individualized medicines. n-Lorem has been able to produce these treatments through funds from founding donors, including the organization Dr. Crooke created, Ionis, and n-Lorem's partner in neuroscience, Biogen, as well as many other individual and corporate donors.
Let's hear more from Dr. Crooke on how, and Lauren has found so many partners in this cause.
Stanley Crooke:
We are the only thing that's available to help them today. We are. These patients arrive at our door, hopeless, helpless, lost. The system is not working for them, and so among other things we provide is, first, realistic hope. And then of course, treatment.
Not every patient is amenable to treatment with ASOs, and not every patient we treat is going to benefit, but certainly we're seeing encouraging evidence of benefit in quite a number of patients we've treated. And it's not just the patient. The patient is destroyed, literally, but the family is impoverished. It's robbed of hope. It's robbed of dreams. And if I can do something about that, then I am going to. It's really that simple.
Todd:
It's quite clear that your philosophy that you just laid out is driving the mission, not just for you, but for anyone associated with n-Lorem or anyone that decides to contribute and help support. And I think that's the great thing about rare disease research is that while these rare diseases may be n of a handful, the plurality together as an industry is so powerful and so inspiring.
It seems to me that your mission as a non-for-profit organization, as you're creating these individual treatments for patients for nano-rare diseases. And I love how you framed this, that the principle that the individual is the indivisible unit of human value. And I just think that's so well said.
Stanley Crooke:
Well, it's the way I've lived my life, and for almost five decades now, I've been a senior leader in this industry, and every day I've worked, I've known absolutely that I work for the patient. We have to make money to pay the bills, but I work for the patient.
When you're developing drugs commercially, you're not allowed to know the patient. You're fully blinded. In our case, most of the patients unblind us because they're on the internet looking for help, trying to find out what's wrong with them. I think the heart of our industry is about the patient, and so often it's obscured by the abstractions of science and medicine and business. There are no abstractions here. Every application that comes in is a desperate patient and a needy family. Then we get to know them and we get to help them. And when we are unable to get an ASO to a patient in time to save their lives, those are bad days too. And so we do have our bad days, but the net of it is wonderful.
Todd:
I'd like to talk about nano-rare disease. For our listeners, what classifies the disease as being nano-rare?
Stanley Crooke:
Yes. Well, first of all, it's a term I coined and I do believe that it's essential that we begin to parse patient populations more precisely, especially down at the very rare end of the spectrum because the patients are different and potential solutions may need to be different. Now, the nano-rare patient is defined as patients with a mutation that's expressed in no more than 30 patients in the world. Keyword, mutation. Not disease, mutation.
Gina:
The patients n-Lorem is able to treat each have very different conditions, but they do have one thing in common. They all have an understandable, definable, single gene mutation. When there is only one patient of a given genetic condition, it takes an average of five to eight years from symptom onset to be diagnosed, if you are diagnosed at all. Many patients are directed to n-Lorem by the Undiagnosed Disease Network, a consortium of tertiary care institutions, but there are millions of patients who fit this category. The more that are sequenced, the more mutations will be able to be treated.
n-Lorem's role is to understand exactly what the mutation is, the function of the gene, the primary and secondary manifestations of the disease, the organs involved, and what's important to the patients. Then, the organization can determine if an ASO can be developed for treatment.
Let's hear more from Dr. Crooke on how the industry can better support these patients.
Stanley Crooke:
If someone were able to achieve commercial approval, which I strongly hope doesn't happen, then patients would have to be charged millions and millions of dollars a year. I think that surely this industry can do better than that. It would be a disaster for patients and far worse for the industry. And so they're a unique patient population, unserved by the current systems, and one of our goals is to derive genomic sequencing into newborn screening protocols. Only then will we know the prevalence of these extraordinarily rare mutations. Only then will we know what fraction are of these mutations cause disease, what genes are involved, and only then will we be able to get to the patients before they become so sick that they're very difficult to treat in the first place.
And you think about the potential that's unlocked by taking a patient who's trying, as a child, to die, not all of our patients are children, but let's focus on infants, and provide a life to that. What you do is you enable that child to grow and produce and become a full human being, and you free that family up from the catastrophic limitations that a child with a terrible disease imposes on a family.
So yes, there are patients we can't treat, but I look at it as my job is to treat the patients I can today. And I think that's a very good way to change the world. One patient, one family at a time, always about that person and that family, doing our best by them. And that's what we do. And I would say if you talk to anybody at n-Lorem, you'd hear the same story. It's a privilege. It's a great privilege to be doing what we're doing, and we couldn't do it without organizations like CRL.
