Watch a compelling virtual Grand Rounds featuring Julia Vitarello, the inspiring founder of Mila's Miracle Foundation. Hear directly from Julia about the challenges and triumphs in the fight against rare conditions. Alongside Julia, an expert panel, including Erica Barnes, Margot A. Cousin, Ph.D., and Radhika Dhamija, M.B.B.S., delve into the scientific, clinical, logistical and regulatory challenges in the field of individualized medicine.
Center for Individualized (CIM) Medicine Grand Rounds
MAIN PRESENTER PANELISTS Erica Barnes, M.A. Executive Director of the Minnesota Rare Disease Advisory CouncilMargot A. Cousin, Ph.D . Radhika Dhamija, M.B.B.S .
We are delighted. All of you have joined us today on Rare Disease Days for a very special Center for individualized medicine Grand Rounds. My name is Timothy Curry and I'm the William O Lund and Natalie C Lund. Program director for clinics and the Midwest, associate director for practice implementation for the Mayo Clinic Center for individualized medicine. The Sim Grand Lounge lecture series highlights the latest in scientists, discovery innovation and shares how individualized medicine is being translated into practice to transform patient care. And I know today's presentation, expert panels can accomplish exactly that Rare Disease Day today is celebrated on the last day of February to raise awareness and generate support for everyone who's on a rare medical journey. This year it falls on February 29th. The Rarest day first celebrate in 2008 Rare Disease Day provides the energy and as a focal point to enable rare disease advocacy work to progress on the local national and international levels. It is my pleasure today to introduce our Rare Disease Day, featured speaker Julia Vitarelli in December of 2016, Julia founded Mila's Miracle Foundation in just a few minutes. We're gonna hear the journey that led to the creation of this amazing organization through Mila's Miracle Foundation. Julia has raised millions of dollars to fund novel treatments and programs for Children with rare genetic conditions. Julie has also co-founded the N Equals One collaborative which serves as the international scientific hub for medicines, as well as everyone medicines, a biotech aiming to prove a viable business model where there is currently not one. Additionally, Julia co runs the first ever single cell atlas, a pediatric disease with Boston Children's Hospital funds basic science research in the US. And Europe and hosts meets with industry experts and families in the rare disease community. It is an honor to have her join us. Now, please join me in welcoming Julia as she presents on Mila the millions. Thank you. I appreciate that and thank you to everyone at Mayo for taking the time to uh listen to my story on Mila, my daughter and, and my thoughts on this emerging field of individualized medicines, which my daughter's story has opened up. Um Before I I tell you anymore though, I do think it's very helpful to um get to know my daughter a little bit. And so we'll start with a very short three minute video that um allows you to see who Mila is my sun shine. My only sunshine you make me. So our daughter's name is Mila Virginia Makovich. Uh She was born on November 5th 2010 when I think about Mila as an infant. I think about smiles and laughter and health. And half an hour after she was born, she was strong enough to hold on to my finger and I could almost pick her up off the bed when Mila was a toddler. She was a climber. She was a hiker. She was a runner. Yeah. Yeah. Yes. Is our sugar high daughter. Very physical. Always love to ride a strider. Nice. But play in the snow. I'll go sledding coming. We noticed that Mila was getting stuck on her words. She would say mommy, mommy, I, I have to, mommy, I have to and not be able to continue. And then suddenly around three years old, we started noticing that her feet were slightly unturned and she was walking strangely. And then at four years old we noticed that she pulled books in close and then around five years old, Mila's feet started moving really quickly in, um, this strange pit pattering way and then she would fall back on her butt and every time she stood up, she would fall back and stand up and fall back. You know, we took her around to different doctors who never could really kind of figure out what was going on with her and then time passes and then in just one month, everything can change. She could no longer see anything. What's brought her so much happiness is playing with her toys and, or looking at her books and watching TV, and playing with her brother and suddenly it looked like she could no longer play with anything. It's so hard to see such a outgoing little girl, not be able to play with other kids and not be able to play with toys and not be able to watch Elmo anymore. I still watch that video. I've watched it hundreds of times and it really, truly feels like I'm watching the story of someone else's life, even though I've lived it. Um, you know, I, I became a mother kind of like anyone else, uh, did in the sense that my daughter was seemingly very healthy. She was very outgoing. She was very agile, very sporty. Um, we live in Colorado so she was skiing when she was two years old. You know, going to the top of the mountain, she was rock climbing 40 ft. She was jumping from the couch to the coffee table and back and forth and running around the house, you know, singing all of her favorite words to Puff the Magic Dragon and all of her favorite songs. And, um, you know, when she was about 3.5, she started having sort of strange symptoms, but they were very, um, subtle to other people and they started building up over time and between 3.5 and six years old, um, I carried around a little scrap piece of paper in my pocket that said neurological symptoms with a question mark on it. And honestly, I barely knew what that even meant. Um, I just started seeing my daughter first have problems with tripping and falling and she had been so agile before and people said, oh, she's just clumsy but she had never been clumsy before. She was started to be covered in bruises. I remember having a big bruise on her eye, you know, big bruise on her arm, bruises all over her legs. Um, she had stepped on all of our toys and books in our house and everything was broken. Um, and I, this is my first child, so I didn't know if this was normal or