Empowering Ultra-Rare Disease Patients to Pursue the Discovery of Treatments
February 9, 2023
Casey McPherson hasn’t taken a typical path to becoming a bioentrepreneur. The singer-songwriter is the frontman for Alpha Rev, an up-and-coming indie band from Austin, Texas. Rather than focus on his music career, McPherson instead put his energy into finding a treatment for his daughter Rose, who was diagnosed with an ultra-rare, neurodevelopmental condition. The issues he faced in working with academic researchers led him to co-found Everlum Bio, a rare disease lab designed to provide a range of services for ultra-rare disease patients seeking to discover treatments for their conditions. We spoke to McPherson, chief innovation officer of Everlum, about what led him to create the company, its “rare-disease-lab-as-a-service model, and how he is working to change the discovery landscape for ultra-rare disease therapies.
Daniel Levine: Casey, thanks for joining us.
Casey McPherson: Thanks for having me, Danny. Appreciate it.
Daniel Levine: We’re going to talk about your daughter Rose, your experiences following her diagnosis with a rare neurodevelopmental condition, and how that led you to create Everlum Bio. Let’s start with Rose though. How did she come to be diagnosed with an ultra-rare neurologic disease?
Casey McPherson: Yeah, so [I’m] a dad of two daughters, Weston just turned nine today, and Rose is seven. And when Rose was born, we saw that she was definitely born different in terms of she wasn’t reaching her developmental milestones. And my story is almost synonymous with every parent’s story with the child with a neuro disease is the doctor saying, “oh, it’s okay, she’ll catch up.” And she was doing things like she was choking on her food. Her motor skills were underdeveloped. She would fall flat on her face without putting her hands in front of her and just bust her forehead or nose when she was walking. But where we really weren’t taking the doctor’s advice anymore was after she lost her ability to speak. So, she had a few words she could say: mom, dad, outside. She could do some signing. And when we saw the words go away, we knew something was wrong. And, you know, typically right now a neurologist will test for diseases that currently have therapeutics. And so they run these panels instead of a whole exome genome sequence. We learn that, okay, we need to run this whole exome sequence, which we did through GeneDx. And I sent that—she was about two at the time, two and a half—to the neurologist. I go in the neurologist’s office and he says, “Casey, Rose has a rare genetic disease called HNRNPH2. There is no cure or therapeutic. There is no clinical trial and there is nothing we can do. Good luck.” And that was it. And that was the beginning.
Daniel Levine: Well, you say she was diagnosed with this condition, heterogeneous nuclear ribonucleoprotein H2. What exactly is the condition? What was known about it?
Casey McPherson: So, at the time, it was still variant of unknown significance in the genetic report. What was on the GeneDx report, and I give kudos to GeneDx for this because I think we need more and more of this, is Dr. Wendy Chung and Dr. Jennifer Bain’s email addresses were on there and they’re out of Columbia. And Dr. Jennifer Bain had discovered this series of variants within this HNRNPH2 gene. So, she had begun to fund and do a natural history study on the few diagnosed patients she could find. What is currently known now is that it is an allele specific disease, and so the boys have a very terrible phenotype if they’re even born—severe developmental delay and seizures. The girls live but many of them cannot speak, [and are] severely, developmentally delayed. Some of them can walk, some of them can’t. And at puberty we see a regression. So, something happens hormonally or something in this gene affects a lot of downstream genes. And so, the phenotype is very wide ranging from a 20 or 30 year old girl who can hold a sentence like maybe a five-year-old could to a 10 year old girl who’s catatonic in a wheelchair.
Daniel Levine: You mentioned the doctor told you that there were no therapies available, but did he suggest any way forward for you?
Casey McPherson: He just said, email these two scientists and maybe they can help you, and of course, that’s what I did and that’s how I got started with all this.
Daniel Levine: And how iss Rose doing today? How has the condition affected her?
Casey McPherson: So, Rose can walk. She can’t speak. She lost her ability to sign, and she’s regressed in many ways from a vocalization standpoint. She used to, you know, I’ve been a musician for most of my life. And we used—she could sing melodies with me. She could repeat vowel sounds with me. Now she can’t even do that. And that’s just changed over the last few years. She’s confused a lot of the time. She is scared a lot of the time. She struggles with controlling, like if she’s very happy, it’s a joy that is some of the most intoxicating joy I’ve ever experienced. And then when she’s pissed, everybody knows, you know? And so I can’t take her to a restaurant as a family. We don’t go out to eat. We don’t go to grocery stores. We don’t do things that normal parents do because Rose can’t handle it, you know? It’s just a different lifestyle. We stay at home a lot, use Instacart.