Todd:
That's well said. I do want to spend a little bit of time talking about antisense therapies, or ASOs, which is the key to treating the untreatable, really. What is antisense technology?
Stanley Crooke:
So an antisense drug is a genetic medicine, that is, we take the genetic code and we design an oligonucleotide, a few nucleotides, antisense oligonucleotide, and oligo just means few. And as you know, your DNA and RNA are polynucleotide. So we're just a little hunk of genetic-type material that is heavily chemically modified so that it has good drug properties. And then we administer the ASO to the patient and then alter the target RNA. These are drugs targeting RNA to either prevent the production of a disease-causing protein or to enhance the production of a protein that is needed for health. And we can do both today.
That little simple statement took about three decades of my life and thousands and thousands of publications and a couple of decades when most of the world scoffed at what we were doing to achieve that. Today, there are now 14 RNA-targeted drugs that have been approved commercially, there are hundreds of RNA-targeted drugs for diseases that range from the single patient to millions in development, and there are scores and scores of companies that are being founded to do this. And we're proud the fact that we drove it, that we created this space, and the fact that this technology now enables the ultimate step to the rarest of patients.
To create this seemingly impossible model to give drugs away is something I never dreamt of in 1989 when I founded the company. But I dreamt of most of the other stuff, and to see it as a reality is, once again, I keep using the word because I keep feeling the way I feel, and that's privilege. I have had the privilege of doing this.
Gina:
For rare disease, ASOs open a new door to treatment. Antisense therapies are designed to seek out, bind to, and destroy mRNA in a specific way so that the amount of disease-causing protein is dramatically decreased. Antisense therapies can also treat diseases caused by too little protein by increasing the production of the protein, thereby restoring the protein to normal levels.
As Dr. Crooke describes it, ASO is not gene therapy. It is genetic therapy. The distinction being that ASO cannot treat a null mutation as it does not involve replacing genes. ASO therapies exist for cardiovascular disease, Alzheimer's, Parkinson's, and metabolic diseases, but its broad application has been particularly life-changing for rare diseases like spinal muscular atrophy.
Previously the most common genetic cause of infant death, spinal muscular atrophy can now be treated with antisense therapy, and, if done early enough, can lead to a normal healthy life for these children. Biogen's novel ASO treatment for the SOD1 mutation of ASL, Toferson, is currently with the FDA for review, and Dr. Crooke expects the future to be bright for additional ASO applications.
Let's hear more on what it takes to bring these treatments to market.
Todd:
So I'd like to talk a little bit about collaboration as a strategy and partnerships in general. Collaboration really is the key to rare disease drug development. Walk me through your approach to experimental ASO drug development that n-Lorem Foundation focuses on.
Stanley Crooke:
Well, we know we can't do it alone. We're a tiny little organization and while we've raised a lot of money, we still have to raise a lot more and we still have to prove that this idea is sustainable. I'm heartened by the progress that we've made and I'm very confident we can do that. I started Ionis with $5.2 million total in a garage, and over the 30 years, I think we raised about $10 billion. So this seemed pretty easy to me, really.
But we can't do it alone. We have to have collaborators that are clinical investigators and institutions that work the patients up, to give us the patients and the information we need to make the drug. We have to have investigators of those institutions who are willing to treat those patients with an experimental medicine. Essentially every vendor to the industry, the oligonucleotide side of the industry, is a supporter, and that goes from small-scale synthesis to large-scale synthesis and toxicology studies, such as we do at CRL, our clinical partners, Parexel.
So all of the industry has stepped up and a good many biotech and pharma companies have contributed dollars and other things. So our approach to collaboration is if it's good for our patients, we do it. If it can help a patient and there's a collaborator willing to help us, they're our friends. And everything gets very simple when you think of it patient by patient and, "Who can help me the next patient?" That's the only question I ever ask. And then figuring out a way that we can work together. Every collaboration is different. Every partner is different. Once again, I don't think it has a single thing to do with me or n-Lorem, it has to do with the tangibility and poetry of the mission.
Todd:
Well, Stan, I don't know if you know this, but you're one of the few great stories that start in garages. I love that you called out your garage.
Stanley Crooke:
Well, our first facility, we had four chemical hoods in the garage and we learned the hard way that if we ran all four hoods, we created such a vacuum that a couple of chemists passed out. It came to me pretty quickly that productivity declined if we had that happen, so we had to open the garage door when we ran all four chemical hoods. So that's a true story, and I have pictures of it to prove.