not. And so I started bringing her around to all the different specialists and, uh, she started having problems seeing and the ophthalmologist had said, oh, don't worry, you know, that she just probably needs glasses. Her feet started in turning. They said, oh, that can happen. It'll, you know, correct itself over time. Um, she would stutter and get stuck on the first few words of her sentence and get stuck on the word mommy, which was really hard for me because she could never get past that word. And it was driving me actually crazy. You know, when I was trying to help her, but she could not get unstuck. Um, and the stuttering therapist said that 25% of Children would grow out of that, you know, grow up have that and then grow out of it. Um, and by the time she turned six years old things had gotten, there are too many, too many different lists on my little piece of paper that said neurological symptoms. And I found myself crying on a regular basis and I knew that that couldn't be, you know, a good sign. I was really tired of having so many people tell me that I was crazy. Um, I'd been to 100 doctor and therapy appointments, often lugging my newborn son at some point along with me across the country and at some point at six years old, I remember I looked for another neurologist because I couldn't get any answers and they told me that it was gonna be six months wait. And I just, that day I gave up and I packed a duffel bag. I went into the, er, at Children's Hospital, Colorado, which was near my house. Um, and I figured there was no way they could let her out unless they figured out what was wrong and they kept her for a week. This was the end of 2016. So it wasn't maybe as simple as doing a genetic, you know, panel right away. Um, after which they did end up doing genetic testing and it came back with an answer which I will tell you that immediately. I was incredibly relieved. Like I'm not crazy. There is a cause and if there's a cause I must be able to fix it. Um, it took me not very long 10 minutes to Google and read about Baton disease, which she was diagnosed with in a very rare form of already rare bat disease called Bat and Seal. And seven to figure out that it was probably one of the worst diseases Miller could ever have. And I didn't know, you know, I thought it was a well read person. I had no idea that a very typical healthy child could, you know, then be told that she's gonna lose every single ability except for hearing and die in the next few years. So, you know, my, the only way to really describe that period because it's very hard to find the words is that, you know, I just turned 40 just my life as I knew it was over that day. Um I'm a very positive person but none of the things that matter to me matter to me anymore. Um It's just, you know, your child's health is everything, you know. So I did everything I could. I cried on the floor of my closet pretty much every single day, tried to hide that from my Children while I then rallied to play with them. And then, you know, by night tried to like read science. I had no idea what I was reading. I was reading white papers on Baton disease and lysosomal storage diseases. Um And I reached out to every scientist and doctor I could until they actually responded to me and, and I learned a lot, you know, in a very short period of time in just a few weeks, I really learned um that this was one of the worst diseases Mila could have ever been diagnosed with. I also learned that there was a tiny glimmer of hope at the time that we might be in time to um uh stop genetic disease, but it was a glimmer. That's all I needed. Um I started a foundation, Mila's Miracle Foundation. I didn't really know what a foundation was. I didn't know what a nonprofit was. I didn't understand the science, but I learned very quickly as I watched my daughter rapidly declining and losing her last words, losing her vision completely, um losing the ability to swallow completely. And over that next year, I decided that I was gonna fight for her as hard as I possibly could because she was still smiling and laughing and fighting. Um I started down the pathway towards a gene replacement therapy because there was little to nothing known about the bat and Seal and seven gene or MFSD eight gene. And, um, that got me going and that did eventually become a gene therapy, but I knew it was gonna take many, many years and many millions of dollars and not be in time for meal. At some point, I realized that along the way, Mila's story took a turn because it's autosomal recessive. They could only find 11 of the two mutations and I had many labs look and none of them could find it. I was fortunate enough through a plea on of all places, Facebook to see if there were a lab that did whole genome sequencing would be willing to dive deeper and try to find Mia's missing mutation. I was afraid that I was going after the wrong gene and I was going to spend all of my time and energy raising money and trying to save Mila's life and go after the wrong gene and that she might have a different disease with one mutation in this MFSD A gene. Um I also was terrified of losing my son and I wanted to be able to fully test him and being able to only test one of the two mutations was not OK with me. So I really pushed hard for that and that led me to Doctor Timothy Yu at Boston Children's Hospital and his, his lab um who unbelievably just really stepped up to help me try to find the answer really, truly just to help with the diagnosis along the way as they stared at a screen because they could not find this missing mutation for a long time. They looked day and night, weekends for a month, they ended up finding the mutation. Um There was a deep and tronic mutation that was very unusual and they not only were able to call me and tell me that, um, they had confirmed that it was Bat and Seal and seven, but that my son did not have, um, the same disease and I wasn't gonna have motherhood ripped from my arms, which was, um, something I could, I could barely sleep at night for numerous months until we got that answer. Um, and that same call doctor, you also said, you know, we have an idea. Um There's been a drug called Spinraza that's been approved for Spinal muscular atrophy and another terrible disease, which I don't need to tell all of you about as you probably know how horrible it is and, and what a game changer Spinraza