Daniel Levine: You mentioned you’re a musician. You were the front man for the band, Alpha Rev. Your career was taking off, but you decided to put your attention into pursuing a therapy for Rose. You started To Cure a Rose Foundation to develop a treatment for her and others like her. The plan was to develop an antisense oligonucleotide therapy. What happened?
Casey McPherson: Yeah, I started the foundation largely due to the mentorship of Julia Vitarello. I was very fascinated by her story and how she raised the money and created a therapeutic in such a short amount of time, because Rose has, you know, for this treatment to work, it needs to happen sooner rather than later. And so I got the foundation together. I put a scientific team together. Obviously Columbia made sense to work with because they had a natural history study going on. Dr. Jennifer Bain, who’s a wonderful human being, connected me with a scientist by the name of Christopher Ricupero, who really was experienced in regenerative medicine and had some experience in neuronal work. And he was building out his lab. So, I began talking to him about funding his lab to do an ASO and a base editing project, and just really come from a multi-modality approach, do disease modeling in parallel with drug development for HNRNPH2 with the idea, “Hey, could we make a drug for Rosie? Why couldn’t we do this for other rare genetic diseases that were amenable?” It was great until I had to work with the tech transfer office. And, up until that point, I had begun to see families funding these drug programs only to see the academic institution licensing this out to a biotech or pharma company. And for very realistic reasons, biotech or pharma company could not commercialize this drug. There just weren’t enough patients, the data wasn’t something their investors or board were willing to take the risk with. So, the drug would get shelved and literally children would die and suffer because this drug, this intellectual property is sitting on the shelf in this company. And I didn’t want that to happen. I was not comfortable with their standard SRA agreement. And so, we began to work on a new type of agreement for family foundations with ultra-rare diseases. During this time, another company was pursuing Columbia for a multitude of neurodevelopmental diseases and with Wendy Chung. And the tech transfer signed an agreement with them while we were negotiating. By the time they sent me, this is about five or six months from the point we started negotiating—scientists ready to go, I’m ready to go with money—and I’m waiting five or six months with the tech transfer office to just get the correct paperwork and they came back and they said, “Hey, we can’t do this anymore. It’s not going to work for us.” That was five or six months in my daughter’s life, I couldn’t get back.
Daniel Levine: Why were the IP rights so important to you and why was the university so inflexible on terms?
Casey McPherson: Well, I wouldn’t say they were inflexible on terms. So first, the IP rights, and I don’t think people talk about this enough. Family foundations are going to be some of your best operators if they’re going after a drug for two reasons. One, because they have the passion to see the program through. This isn’t just a money play; this is saving a bunch of kids’ motivation. And then two, you get potentially non-dilutive capital and perpetuity when you have a family foundation at the helm because this is coming from donations and grants and whatnot. And so, because the landscape of these diseases that are under, say, a thousand patients, they’re just not commercializable with the current FDA regulations and where insurance approves a drug. Knowing that, I think, is incredibly important for the people that want to take this drug. So, for me, I could leave an open IND forever if I need to and just keep raising whatever, $150-250,000 per patient to treat these kids, which we see with Columbus Children’s Foundation around the gene therapy programs that they do for ultra-rare. I didn’t want to be in a situation like we’ve seen at some of these other larger institutions where the academic institution will come back and say, with your typical SRA, “Hey, you guys funded a drug, now your milestone payment is a million dollars if you want to take this to the FDA and where are we going to get that money to pay an academic for a drug that probably doesn’t even have a whole lot of worth at this moment? You know? And I’m watching that happened to another family foundation just months ago, so that’s why the IP was very important to me. I think they wanted to work with me. Foundations, unless we have an incredibly large population and some sort of political power, we’re the little guys and tech transfer, in my understanding, is where universities are making most of their money. It’s not with admissions. And this is a money making machine. And so, even though they’re nonprofit institutions, the tech transfer is very much a business and most rare diseases, especially N-of-1s and ultra-rare, there is no business model yet for that. So, it lays on the backs of the parents and the foundations to see those programs through.
