4.09 | 04.30.21
We’ve spent decades trying to understand human biology, health, and illness at the level of our genes. For people with extremely rare genetic conditions, that work is finally starting to pay off. Thanks to the emerging field of hyper-personalized medicine, and the work of new organizations like the N-Lorem Foundation, we're entering a future where diseases linked to rare mutations don’t always have to be lethal.
In this episode you'll meet Stanley Crooke, the former CEO of Ionis Pharmaceuticals and the founder of N-Lorem, a non-profit that’s working to make mutation-correcting "antisense oligonucleotide" drugs for people with uncommon genetic diseases. These are conditions so rare they often don't have a name. But while the diseases themselves are unusual, the problem isn't: as many as 350 million people worldwide are thought to carry mutations that give rise to unique "N of 1" health problems.
The debut of hyper-personalized antisense medicines is a topic I covered in a March 2020 episode of the podcast Deep Tech for MIT Technology Review. Back then, N-Lorem was just getting started. So I was excited to connect with Crooke one year later and to have the opportunity to go into more depth how antisense drugs work, why they're well-suited for treating some genetic diseases, and how Crooke realized he could give some patients personalized versions of these drugs for free—and for life. "It was literally impossible until just now," Crooke told me.
Listen to find out what changed—and what it could mean for the future of drug discovery and the way we regulate and pay for advanced therapies.
Mentioned In This Episode
See one mother’s fight to shine a light on ALS, NBC Today
Jaci Hermstad laid to rest in Storm Lake, Iowa, KTIV
A Family On the Frontier of Hyper-personalized Medicine, MIT Technology Review Deep Tech Podcast, March 11, 2020
If DNA is like software, can we just fix the code?, by Erika Check Hayden, MIT Technology Review, February 26, 2020
Neil Shneider, Department of Neurology, Columbia University Medical Center
We’ll Always Have Casablanca from Open Source
Chapter Guide
0:09 Soonish theme
0:23 Jaci's Story
2:29 Treating Rare Mutations
4:52 N of 1 Medicines and N-Lorem
6:11 The Era of Hyper-personalized Medicine
7:40 Welcoming Stanley Crooke
8:45 Science Digression #1: Genes, Proteins, RNA, and Anti-sense
13:22 Founding Ionis Pharmaceuticals
15:23 Science Digression #2: SMA, Spinraza, and Custom ASOs
20:32 Why N-of-1 Medicines are Impossible...and Not
26:33 Persuading the FDA
29:24 How to Pay for N-of-1 Drugs
32:56 The Limits of Antisense Treatment
35:25 Distributive Justice
37:40 The Role of For-Profit Companies and Government
39:44 The 10-Year Plan at N-Lorem
42:20 End Credits and Acknowledgements
43:47 Hub & Spoke's Open Source Goes to Casablanca
Notes
The Soonish opening theme is by Graham Gordon Ramsay. All additional music by Titlecard Music and Sound.
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Full Transcript
Audio Montage: We can have the future we want. But we have to work for it.
Wade Roush: You’re listening to Soonish. I’m Wade Roush.
ALS, which is also known as Lou Gehrig’s disease, is the third most common neurodegenerative disease, right after Alzheimer’s and Parkinson’s. But out of those three, ALS is arguably the most devastating, because it moves so fast. Patients lose so many of their motor neurons that they usually die of respiratory failure within two to four years.
ALS strikes about 7,000 people every year in the U.S. and the typical ALS patient is in their 50s or 60s when symptoms set in, so you could argue that they’ve had relatively full lives.
That wasn’t the case with Jaci Hermstad.
The native of Storm Lake, Iowa, loved horses and worked in marketing for a company that sold livestock feed.
Jaci and her parents had slowly rebuilt their lives after losing Jaci’s identical twin sister Alex to an aggressive form of ALS back in 2011, when Alex and Jaci were both 17 years old.
And then in 2019, Jaci herself was diagnosed with the disease.
Tape from NBC's The Today Show: Twenty-five year old Jaci has the same rare genetic form of ALS not only as Eitan but also her identical twin sister, Alex, who died eight years ago from the illness.
Wade Roush: Both Alex and Jaci developed ALS because of a rare mutation in their DNA that must have occurred at the moment of the twins’ conception.
Their particular mutation is so rare that it’s only been observed in about 20 people, ever, across the entire planet.