was, it had just been approved a month before by the FDA. Um and it was on everyone's mind, especially the neurologist that we're working with Tim you. Um And it gave them an idea of creating an A so or anti Senso Conlee similar to Spinraza formula. The problem was is that they searched far and wide and there were no other patients that shared her uh mutation. And as you can imagine, a number of people said that's crazy. How could you ever do that? How could you make a Spinraza like drug just for one person? Um But thank goodness um Doctor Yu and his team continued forward and over the course of that next year as Mila rapidly declined, they designed and uh and manufactured and tested in a way that had never been done before a drug for one person. And they named it Mili after my daughter. Um, within one year, we moved to Boston and Mila was receiving this anti Senigon nucleotide called Mien, which I didn't know about. Actually that it was even named that I didn't even really fully understand how, what a big deal this was until I think I moved to Boston and started, you know, talking with doctors and scientists and there were tears in their eyes and they were crying to me about that. They couldn't believe that this was happening in their lifetime. Mila did unbelievably. Well, the first year she, I, I really had no idea what to expect. I knew that I had nothing to lose in the sense that this had been a modality that had been around for 30 years and tested in animals. Um, and more recently in humans and, and the risk of not treating Mila was black and white. She was gonna lose all of her abilities and die. The risk of treating her was a modality that had been around for a long time and it was showing um really great promise in the lab, restoring health to herself um in three independent labs. So, you know, it was a no brainer for me. Um but I didn't really know what to expect. And in that first year, despite the fact that Mila had lost her vision. She was having seizures 30 times a day. Um She was no longer eating by mouth but, but she too, um she was smiling and laughing less than before. Um In that first year, we saw maybe subtle to some people but incredible to me changes in the sense that she was pretty much seizure free. She occasionally had a little myoclonic jerk but she went from 30 down to pretty much zero or one tiny little short seizure. She was sitting up straight, she was holding her body up so I could hold her from behind and she could take steps even alternating up the stairs. Sometimes she had stronger legs. Um, she was eating by mouth. It wasn't perfect, but it was, you know, pureed foods, but it was a lot better than just by youtube. And most importantly, she was just laughing and smiling at the times that she used to in the funny books and songs, you know, that I would read and sing to her. Um, you know, crying babies and Santa Claus sneezing and stuff and she was doing it more than she was before. And that was probably the most meaningful thing to me. Um In the second year on Miesen, it was unclear whether or not it was, her disease had been kind of stopped or if it was slowly, um, you know, kind of taking over. It was hard for me to look back and remember. Um, but her, our life was very not dramatic. She was still virtually seizure free and, and generally happy despite having lost a lot and she was at a very progressed state when she began me listen. Um and then in the third year, um I could tell that the disease was, was, was, was continuing and it was something that doctor Yu had set correct expectations to me. For me, he had explained to me at a time when I didn't really understand all of this, that Mila's neurons were dying and that some of them would have already died going into Mili and some of them were dying. Um and we might be in the process to stop them and some of them were being um were dying and, and we might not be in the process to stop them. And that does feel actually pretty accurate in the sense that Mila. Um There's no doubt about what a dramatic effect Miesen had on Mila, but she was very progressed and probably a lot of her neurons had already died or already, you know, accumulated a lot of lysosomal storage and too late to be helping some of those neurons. Um At the end of the third year, I was faced with decisions that I just ii I still can't believe any parent ever anywhere in the world has to face the decisions I had to face for my daughter who could not see, she could not talk, she could not take a fly off of her nose. Um And her brain was um starting to atrophy. It had not been during me lesson but it continued, which is part of bad disease and I was just forced with decisions that yeah, no parent should ever have to make. And three years ago, my daughter's very big spirit left her very tiny body and it would been just, you know, unbearable. I'm a positive person. I have so many great things in my life. Thank God, I have my son. But it's still something that I don't understand how any parent anywhere loses their child and continues living. It's, it's um a part of the rare disease story that isn't often really talked about. So I try really hard to make sure that I always talk about this because you hear about the child being diagnosed and a parent maybe taking care of them or fighting. But you don't really hear how hard it is to like live the rest of your entire life without your child physically there. And you know, the reason that I am here right now is because this wasn't in time formula, but it showed what's possible and it's a big deal, you know, and um I've been very fortunate to be part of thousands of conversations because Tim Yu and many others, including many mayo have have, you know, in, included me in these conversations around the science, the regulatory, the reimbursement, everything possible. I've learned a lot. And what I've learned is that while it wasn't in time for Mila, it showed what's possible. You know, her story showed that we can now, um, you know, find the underlying genetic cause and we can design a medicine to treat it even if it's unique to one person. And I know that that's an incredibly different paradigm to how we've been developing medicines and treating um sick Children in the past. And for me, it's allowed me to listen and learn and look at the big landscape and think, how do we change things right now? How do we allow for