Daniel Levine: How did that experience lead to you creating Everlum Bio?
Casey McPherson: Well, after this happened, my CSO at the time was Dr. Rodney Bowling who worked at XBiotech and had created multiple therapeutics and licensed them to Johnson & Johnson, and other companies. He had in many ways been my teacher on the drug development front. And we were on the front porch thinking, man, wouldn’t it be nice to have a lab for people like us to at least do all the preclinical work to get to a proof of concept drug, which is primarily what the academics have been hired to do in the past with these genetic treatment platforms that most of these foundations are using. And within a month of that, wouldn’t it be nice? I met a very, very successful tech entrepreneur here in Austin who also had some special needs kids, and one in particular is still undiagnosed. And I was pitching him for donations. He said, “I could donate some money, but why don’t we just start this company? Why don’t we just start this lab?” And we did, and Rodney quit his job within months of that conversation. And we hired a few more people and we started with about a million and a half and put ourselves in a bio incubator to say, could we do preclinical drug development for these families where they own all their data where we’re not a CRO that’s just performing cold services, but we’re literally doing the preclinical proof of concept drug development work for these foundations—just a different approach than your current CROs.
Daniel Levine: Expand on that for me. How does Everlum differ from CROs and what’s the business model?
Casey McPherson: Well, in some ways we’re still trying to figure that out in terms of the business model. But we found a product fit with doing preclinical drug development services. So right now a parent like me has to become an expert in their disease and in drug development in order to see a program through. And I should never be here, right? We should never be talking. But if we could take away that pain point for a foundation and say, “Hey, we can make your cell lines. If we don’t know the target, then we can do some disease modeling to determine what the best target will be and what the best modality will be. And then we can go and design that modality, whether it’s a gene therapy, an ASO, siRNA, or maybe it’s a repurposed drug screen which I still believe almost everybody should do. If you have a target, we can do all that.” So, for them, it’s very understandable language because for rare disease, it’s not necessarily a science problem, it’s a systems problem. And so, if we’re thinking about drug development differently, then we’re doing, FDA regulatory requirements, disease modeling, and proof of concept drug work, all in tandem, you know, in parallel. So, we can get through a proof of concept drug in six months if we know the target as opposed to the five years it might take with an academic institution, or not, knowing how to navigate the CRO space.
Daniel Levine: How does Everlum work? If I wanted to come to Everlum, what would I need before approaching you? And is it an all comers, does it have to be an ultra-rare disease? What’s the parameters?
Casey McPherson: Well, I think we’re still trying to figure that out too. We’re primarily working on neurological diseases. I think largely because most of the foundations that have those neurological rare diseases we have some really great modalities to go after. But in terms of a requirement, I don’t think anyone has to have anything. That’s part of the beauty of it. It’s almost a direct to consumer drug development company. I believe that personalized medicine is what’s going to fix the rare disease problem in terms of a business model, in terms of how we approach drug development. And so, we’re happy to work on an N-of-1, – but we are focused on rare diseases. And primarily what that means is we only have to use a couple of cell lines. If you have your control line, you’re not looking at this huge, massive project. You can really zero in with a few lines on what you want to do.
Daniel Levine: Everlum is a for-profit business, how is it funded?
Casey McPherson: Well, Rick, the CEO, the tech guy I was telling you about, he funded it first with the first million and a half. We didn’t have to really buy a whole lot of lab equipment. So, most of that money has gone to salaries. We have a small team of five and our hope is that we are working with some rare disease biotech companies too, to do some validation, to do some preclinical work for them. And our hope is we’re more expensive than an academic, we’re less expensive than a CRO. We’re hoping that we’re faster than both. And so, that’s sort of where our sweet spot is. And if we can be profitable by this summer, then we can start expanding our team and serving more people, which is certainly my hope.
Daniel Levine: And where are you in terms of developing a treatment for Rose?
Casey McPherson: Yeah, it’s actually pretty exciting. What we’ve been able to accomplish over at Everlum has taken me a 10th of the time than it did with utilizing CROs to do any similar work. We have some really great ASO candidates that are doing what we want to see them do in her cell lines. And so, I just got finished meeting with a clinical trials partner that is going to help us navigate the clinical space and the regulatory path for this drug. And we still have to do some more validation. We still have to do some early stage talks, but we have really good reason to believe that this is going to be a pretty impactful drug.