Considering that both sisters carried the mutation, it’s unclear why it took so much longer for the symptoms of ALS to show up in Jaci.
But in the eight years that passed between Alex’s death and Jaci’s diagnosis, something pretty amazing happened. Scientists studying Jaci’s mutation realized they might have the technology to reverse it.
And advances like that are what today’s episode is about.
In the past the idea of developing a new drug to treat just one person would have been completely impractical.
But we’re now entering an era when it is possible to make drugs to treat people with extremely rare mutations.
And at the same time we’re also starting to figure out how to pay f or the development of those drugs, and how to get them through the regulatory approval process fast enough that they can actually help patients.
We’ve spent decades trying to understand human biology and human disease at the level of our genes and proteins. And this latest progress is a sign that we’re heading toward a future where all a rare genetic mutation doesn’t have to be a death sentence.
And that’s a big deal, because, rare mutations aren’t all that rare. The number of people with a specific mutation like Alex and Jaci’s might be just two, or 20. But worldwide, as many as 350 million people have rare genetic diseases.
At the moment, though, creating a drug for an extremely rare condition is still… extremely expensive. And so the big question right now is how to make them more accessible
Jaci Hermstad was one of the pioneers.
She got several infusions of an experimental drug called an antisense oligonucleotide, or ASO. It was custom-designed to block the effects of her specific mutation.
Jaci did regain some strength and motor control, which was a sign that the drug was working against her ALS.
Sadly, the disease was already too far along for the drug to catch up, and Jaci died in May of 2020.
KTIV news clip: KTIV’s Stella Daskalakus was in a Storm, Lake, Iowa today where Jaci Hermstad was laid to rest…. Jaycee Halmstad was a friend to many people, she will be remembered for her devotion to faith, her love for her family and her horse bud, and especially for her smile and quick wit….Jaci Harmstad has provided the momentum for the rest of us who go forward on their mission that she fought so hard on. She did a lot of good things for the ALS community and we need to keep fighting for her.
Wade Roush: Already, at least eight more patients are being treated with the same antisense drug, which was named in Jaci’s honor. It’s called jacifusen.
When you test a new drug on just one person, like Jaci, it’s called an “N-of-1” trial, because there’s only one person in the study.
On today’s show we’ll hear from a scientist who’s trying to streamline the process of creating, testing, and approving N of 1 drugs.
At the same time he’s trying make sure that patients and their families don’t have to bear the expense on their own.
His name is Stanley Crooke. He’s the former CEO of a pharmaceutical company called Ionis that made the very first antisense oligonucleotide drugs back in the 1990s.
And now he’s taken on a second or third career as the head of a nonprofit called the N-Lorem Foundation.
I’ll let Stan describe it.
Stanley Crooke: The N-Lorem Foundation is a charitable foundation that I initiated in January of 2020. And its mission is to take advantage of the technology that we created at Ionis to bring experimental treatments to patients with ultra, ultra-rare diseases and to do that for free, for life. And I always sort of feel like I have to repeat for free, for life, because it was literally impossible until just now. And it's pretty exciting that it is actually possible.
Wade Roush: Today we’ll talk about how it became possible, and what that means for people with rare genetic conditions.
Folks in the healthcare industry have been talking for a long time about precision medicine, or the idea that each of us might eventually get treatments or prescriptions tailored to our specific genetic makeup.
But N of 1 drugs are more than just precise. In a way they’re hyper-personalized.
And the concept of hyper-personalized medicine was actually the subject of a different podcast episode I made last year, when I had a gig as the host and producer of a show called Deep Tech from MIT Technology Review magazine.
I’ll link to that episode on our website at soonishpodcast.org.
But the thing about it is, it was a really complex story with multiple layers and a bunch of characters and a lot of science to keep track of. We tried to cram it all into about 23 minutes and I was never quite happy with the way it came out.
Also, we released that episode on March 11, 2020. And as you might remember, that was the day the World Health Organization declared the covid-19 outbreak was a global pandemic and much of the US went into lockdown.
When you’re worried about a viral plague with an N of thousands or millions, you’re not really in the mood to hear about problems that have an N of 1. So I don’t think a lot of people even heard that episode.
You don’t get many do-overs in life, but for me, the opportunity to talk with Stan Crooke was one of them.
So today I’m going to play parts of that interview for you. And in a few places I’m going to pause the conversation to jump in and try to make the science-y parts extra-clear. Here we go.