exponentially more Children to be able to access medicines? And the way I think about it is, you know, statistics are not great and rare disease, but we have to go with what we have right now and global genes, you know, points to 60 million Children that will die before the age of five from a rare disease. I lived in Italy, all of my twenties. That's the population of Italy. That number does not include Mila who died at 10 years old. It doesn't include Children with lifelong debilitating diseases. It doesn't include adults. Um, this number is massive even if it's not correct. And let's say it's instead of 60 million, 40 million or 20 million or 10 million, that number really actually doesn't matter. To me, it's tens of millions of dying Children on one side and I see kind of you know, the names of them listed in this long list. On the left side and on the right side, I see what used to be sort of like an empty toolbox and all of, you know, this more than I do, I don't want to ever pretend to be a scientist or physician. But II, I do realize there wasn't really any hope for these people, but now there is, and now there's a toolbox with modalities like antisense oon nucleotides. Um a lot of which are programmable, meaning that the process kind of can stay the same. Um And, and what does that mean? How do we, how do we create access between the patients and the modalities right now? That depends on luck that luck is, is whether or not you're part of a, a large enough disease to be commercially viable or you have an herculean effort from a parent and a, and a clinician who are willing to um who are willing to, to do what I did and fight for that child. So access depends on luck. What about everyone else? And I think the way I think about this is that, that the current system or if we want to call it a house, let's say of drug development was never designed for this paradigm, right? It was designed for one drug for, you know, tens or hundreds of thousands of people. Now, Milo's story points to this future of maybe the opposite right. Maybe it flip flopped of tens or hundreds of thousands of drugs each for one or six or 20 or 100 small numbers of people. Um, especially as rare disease. You know, we're starting to learn sort of in Mila's case, right. The underlying genetic, you know, mutation was unique to her. So another way of thinking about it is instead of categorizing um, patients, maybe by disease and with rare disease, you end up with 10,000 different diseases and it will take us thousands of years if we go, you know, do business as usual like we're doing now to to cure, treat and cure those diseases. But if we think about them, perhaps by mutation, for example, that's just another way to categorize. You look at, you know, a splice a slice mutation like Mila's and that is amenable to a splice modulating a. So, so now by categorizing that differently, you can now think that the approach for Mila is applicable across many, many diseases. Um and that should also change things like the regulatory path as well, right? That's obviously a critical, critical place that we need to change. So we, we have the Children, we have sort of the the more and more Children as we diagnose them and early and earlier, we have the these modalities more and more they're not perfect and many of you thanks to you are, are, are are allowing for these, you know, modalities to mature and have more and more modalities, let's say in that, that toolbox. Um and I, this is a bold thing to say in front of all of you. But I would say what I've learned from all of you and from others is that we're in a really unique time where science is not the limiting factor, meaning we still have to do all the science without it. We'll never get there. That's the center of everything. But before I've learned that we couldn't find Mila and we certainly couldn't treat her. But now we have the technology to find Mia. If we wanted to, we could find all the Milas at birth and we could treat not all of them yet, but there's a good percentage of them that can be treated. And with time, we'll have more and more tools and they'll then percentage will go up. So we have the technology to find Mia and to treat her today. And what we don't have is we don't have like kind of the infrastructure and the processes that allow for that access to connect the Children with treatments and that by that, I mean, obviously, regulatory, what does that mean in my mind? You know, we're going product by product, we're doing product approvals, we can't do that if we have to go through what we did for Mia, which is currently six years later, just as hard, if not harder, it takes year or years, it takes 50 to 100 or more people involved from academics to companies, to families, et cetera. It takes 1000 page IND, it takes millions of dollars. This is not replicable, this is not sustainable. Um And we still six years later are doing this and in fact, I actually think it's getting harder and slower and more expensive. Um So something is not working and there's a lot of great people out there who want to do this, you know, the end of one collaborative which um Tim Tim curry, you mentioned earlier, you know, which I helped start together with um with, with Tim, you and some others has now 500 members of which, you know, Margot Cousins. Thank you for inviting me by the way from Mayo uh is part of as well as others and 500 people raising their hands around the world to say we want to do this and really want to learn how to do this or already actually working in this field of individualized A S OS to start with 500 people. That's, that's a lot. And so you have all these eager people who want to actually help you have the patients, you have the, we don't have the correct regulatory path it needs to, we need to be able to shift towards sort of a process approval instead of a product approval and to do that. Of course, we need the data and learnings from each of these patients starting with mi as shared, which is the concept behind the NF one collaborative. Um But we also need regulators and everyone to start thinking differently about this. And I, I do think that the, the foundation um if you want to call this house, the Drug Development House, we've been trying to renovate it to kind of fit this paradigm. And I, I personally don't think that renovating or modernizing the current houses is working. And