Todd:
That's great.
Stanley Crooke:
A lot of people claim to have started in the garage, but I have pictures.
Todd:
Yeah, you got pictures to prove it. I love it.
Stanley Crooke:
Yeah.
Gina:
And today, more and more missions are being carried out in the drug development world. New therapies previously needed to meet a higher threshold for commercialization, but today, the growth of contract research organizations has allowed even startups within the pharmaceutical industry to take an idea from discovery through to safety testing and manufacturing.
We are also seeing greater collaborations between patient advocacy organizations and agents of the pharmaceutical industry, creating a feedback loop for drug developers to recognize the needs of patients and how to meet them.
Let's hear more from Dr. Crooke on how awareness of these needs is driving innovation within drug development.
Todd:
When it comes to ultra-rare disease, especially those that drug developers may be unaware of, advocacy and awareness is just so important to treatment being developed. As a nonprofit, how does awareness play into your mission and funding these therapies?
Stanley Crooke:
Well, I do think we benefit from a good many patient advocacy groups, and there I think we have to go back to the AIDS activist to thank them for the voice that is so prominent now, both in regulatory processes and everything else. And so we have the benefit of these patient advocacy groups that have matured so effectively and the internet that enables.
My job, our job over the last three years, is to make people aware that in n-Lorem exists, that we are available to try to help some of these patients. And we're taking advantage of all the modern communication devices. Podcasts are really pretty cool, and it seems to be the way that most people are learning these days. And so this podcast, which goes to folks at CRL and others, is a step in the process of informing people that n-Lorem is available. And if we can help, we want to. I don't think there's any magic formula. I wish there were.
Todd:
Thinking about the future, future aspirations, what does the future hold for rare disease research and drug discovery?
Stanley Crooke:
Well, I'll just talk about n-Lorem. That's a big enough topic for me. Our intention is to demonstrate that this is a sustainable model, that it's a model of quality, that our patients are only exposed to prudent risk, and we intend to treat thousands of patients and create a path, blaze a path that others can follow with other technologies.
And I look at it very much like what I did with Ionis. There was nothing but skepticism about the technology for most of the time that we were at Ionis, and we were the only voice in the wilderness saying, "Hey, we're making progress." And now there are just literally scores and scores of companies in the space. So I want to repeat that. I want to show that this is possible. I want to blaze a path of quality and professional management of patients exposed to experimental medicines that others can follow as their technologies mature to the place that they can help these patients.
And I think that's the leverage we'll get to move from treating thousands of patients, that's all we're going to be able to do, to treating the millions of patients and be the tip of the spear that drives genomic sequencing into newborn screening protocols.
And the other thing that we've tried to do is create a community for these patients. It's our patient empowerment program. And the Centerpieces podcast series that I've been doing lots of interviews with patients and experts and also just basic lessons on what is a chemical. Many of these patients and families have done amazing work and they don't even have the basics. They have to go back and try to learn high school chemistry. And so providing that, I think, is another big thing that we're doing, and I think it's going well. To reduce the isolation of these patients and families in a meaningful way and to educate, I think is another big test that we are trying our best to take part in.
Todd:
So Stan, this was great. So how can our listeners help you and n-Lorem get there?
Stanley Crooke:
Well, first thank you, Todd, for the opportunity to make my pitch. We need your help, and we need help of all denominations and all types from all people. We don't, our patients do. Our patients need your help. And you can certainly go to the n-Lorem website. All kinds of cool stuff there.
So if you're interested in learning more about n-Lorem or feel that you might be able to help us, simply go to our website, nlorem.org. Failing that, you can call us at any time. You can call me and we'll either put you to work or put your dollars to use. I guarantee it will be used for helping a patient.
Todd:
Well, Stan, this was great. We really are grateful for you joining the Vital Science Podcast, and it's great to see how it all started in the garage to now really impacting and creating awareness for nano-rare disease research. So thank you so much for your mission and what you're doing for patients all around the world.
Stanley Crooke:
Well, thank you. I appreciate the opportunity to talk about what I care about.
Gina:
Dr. Stanley T. Crooke is the founder, chief executive officer, and chairman of the board of the n-Lorem Foundation.
Looking ahead to our next episode of Vital Science. In May we'll talk with Jennifer Panagoulias from the Foundation for Angelman Syndrome Therapeutics, or FAST, about how the organization's collaborative multidisciplinary approach is accelerating the development of treatment. Until then, thanks for listening.