Wade Roush: Stanley Crooke, thank you for joining me on Soonish.
Stanley Crooke: It's great to be here and I'm looking forward to the interview.
Wade Roush: Can you briefly define what an ASO is for us?
Stanley Crooke: Yes, maybe it won’t be quite as brief as you like, but let’s begin with traditional drug discovery. Traditional big discovery uses small molecules to bind to proteins that do the work of the cell. And that's the source of most of the medications that people take today still. And it really hasn't evolved dramatically in in decades. Antisense technology is absolutely different. With antisense we focus on creating short, chemically modified genetic material designed to interact with the RNA that produce the proteins to do the work of the body. And and then after that, we've now learned how to design ASOs afterr binding to RNA to do a wide variety of different things. And so the technology is quite versatile.
Wade Roush: Okay, here’s the first pause. Antisense is an extremely cool idea. But if you don’t remember all the details about genes and proteins from your high school or college biology class, you might not realize just how cool it is. So here’s a refresher.
As Stan Crooke just said, it’s proteins that do all the work in our cells.
They build things. They move stuff around. They carry important signals inside the cell and between cells. They’re essential to everything that happens in our bodies.
Proteins can do thousands of different jobs because they all have different three-dimensional shapes.
For instance, the most famous protein in the world right now is probably the spike protein on the outer shell of the coronavirus. The shape of that protein allows it to fit like a key into a receptor protein on the surfaces of human cells, and that’s how the virus breaks into our cells and starts replicating.
Now, every protein is actually a string of of thousands of small molecules called amino acids that together fold up a ball with a specific pattern of bumps and grooves and protrusions.
The exact shape a protein folds up into is determined by the sequence of amino acids in the chain.
So, what determines the amino acid sequence? Well, that’s where DNA and RNA come in.
Our DNA hangs out in the nuclei of our and it’s basically a twisted ladder where each rung on the ladder is a pair of nucleotide bases.
Those bases come in four types that biologists abbreviate A, T, C, and G.
The A’s can only pair up with the T’s, and the C’s can only pair up with the G’s. They kind of click together like magnets.
That means the two sides of the DNA ladder are complementary. If you split it down the middle, each side would carry all the genetic information needed to recreate the other side or to direct the work of the cell.
In fact, when a cell needs to make some new proteins, all it has to do is temporarily unzip the DNA down the middle, and copy out the sequence information from one half of the ladder into an information carrier molecule called messenger RNA.
The RNA leaves the nucleus and floats out into cell, where it becomes the blueprint for building a protein.
Now, billions of years ago, the process of evolution here on Earth settled on a coding system where it takes exactly three DNA bases to specify one amino acid.
For example, when the machinery of the cell sees the sequence CCT, it translates that into an amino acid called proline. The sequence CTT codes for the amino acid leucine. And so on. There are 20 amino acids in all.
Now, here’s where this super science-y digression connects back to rare genetic diseases like the form of ALS that afflicted Alex and Jaci.
If there’s even a single mistake in the gene that specifies a protein, it can totally mess up how the protein folds, and that can keep it from functioning.
To take one example, completely NOT at random, there’s a human protein called FUS that normally helps to repair damaged DNA.
At one crucial spot in the gene for FUS, Alex and Jaci’s DNA had a T instead of a C.
So what should have been a CCT codon for making a proline amino acid became a CTT codon, for leucine. That’s called a missense mutation. And it meant thatr the FUS protein in their cells couldn’t fold correctly.
So not only could FUS not do its job of helping with DNA repair, but even worse, it clumped up in these horrible little blobs called aggregates that are thought to be toxic for vr neurons.
Now, here’s where antisense drugs come in. You’re about to see how brilliant they are.
I said before that a messenger RNA molecule is like one half of the DNA ladder.
If you designed a synthetic RNA molecule with a complementary sequence of bases, like a C for every G and a G for every C, it would click in with that messenger RNA and keep it from being translated into a protein.
In biology lingo, the original messenger RNA is called the “sense” molecule and the complementary drug molecule is called the “antisense” version.
Now, I wrote my first story about antisense technology back in 1997 when I was just a baby science reporter. At that point Ionis was already eight years old. So this whole idea isn’t exactly new. But it took a very long time for people like Stanley Crooke to figure out how to make it all work.