I do think we almost need to just accept that that house might work for large indication, which is what has traditionally been, how we've approached disease. But now we need to kind of build a house next door and when we build that house next door, um which I think it needs to happen urgently. And right now, I think we need to pull from regulatory flexibilities in other areas that allow us to move towards a process approval that may be looking more at sort of accredited partners along the way. Uh Not so dissimilar from um neurosurgery. Um Many have claimed that Milo and fell between drug and sort of neurosurgery, a hyper individualized approach. And some of you in the listening may be may be part of that world. Is it that in some ways it fell in this no man's land between um There's a lot to say about that. I don't have time to talk about, but I do think that that thinking that way and starting to think about things a little bit differently needs. We need to pull from that in order to really, really truly greatly shift the regulatory path and move toward this sort of process approval. Um I think that we also need to think about reimbursement. I think that the regulatory path is half of the battle of access. But this must be in my mind, not only reimbursed, but I believe there need to be companies in this space working with the academics. There needs to be a collaborative model where each brings their expertise to the table. Why not? Because I don't think that academics can do it. In fact, thank goodness they are because we wouldn't be here without them. And they're, they're the only ones pursuing drugs like me. Listen right now, but there's been 12 or 14 treatments in the last six years because there's only so much, you know, with this many people, an amount of money that's needed in time that the aca amazing academics that are leading the way can, can do this. So we need to bring more companies in to be able to do this at scale because the numbers of Children that need to be treated are so enormous that we have got to be able to do this in, in, in a much more scalable way. And therefore, that also means allowing for reimbursement of these drugs. Otherwise it's parents, you know, selling lemonade and cookies and raising millions of dollars and that's not acceptable and it's not um scalable. So all of this to say that I do see hope I found great alignment in the UK for many, many reasons. Um And we have started a pilot in the UK to actually create a model for exactly this, of how do we shift drastically, shift the regulatory process to process approval. Um where you can push, you know, many, many, many individualized starting with A S OS, but many individualized medicines through um without having to stop every single step of the way for every single molecule. Um we plan to be able to learn how to do that over the course of treating patients over the next few years as well as how do we come up with a reimbursement model? And my hope is that, that will prove a model which um can greatly help other countries because I hope this is eventually throughout the world. This is not just about the US or, or, or the UK. I hope that, that, that this creates a model that then we can um that kind of unravels the rest of the world and shows a very different way of, of doing this. So I leave you with my thought, which is what I go to bed with every single night is how do we get from Mia to millions? It's the name of my talk. It's really how I think about this is, is we have the ability to do this. The question is, will we? And that is a moral imperative and an ethical question. And all of you guys are playing in an unbelievably important role in this. But I think it requires all of us to shift the way we think. Um And together, I hope that we're here again, maybe not in a year but in 2 to 3 years that we see exponentially more Children, um dying Children treated. So, thank you very much for inviting me to, to tell me the story and my thoughts on this. And I'm happy during the panel discussion to ask um um to answer any questions you might have. Thank you so much Juliet for a really inspiring story and instilling in us a sense of resiliency and innovation. Thank you. My name is Mira Kiss. I'm the Director of Education at the Center for Individualized Medicine and I will be co moderating the second segment of our talk uh with a panel discussion with Doctor Laura Lambert will be co moderating with me. She's a director of the Mayo Clinic, Functional mix resource lab, the lab designs and executes functional genomic studies across Mayo Clinic. We welcome our panel members, MS Erica Barnes, Miss Erica Barnes is the executive director of the Minnesota Rare Disease Advisory Council, which is a Minnesota State Agency created in 2019 after grassroot efforts by a cross sector coalition of Advocates. She has over a decade of advocacy and nonprofit leadership experience and has co-founded with her husband Chloe's Fight Rare Disease Foundation in honor of her late daughter, MS Barnes also chairs the NIH funded global Leco Dystrophy Initiative Clinical Trials Network patient advocacy consortium. Our second panel member is Doctor Margaret Margot. Cousin, Doctor Margot is an assistant professor of Medical Genetics in the Department of Molecular Medicine. She's the director of the Nr One Therapeutics Program in the Center for Individualized Medicine. She's a KL two scholar and had completed her phd in Clinical and translational science and postdoctoral training in translational S program with the Center of individualized Medicine. Her research focuses on developing and translating novel therapeutics such as antisense gan nucleotides for rare genetic disorders. And last but not least we have Doctor Radica Demia who's an Associate Professor of Medical Genetics here at Mayo Clinic in Rochester and she's a consultant in the Department of both Clinical genomics and neurology and dual and dual and dual board boarded in both neurology and genetics. She's the associate program director of Medical Genetics and genomics residency and she has interest in neuro cutaneous disorders and is the co-director of neurofibromatosis clinic uh at Mayo Clinic. So I'd like to start with our first question. I'd like to um ask Doctor Erica Barnes to comment to us about uh her perspective from a state agency standpoint. Um in terms of where do you see the opportunities