Daniel Levine: Have you started working with other families and foundations to develop therapies for other conditions?
Casey McPherson: Yeah, we’re working on about four other neurological diseases. And some are ASOs, some are small molecule screens, some are disease modeling, because still unsure of a good quality target. The other thing I’d like to mention is that we saw with RNA therapeutics that because companies and academics don’t show their bad data around toxicity, that we’re working on a tool that we want to develop to design and screen and store RNA therapeutics. And so, we believe if we can collect global data that we can start implementing predictive technology on ASO drug design. That’s a project we’re working on now. We have a great design tool we use in-house for our programs, but I am currently trying to raise more money for that on, on the Everlum side, which I’m pretty excited about.
Daniel Levine: And how scalable do you think Everlum’s approach will be?
Casey McPherson: That’s a great question. Services are really hard to scale and that’s why we started this AI software platform because ultimately at the end of the day, if we’re going to talk personalized medicine, if we’re going to talk platform genetic treatments, we need to be able to have a computational approach with a massive amount of data so that we can begin to avoid these huge high throughput screenings. You know, we see that with small molecules, we see that with all RNA drugs. I’ve talked to enough people that I believe if we can collect enough data and utilizing robotics and the vertically integrated lab and this AI tool we’re building, I think at that point it becomes scalable. Services I think are hard to scale. The way we’re going to be scaling that part is just with pods, a team of two or three scientists and a project manager, similar to how Ultragenyx does it. I really love their model, regardless of the modality, that we have these teams that can take on about three, four, or five projects at a time. But where we really see our model scaling is on the computational side. So, if we’re able to collect enough data to design an ASO and not need to screen them and not need to go into animal models because we have enough data of off-target toxicity that we can go straight into an IND, I think that’s scalable. And so, we’re working on that. Obviously it’s a lot of work that’s going to have to go into that and we want it to be relevant now, and so that’s why we’re sort of taking both approaches.
Daniel Levine: We’ve seen a number of efforts to help people develop N-of-1 therapies. How do you think Everlum changes that landscape?
Casey McPherson: Well, we need more data around N-of-1 therapeutics. There’s no business model around it, and the only way to really scale that is if there becomes one. We are actively trying to create technologies and tools that could make that faster and cheaper. We’re certainly not getting into manufacturing, but we’re also a part of an ecosystem of companies that believe this is the future. And so I think we play a part in this, and I hope that the work that we do helps move that field forward especially for the rare disease community and most importantly for these kids.
Daniel Levine: As you think about the barriers for others hoping to follow suit in developing therapies for individual patients or small groups, are they financial, regulatory, other? What needs to be done to lower the barrier to doing that?
Casey McPherson: Well, there’s a lot I think that needs to be done, but three of the main things to me would change a landscape. One is manufacturing. You know, we make drugs like Budweiser makes beer. So, when it comes to GMP manufacturing, I don’t know if you’ve ever seen these facilities, they are huge. And to small batches it’s not as common, the home brews, the boutique breweries. So, I think the pipeline for manufacturing’s got to change. And then there will be no business model until the FDA allows commercialization at what we call a phase 1 because these diseases, if you consider my daughter as a customer, a patient for a biotech or pharma company, all your customers are gone by the time you could commercialize one of these drugs, or at least a lot of them are gone. And so, I think we have to start thinking about genetic treatments as molecular surgical procedures and less like drugs in terms of drug approval. You know, I can go to a doctor’s office and get a brain surgery or a stent and then I sign off on that risk and that doctor decides whether or not I need that. I think those are the changes and ways of thinking that we’re going to have to move towards so that there is a viable business model so that companies can get into this. And the next dad like me, that’s been a full-time musician for most of his life, doesn’t need to become a drug developer just to save their child.
Daniel Levine: Casey McPherson, singer songwriter, founder of To Cure a Rose Foundation, and co-founder and chief Innovation Officer of Everlum Bio. Casey, thanks so much for your time today.
Casey McPherson: Thanks for having me. Appreciate it.
This transcript has been edited for clarity and readability.
Sign up for updates straight to your inbox.