Stanley Crooke: Even as a student, I thought RNA was going to be a much better place to make drugs. And so when the opportunity appeared to be possible, then I founded Ionis. And I'm fond of telling this story. It's a bit apocryphal, but generally close to the truth. I told venture investors at the time that nothing was known about the technology, that the probability of success would be, was close to zero, too small to measure and that it would be at least 20 years and $2 billion before I knew. It turned out, you know, maybe 20 years and maybe two and a half billion dollars before I knew and probably 25 years before, I think what we had accomplished has become more generally accepted.
Wade Roush: And that that didn't drive them screaming from the room, somehow?
Stanley Crooke: You know, what I've learned in my in my life is that big dreams are captivating. And generally, people, whether they're investors or scientists or physicians or business people, would like to do good with their money, not just make money, but do good. So it was a big dream. And as it happens, I guess I'm not terrible at selling a big dream.
Wade Roush: Year after year, Crooke and his team at Ionis kept chipping away at the problems with antisense.
One challenge for researchers was to design backbone molecules that could carry any desired antisense message into the cell.
Another challenge was to figure out which parts of a mutant RNA you should block to stop it from making a defective protein.
Finally researchers had to figure out how to actually get their drug molecule into cells, and how to make them stick to their RNA targets, all without causing a horrible immune reaction.
They had some big wins along the way along the way.
In 2013 the FDA approved an antisense drug that blocks the production of LDL cholesterol. It works by binding to the messenger RNA for the protein ApoB, which is the main component of LDL. That’s a big deal, given that millions of people suffer from high cholesterol.
But it wasn’t until 2016 that that the story turned in a direction that would be crucial for people with much rarer conditions, like Jaci’s form of ALS.
2016 is when the FDA approved Spinraza. It’s an antisense drug from Ionis that treats a muscle wasting disease called spinal muscular atrophy, or SMA.
I’m going to tell you about spinal muscular atrophy and it’s going to sound like another sciencer digression, but trust me, it’s worth the time.
It turns out that there’s a protein in our motor neurons called SMN that’s crucial for their survival. In fact, SMN means Survival for Motor Neurons.
Thanks to an accident of evolution, all humans have two copies of the gene that makes SMN. But the second copy of that gene is defective, in everyone, and it makes a truncated version of SMN that can’t do its job.
People with spinal muscular atrophy also have a mutation in the first copy, which means their neurons don’t have any SMN at all.
Researchers at Ionis figured out that they could use an antisense drug to repair the messenger RNA from the defective second copy of the gene, so that it makes a full-length version of the SMN protein.
They called that antisense drug Spinraza, and today it’s being used to treat thousands of children and adults with spinal muscular atrophy.
Which, again, is a big deal. But what was even cooler was that the backbone of the Spinraza turned out to be incredibly versatile. It was like an electric drill where you could insert any type of drill bit. Except in this case the bit was the exact sequence of antisense RNA that you need.
Wade Roush: Was it deliberate or was it more accidental that the Spinraza molecule turned out to be so adaptable?...I am just curious whether that was a happy accident or was it designed that way to some extent?
Stanley Crooke: It was absolutely designed. That was one of the reasons to do this. And so that the technology is efficient, but it's also portable. We know we know the rules. It's really very simple. If you know the rules, you can do the work. And if you don't know the rules, you spend your time in the dark. hoping.
Wade Roush: So spinal muscular atrophy or SMA, the disease that Spinraza was developed to treat, is not an ultra rare disease…. So can you pivot a little bit and explain…what the ultra rare disease landscape looks like? So how long have we known, to start, that there are lots of diseases out there where there might be only one or five or 10 people in the whole world with a specific mutation causing their specific problem?
Stanley Crooke: That was learned almost as soon as the Human Genome Project started. It's entirely to be expected. Mutations happen all the time. You have a whole bunch of systems in your body to try to correct them, but it's not a failsafe. Otherwise we'd live forever, which we would. But so that was understood. What was not understood was the scale of the problem. And as as more humans were sequenced, it became more and more apparent that there might be a single patient with a mutation. But there are millions of patients with unique mutations. And even within a disease that's well defined with a name, for example, there are unique mutations in that patient population that can't be served with the medicines that typically produce benefits in those patients. And so those two things came together to demonstrate that this was a large and growing patient population that needed an entirely new solution, or there was no hope that we were going to be able to help them.