for currently available uh treatments for rare disease patients. What does that look like from a policy perspective? First of all, thank you so much for having me. This is, this is uh been so wonderful and Julia, thanks so much for sharing your daughter's story. I often meet other fellow mothers and I your story is my daughter's story and we know that this is the story of so many individuals with rare diseases and this is why I got involved in the work. And um yeah, so from, from the perspective of um now being um someone who um is the executive director of an, of a state agency and kind of having a policy lens, um what I would say is I, I think that what Julia was saying in terms of needing to make paradigm shifts, not only in um the research landscape, but also in regulatory landscape. I would say that we also need to make um those shifts in the policy landscape. And one of the things that, that really struck me when you were talking is, you know, so many of our patient communities mine included, we work so hard to, as you said, like you're lucky if you, if you're able to raise enough money or if you find that researcher that happens to be able to um work toward a cure or an effective treatment. And then you get to the FDA and maybe even at the FDA, you have that regulatory flexibility for clinical trial design. But, but what good is it? If all of that flexibility then hits, let's say a state formulary committee and there's pol those policies don't accommodate some of all of that flexibility from. So from a state agency standpoint, one of the main things I want to do is help the state understand that what's common sense for common diseases isn't always common sense for rare diseases. So we need to make sure that our drug formulary committees understand if, if there's um a novel clinical trial design and not exclude patients based on that. Um And then also helping uh this really working and I know that this is uh something that all states are struggling with. But really understanding how do we prepare ourselves for the future for re reimbursements, right? Our reimbursement structure especially in Medicaid is really designed for chronic diseases, for paying costs for, for diseases over time, it's not designed for these one time curative treatments. So, one of the things that we as a state agency are working toward is really helping the state understand how do we restructure those reimbursement pathways and models for a sustainable future? Fantastic. Thank you. And thank you again, Julia for sharing your story with us. It's, it's the reason we're all here doing what we do and it's so inspiring. Um The question for Doctor Cousin Margot, could you speak to what we're doing at Mayo Clinic specifically to further individualized treatment and rare disease therapeutics. Yeah, absolutely. Um And yeah, thanks again, Julia for coming. I, you're such a great speaker and to hear your story and share it with this community, I think is really important. Um So as you might imagine, Mayo Mayo C is rare all the time. So I don't wanna pretend like it isn't something that, you know, we don't do here every day we do. Um But when we think about these really ultra rare conditions and really severe patients, you know, I think again, there is that opportunity that you speak of Julia that, that we have the ability. It's just a matter of figuring out how to get there. So, you know, within the center for individualized medicine and in partnerships with our many different clinical departments, um you know, we're trying to do more and we're trying to get organized and, and use our resources wisely to get patients to the right therapeutic opportunity. And maybe that's working in my lab um on patient cells to try to devise a, a therapeutic strategy or working in Doctor Lambert's lab or collaborating with another academic somewhere else or a foundation, right? Putting all those pieces together to try to figure out what that that path is to go from a single patient or a small number of patients to a clinical trial, right? And those are a lot of different pieces that involves clinical trial readiness that involves um biomarker discovery that involves, you know, all this, in addition to just thinking about what that drug might be um establishing disease models, right? All of these steps need to come together. So we're, we're really thinking hard about, you know, these different components or modules of, of, of um work that needs to be accomplished to go from, you know, from A to B to kind of get to that finish line. Um And there's a lot in there, but um you know, as we get more organized and continue to pull this rare disease community, which is a really fantastic, motivated and collaborative community together, I think as those policy changes, you know, come about that you all are talking about that need to change. I'm I'm hoping that we'll be ready to implement, you know, the strategies that we have. Um so that we're, we're ready and not fumbling, you know, when, when it's time to hit go. So those are some of the things that we're working really hard to do. Thank you, Doctor Cousin. Next question is for Doctor Demean and we heard from Juliet that the fight to know what the diagnosis is and maybe a temporary relief of um that you felt knowing what your daughter has. It's just knowledge of, of affirmation that there's an explanation. Ho how are we doing right now in terms of diagnosis, diagnosing rare genetic disorders, where, where are the advances in diagnostics? Yeah. Thank you, Doctor Ketta for the question. I want to echo everybody. What everybody said, Julia, thank you for your talk. I've heard you talk many times and um it's always a pleasure and uh to be uh to hear it over again. So, um I think we've come a long way in terms of being able to diagnose genetic disorders or rare genetic disorders. So rare disorder, over 80% of rare disorders are genetic in nature. And um I think the first step is typically phenotypic driven testing. Um Next generation sequencing technology has enabled us to um offer these panel testing that Julia did mention, took a while for her daughter to access now very quickly. Um and HO aom and whole genome sequencing have become quite routine for us. Uh when we're dealing with uh complicated patients, either with phenotypes that, that we think are genetic but don't quite fit into a syndrome and not only in the