Wade Roush: Was there a specific moment…when it first hit you that ASO drugs similar to Spinraza might be customizable for these n-of-1 patients? And can you kind of go back and tell that story?
Stanley Crooke: It was four years ago, like, I can't remember the precise date, but I can remember the precise emotion.
Wade Roush: Oh, tell me, what was that emotion?
Stanley Crooke: Well, you know, I was completely aware of the of the efficiency of the technology. After all, I, I led the invention of it. But it hit me that that I could actually make a medicine for an individual patient and I could do it probably cost effectively enough that I could give it away. And that was a stunning event for me. I've been in the drug discovery development business for a lifetime and it was inconceivable to me that that would ever happen. And so I realized that. And then then the question shifted. Right. I mean, what you really what you think you have a possible solution for some of these patients becomes a moral question. How can you not do it?
Wade Roush: Okay, I want to step back here and underline what Stan Crooke is staying.
He realized that the science Ionis had been doing to treat diseases affecting thousands or millions of people could be adapted to treat a disease affecting just one person.
More than that, he realized there was a moral imperative to do it.
But he also knew right away that it would be impossible within the framework of a commercial drug company like Ionis.
Wade Roush: This is going to sound like a dumb question because it should be obvious to anybody with a sort of business background or anybody like you who's been in the business for so long…But just for the sake of completeness, can you can you spell out…why it's not possible? Right. Why shouldn't it be possible for Ionis, for example, to make a drug for one person?
Stanley Crooke: Well, that begins with the regulatory requirements for approvals. I mean, the words sound simple, but they're not. You must prove safety and efficacy. Prove. To a very high degree of satisfaction. To do that requires trials in vastly more than one patient. Often we're doing clinical trials now that involve thousands of patients to gain approval. So if you just think about one patient, there is no way to prove safety and efficacy. What do you compare it to? How would you ever prove that so that you could get approval and then sell the drug? So the first step is it's essentially impossible regulatorily, at least based on existing legislation. The second is it's also simply impossible from just a tactical, can you do it sort of a process because you could think, well, maybe 20 or 30 patients, we might be able to work. But unfortunately, most of these mutations are de novo. And so the patients are spread all over the world and they're varying ages and they're varying stages of the disease. And a patient who is near death from a disease is much less likely to respond than a patient early. So technically, it's impossible. … Then you suppose you were somehow successful, then how do you make money? Ionis is owned by shareholders. My responsibility as chairman and CEO of Ionis is my shareholders' money. And so as much as I would have wanted to do it, and I'm sure many of my shareholders would, they wouldn't be happy with me if I made a bunch of medicines that only cost money. That's called losing money. Wouldn't work. So it's quite literally impossible.
Wade Roush: Meaning, it was impossible to do it inside of Ionis. But that didn’t mean Crooke couldn’t do it outside of Ionis. And that’s where his thoughts took him next.
Stanley Crooke: First of all, I had to assure myself that I was going to treat Ionis shareholders properly and, you know, find a charitable solution that would not be detrimental to the company. Then we had to assure ourselves that we'd have the the upfront information that we needed. We need a ton. These patients have to be fully genetically characterized. They have to be in a tertiary care center where there's a research investigator, physician who can do all these things. And they have to be characterized clinically. We need to know what organs are involved, what are their signs, what are their symptoms, what are we going to treat. And then and that was when I was introduced to an organization called the Undiagnosed Disease Network, that's called the UDN. And it's a consortium of a bunch of major medical centers in, in America that saw this problem and said that what they wanted to do was to at least make a diagnosis and tell the patient what was wrong with them. But, of course they all were hitting the same wall, which is, it's great to be able to tell a patient or a parent what's wrong. But then in your next breath, you have to say, and there's no treatment and there never will be.
Wade Roush: And just to connect the dots here, you're saying a lot of the undiagnosed diseases that this network was helping to diagnose turn out to be single point mutations that turn out to be caused by a single nucleotide that's been mis programmed basically during reproduction.
Stanley Crooke: It's a unique mutation. It's a not necessarily a single nucleotide mutation yet. It's minor, but it's actually fairly important technically. But that's exactly right. And most of these patients I mean, the stories are horrible, even with a patient with a disease that's got a name typically, because they're so rare, no one ever sees them. These patients, if they live, three or four years just trying to find what's wrong with them. And then at the end of that, to hear there's no hope. So I developed a collaboration with the UDN.
Stanley Crooke: And then the final piece was the FDA. This there are no policies that contemplated this….And so this, you know, creates incredible policy issues for the FDA. So I introduced the concept to the senior leaders of the division, the drug division. And they were very rapidly positive and constructive. Then I had everything in place and we started. And we had two investigators that we were helping get ASOs for patients. One was Tim Yu, which is and he was taking care of the baby with Batten Syndrome named Mila…M ore important to us was Neil Shneider at Columbia, who was taking care of a pair of twins who had a what's called a FUS mutation ALS. FUS mutation, very rare and it produces extremely aggressive ALS. Typically from symptom onset to death is, you know, a few months.
Wade Roush: I’ll just step in here to note that the twins Stan is talking about were Alex and Jaci Hermstad.
Stanley Crooke: And so we had the opportunity to help these investigators get medicines. And that gave us the opportunity to work with the FDA. And again, we learned that even before any real guidance was issued, the FDA was willing enough to work to make it possible for us. Then, of course, it became obvious that it was doable. Now, I just needed to fund it.
Wade Roush: Before we talk about funding, I want to jump in an underscore this point about regulation. Crooke makes it sound like it was an easy thing to finesse. It’s anything but.
The FDA has a very big and important job. It’s to make sure that no one gets a drug until it’s been shown to be both safe and effective.
When Neil Shneider at Columbia heard about Jaci Hermstad’s case in 2019, he reached out to her family in Iowa.
He told them that he thought he could build on Ionis’s work to create an antisense oligonucleotide that would block the production of mutant FUS protein in her cells.
The problem was that the FDA wouldn’t let Shneider actually try the treatment on Jaci, since it hadn’t even been tested for toxicity, let alone efficacy.
There is a so-called Right-to-Try law on the books at the federal level that allows access to experimental therapies for otherwise terminally ill patients.
But that law only applies to therapies that have completed Phase I clinical trials. That’s the part where manufacturers study a drug’s safety and determine the best dosing regimen.
Jaci’s parents went into action. They started a petition to get the FDA to let Jaci get the new ASO drug anyway.
Their local member of Congress, Iowa republican Steve King, even wrote a bill to force the FDA to grant an exception just for Jaci.
The bill was never introduced in the House, but thanks to King’s Bill, Iowa Senator Chuck Grassley and even Nancy Pelosi joined the campaign to pressure the FDA.
And eventually the agency agreed to let Jaci get the drug as soon as basic toxicology studies were complete. Crooke thinks that was a big step along the way to making N-of-1 drugs more available.
Wade Roush: How do you approach the FDA and get them thinking in a different way about whether it even makes sense to insist on the same safety standards, when a drug isn't meant for millions of people, it's meant for exactly one person.
Stanley Crooke: And a desperate person. So it is very much outside policy and outside the mindset of regulators who above all, want to protect patients from potential safety issues. So the first step for me, and this happened early 2019, I wrote the senior leadership of the Bureau of Drugs, introduced the idea, that I was, that I felt that I could provide these ASOs for free for life in a charitable foundation. I thought they might not believe it . But the response was very rapid and very, very constructive. Well, then the next step was the FDA announced that it was going to develop guidance for n-of-1 patients' treatment, which is a key step. And they invite comments. And we submitted a very lengthy, very specific set of proposals. And, um, and I'm confident we'll get what we need, whether we'll get everything we asked for, who knows.
Wade Roush: So that’s the regulatory side. But there’s still the problem of how to pay for these drugs.
Jaci’s family raised a couple hundred thousand dollars on GoFundMe to help cover the toxicology studies.
But Stan knew that not every patient who needs an N-of-1 treatment would have the community around them that you need raise that kind of money.
Wade Roush: There are plenty of examples out there of foundations that exist to shine a spotlight on a particular disease or raise money for research for a particular disease. But I can't think off the top of my head of foundations that are set up specifically to find people with diseases and create free drugs for them. [00:29:18] That seems like an unusual, unorthodox and somewhat risky way to approach the question.