outpatient setting, but we're offering whole genome and whole exome sequencing to critically ill infants in the neonatal IC U and critically ill pediatric patients and the Pete's IC U and sometimes even on the floor when we're trying to get to a genetic diagnosis early. Um I would have to say that when, when we were talking about red disorder several years ago, we would say that time from when the symptom onset to a diagnosis were sometimes over a decade, that number is still long, but it is about five years now based on global genes or review. Um But I think um there's certainly a disparity. So patients who have access to big academic centers often get these testing first line and diagnosis like Julia pointed out can be made at birth. The technology is there. Um And some academic centers are perhaps pushing it a little bit more than others. So there's clearly a disparity but I think we have come a long way, we can find Mela every day and we are doing it in our clinic. It's just what happens after that. I think for some families, it is an end to a diagnostic Odyssey. For example, Julia said that for a second, she did have a relief that it was AAA nod in her head, but her daughter did have real symptoms. And I think we hear that from most families that they, you know, went doctor to doctor before somebody said this could be genetic and let's run this testing. So for some families, it is end to our diagnostic Odyssey journey. Uh while for others, it does open up doors to potential participation in clinical trials or, or if I if they are lucky and they fall into that 10% of rare genetic disorders that have therapeutics in the pipeline. Uh you know, they they could be connected to with the right people where the therapeutics may be an option or clinical trials may be an option. So I think this field is moving fast. Uh diagnosis is um uh it's certainly happening much quicker now and then we are doing a lot to be ready to then translate it into therapeutics with the help of certainly academia, industry, patient advocacy. Very, very important. Thank you so much. That's uh a lot of really good points there. Um My next question is for Julia, you mentioned in your talk that, uh you spoke about a model in the UK that's been adopted over there. I think we'd all be really excited to hear more about what's working. Yeah, I'm happy Taylor. Um I noticed about a year and a half ago that it seemed that the stars were aligning in the UK uh in my sort of like humble opinion at the time that what might be the right place in the right time to scale what we've done for Mila there for the reasons that um their former Prime Minister's son died of a rare disease that changes everything. In fact, I think that if tomorrow, uh all the people in positions of power, unfortunately had Children, you know, diagnosed with bat and disease, things would change pretty much overnight. Um, that changed the uh the mindset of the UK. I think when that happened, this was David Cameron's son who died at a very young age. Um It really hung their hat on genomics. They obviously have an incredible uh lots of wonderful academic centers, um some biotech as well in the rare disease space, but really, also, I think that the M hr A um the regulatory body really has a very interesting take on um what they need to do to change and how they interpret, protecting public health. It was something that really, really resonated with me. So very obvious that protecting public health is protecting all of us from scary drugs like thalidomide. I understand that and everyone kind of gets that but to have the M hr A and my first discussions with them, you know, starting a year and a half, two years ago, say that that another definition of that is to ensure access and actually rapid access to technologies that exist today is like, maybe seems small, but it's revolutionary in the sense that that's where I was getting stuck. Like, hey, there's Mila and then there's these technologies and there's lots of Milas and like, how, how, how is it that, that it seems to me that the regulators are maybe not purposely but are impeding access by continuing to kind of use the same regulatory um uh guidelines and pathways, more or less, some adaptions but not quite enough. Um And the M hr A really gets that and they were very, very motivated, especially to be honest, post post Brexit as well being in is not a minor thing. They are not attached, you know, to the US, very conservative FDA or, or perhaps somewhat conservative Europe as well. Um And they're, and they're independent um they also have one system where all of their clinical, you know, the NHS, they have all their clinical and genetic data in one in one place. And then what really sort of like got me there physically and got me there to start meeting with each of the different players was that um genomics, England is just a really fascinating model. If any of, you know, it, it's, it's owned 100% it's a company but owned 100% by the government. Um and their job was to do genetic sequencing um for the NHS. And then obviously, it's up to the physi, you know, clinicians, you know, in, in the NHS to decide what to do with that. But they spent the last 10 years, um you know, sequencing whole genome sequencing hundreds of thousands of people. And now they're moving into newborn, a newborn program right now and, and I think they're kind of leading the world in a way and trying to solve the first half of the problem. And so when I went there as kind of slightly maybe naive Julia, um I kind of worked my way through genomics, England and, and you know, the top of genomics England M hr A Department of Health, Oxford Harrington Rare Disease Center. Others and said this is so exciting. You're, you're solving the first half, but you're actually, she's sitting on the data with whole genome sequencing data. You're sitting on the data it's what I needed for Mila to not only diagnose her but also to, to create Mien, right? And so you're sitting on the data to solve the second half of the problem. And um that has then turned into not only just discussions where I then said, you know, I have a foundation, I don't have any red tape where I just called these people together and the, and the, and, and the aligning of the right people. There are a lot of sorry, I have to say this out loud, but there are a lot of Rs in this world and especially in science