Stanley Crooke: Well, I didn't know any other way. If I can't do it commercially, what do I get the money? And if I want to give drugs away, then then what am I doing? I'm engaging in a charity. So the way I looked at it, I don't know if this is a good explanation, is that we we benefit today because of all the various patient advocacy groups who have focused on understanding the disease, getting a diagnosis in the hope that treatment would be made available someday. And everybody knows that for that to happen often takes 20, 30 years. And in the meantime, patients progress and die. But armed with genomic work that was going on, all the work that many natural history studies have been conducted by these patient advocacy groups and and the support systems they put together, it was an opportunity for me to take that from where they got it and move the ball across the goal line and actually make somebody better. So the only question I had really, by the time I started, because I had put all the other things in place, is kind of kind of can I afford this?
Wade Roush: So you started out by putting in some of your own money, I guess, and some close partners also pitched in.
Stanley Crooke: Well, the most important collaboration was with Ionis. And Ionis donated to our cause $2.8 million. And of course, provides a lot of services in kind. We have a formal relationship and we live within that. Our partner in neuroscience, Biogen, and I have to thank them tremendously Michel Vounatsos, the CEO, has been an incredible supporter and help. They put in a similar amount. They don’t like us to give it precise. And my wife and I have given $3.2 million. And we feel very fortunate to be able to give $3.2 million. But it's a lot of money for us. And that got us started. And then despite the fact that we haven't attempted to raise money, we've been extremely gratified, even in the midst of covid-19, that many, many other folks have asked to donate. And so on top of all that, I think we've gotten three or four more million dollars. So it that all gives me confidence that I'm going to be able to raise the money we need. But on the other hand, the demand is much greater than I expected. Much greater. We now have, we're approaching 75 applications. We expect this year to be treating in addition to the ones that we're treating parallel to N-Lorem, five or six patients. And then next year I expect we'll be treating 20 or more.
Wade Roush: Crooke stays there are some limits on who the N-Lorem Foundation can help. First off, the foundation has to stick with treating diseases affecting the five organ systems where Ionis already done extensive studies and where they know how to get antisense drugs to their targets. That means the central nervous system, the liver, the kidney, the lungs, and the eye.
On top of that, N-Lorem can’t treat genetic changes known as “null” mutations, where the body just doesn’t make a required protein at all.
And another limitation is time. Even though the basic antisense technology is already in place, the foundation needs about 10 to 12 months to identify the RNA sequence that will work best in each case and then do the required toxicology studies, which are the still slowest and most expensive part of the whole process. If a patient with a rare genetic disease doesn’t have that long to live, then sadly N-Lorem can’t help them.
But on the positive side, the antisense molecules themselves are really cheap to make. And it only takes a tiny dose of an antisense drug to change the way proteins get made inside cells. 10 grams of antisense RNA can be enough to treat a patient for life.
Another big advance is that the FDA says it will come out with more detailed guidance about using N-of-1 medicines by the end of the year.
Stanley Crooke: Which again, is astonishingly rapid given all the policy issues that are at issue. And we're looking forward to that. And that will give us our clear roadmap. And we won't be making a guess anymore about how the FDA might react to this or that or the other.
Wade Roush: When you get that roadmap, are you hopeful that there will be waypoints in it that allow you to either speed things up or remove costs or both?
Stanley Crooke: Both. It has, the FDA recognizes all of that has to happen. There is no way that we can get a patient a medicine in a year or less without fundamental shortcuts. And the short cuts would not be possible if we didn't know how these drugs are going to behave, because you wouldn't be able to convince yourself, I wouldn't be willing to treat a patient unless I did full studies. But with this technology, we know enough. And the FDA agrees we know enough that this is possible and still do it with quality, but of course do it with far less investment in pre-clinical studies and far less investment in other areas..
Wade Roush: It's amazing you've made this much progress this fast. It's amazing this is possible at all. And so this next question is going to sound a little bit like looking a gift horse in the mouth… The more you realize that these rare genetic diseases are actually not so rare, that… cumulatively, there are millions of such people around the world who could benefit from this kind of treatment, it starts to become sort of a question about distributive justice. And a big part of the problem is happening on the other end of the pipeline. Right. There may be kids who who never get their genome sequenced or who are …not treated at a tertiary medical center where there might be a qualified investigator who knows that you exist and who knows how to get in touch with you. There are just all sorts of reasons why people might fall by the wayside before you ever get to look at their case. So how do you think about tackling that bigger question of making this treatment equitable and available?
Stanley Crooke: Yeah, and I would add to that we're only in the U.S. and of course, we've gotten applications from outside the US. And so at some point, as we get our legs under us, we will want to set up similar systems in Europe and Asia. And then there are all these patients in the undeveloped or poorly developed countries that we can't possibly even fix. What I'm doing from my perspective is providing a justification and a goad to the rest of the community to do better, to provide more information, to understand that these patients exist and make sure that's a part of the residency and medical school curriculum and that people walk away. They may not know a single thing about mutations or rare diseases, but they understand they exist so that when they see a patient they can't explain, they make the right decision and move that patient to a tertiary care center where they can be handled. And then we have a whole set of other societal issues that will come into play here, like care of the patients long term and all those things. My position is I'm going to fix what I can and then that will be a stimulus for the broader community to fix the entire problem.
Wade Roush: Do you feel that developing these treatments for ultra rare genetic diseases is something that will never be commercializable? Or is it just that we haven't solved the problem yet and so that for now it needs to be addressed by the nonprofit realm?
Stanley Crooke: Well, I'm a scientist, so I'm not going to say never. But for me today, it's inconceivable that a commercial model could ever be used for an N of 1. There are several things that probably are important to add to that. The first is we understand and we understood when we started N-Lorem that we may initially find a mutation that's only been identified in one person or two people, but that may stimulate the community to look harder and they may find patients that number in the hundreds, even. O nce that happens, then there will be commercial companies like Ionis and others that will jump into that and and make a business of it. That's good. That's that's the way it ought to be.
Wade Roush: Is there potentially a role at some point for the government to step in to either fund this work or to create incentives so that companies will undertake this work?
Stanley Crooke: No…I hope not. I think this is a small task. Each patient is small, so I think keeping it small is the solution. What I'm hoping is that there are more small things like N-Lorem that pop up. Where I think government is going to play a role in facilitating the charitable model. And it appears to me that they're doing it. Now in Europe, we have a very different payer system. Here we have multiple insurers, but in Europe and the rest of the world, all of the payments are handled centrally by the government. So I think the government will play an extremely important role there. And I'm hopeful long term in the U.S., the government will play a significant role in encouraging insurers to provide support for these patients.
Wade Roush: And to finish off, what's your long-term dream for the N-Lorem Foundation? Do you think you'll continue to expand and expand and expand until you can basically treat every findable person, every person who comes forward with a rare genetic mutation that fits your criteria, you can actually help them? Or, you've talked a lot about stimulating and goading other people to get better at thinking about these things. So could you eventually find yourself in a position where the medical establishment knows how to do this stuff, there's no need for you to do it anymore, and you can fold up your tent and go home?
Stanley Crooke: Well, that would be Nirvana. I actually don't think that because the medical establishment generally doesn't understand drug discovery. I mean, they shouldn’t . But that's not their job. That's my job. Right. So I don't think N-Lorem will become antiquated. I've only thought 10 years out. So I can't tell you what my 40 year vision is, but my hope is that we will be receiving 100 to 200 applications a year. We will run these clinical trials for one year, because longer than a year would would be very difficult for the patient and the physician and impossible for us. Oh, you know, we might be running 150 different clinical trials at the same time. And the plan I built entertains all that and lays the groundwork to get it done. [01:14:00] I like to end my presentations with: at N-Lorem I have a very tiny dream . All I want to do is help one patient, one family at a time. If I can do that for the patients, I can help. I change the world.
Wade Roush: Antisense technology didn’t arrive quite soon enough to help Jaci Hermstad.
But it is advancing fast enough that it could help the next group of people with the same mutation, or similar mutations.
And the whole story of antisense looks like a case where biomedical innovation is meeting up with creative philanthropy to solve a problem that affects millions of people -- just one at a time.
KTIV news tape: Jaci's story isn't over.
Wade Roush: Here’s one of Jaci’s family members talking to a TV reporter after her memorial service last May.
KTIV news tape: She, with the sacrifice and the contribution she's made to ALS research, hopefully you'll run another story in the future where a cure there's big developments, hopefully, to help future Jaycees and Alexes so they don't go through what our family's gone through.
[Musical break]
Wade Roush: Soonish is written and produced by me, Wade Roush.
Our intro theme is by Graham Gordon Ramsay. Our outro theme and all the other music in this episode is from Titlecard Music and Sound.
You can check out a transcript of this episode and links to more resources on our website at soonishpodcast.org, and you can follow the show on Twitter at soonishpodcast. And you can learn more about the N-Lorem foundation at nlorem.org.
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