and that there's a reason for naysayers because they protect us from doing, you know, crazy bad things. But there are so many barriers right now between a child and treatment. I mean, there's mostly just barriers that finding just the right people who are really aligned and saw how this might change and how the regulatory reimbursement path needed to change, putting them in the right place altogether, has proven to be incredibly powerful. And that ended up turning into something called the rare therapies launch pad, which was endorsed three months ago by the UK government as one of their top priorities in, in health and announced in their kind of big annual autumn statement, which happened at the end of November. And that's been huge for us because it means that the country is on board and willing to do things very drastically differently. A think about protective how to protect public health. They are, they believe that they're impeding access to public health. Uh Right now, access to technologies and they need to change that. And the c which is a subtle thing and I'll end here is, is that it's hard to figure this out. I've been part of thousands of conversations about how to do this and, and we, it's not an easy fix, but the premise of this rare therapy launch pad was we can't figure this all out by talking about it, but we can more likely if we actually treat patients so dying Children that have no other option. And there's small numbers of them with A S OS that are the most kind of mature of the programmable modalities. Um Can we start there as the tip of the spear and treat Children and not just learn from the data and experience, which is necessary but also try to shift over the course of patients in the next number of years. Can we rethink with every few patients? Like what is regulatory oversight? What is appropriate? Should it be every single A to Z for every molecule? No, because we'll never get there. So then like where should there be oversight and where can we pull from other ways to keep this safe? You know, and that's been revolutionary. So I just really, really am excited that the UK is thinking about this and now it's up to us to over the next few years to, to prove it. So that is wonderful. Can't wait to bring you back for updates on that. I, you know, be really curious to see lessons learned and what we can adopt here in the US. I'll take this next question uh to Erica. Can you reflect with us on how the state of Minnesota um or what the state of Minnesota is doing to improve the care for the rare disease community? And how have they prioritized that in recent years? Yeah, thank you so much. And I, I would say um something that Julia said in terms of just uh a paradigm shift that feels small but is really, really quite important is something I would say the state of Minnesota has done. And I would say that in the last, since, since the passing of the legislation for the Rare Disease Advisory Council, one of the great shifts that I've seen in the state of Minnesota is really um accepting the uh mentality that the rare disease community is a significant subset of our health care population. So not thinking of rare diseases in terms of this individual diagnosis, that individual one, but really saying there is a subset of our health care population that is a significant portion of our community, one in 10 Minnesotans. And we need to be looking at their needs collectively and taking a collective approach to their need. Um So, through the Rare Disease Advisory Council, we've really been able to start to look at different policies and different uh types of legislation that would help us collectively address those needs. So, for example, um I'm very excited last year, we passed legislation whereby um any individual in the state of Minnesota that has a rare disease um can go out of network. Um They, their insurance companies can't require that they stay in network. So, um if you are diagnosed with a rare disease and, and you can go out of state, you can go to, to any care provider that you need because that's one of the collective barriers we were seeing around the rare disease community. So, um and that addresses the issue that we've all been talking about. How do we get these uh individuals diagnosed more quickly? Um So that's one of the big things we've been able to do in the State of Minnesota. Um In addition, we passed legislation last year that um requires that our state drug formulary committee have someone with expertise in rare diseases on the drug formulary committee. So that we can hopefully um make sure that when, when we do see some of this regulatory uh paradigm shift, um our regulators and our policymakers in Minnesota understand um how to make decisions, policy decisions um based on these new paradigms. That's fantastic. I, I hadn't heard that that's a fantastic breakthrough. Being able to go out of state. Excuse me. Um The next question again is for doctor cousin. Um We all know and as we've heard today, Rare Disease takes the community. So I wonder if you would be able to share some stories from your experience about how these patient families and groups have come together and you've engaged with them um in your experience. Uh Yeah. Happy to. Um uh it's been a quite, um, I don't know, quite a ride. I think being a participant in rare disease, you know, research and diagnostics and therapeutics. Um And the community has been an amazing um amazing community and very resilient. Um And I would say I got my phd in part because I was not terribly comfortable, maybe interacting with patients on a daily basis and wasn't really wanting to treat an individual patient. And yet I find myself really, really rewarded by exactly those interactions that I've had and, and the communities I've been able to engage with. Um but it does take, take this village, right? And I think the power of the patients to assemble and form an organization and to advocate is really, really powerful. Um And, you know, sometimes they bring funding that's critical to get started. I mean, how many times do you need significant preliminary data to get a grant funded? Um And, and I can't, I can't get those super rare studies funded all the time on my own. Um So just to get going to get the momentum to carry things forward. I think those, those interactions and um um with patients and families and, and organizations is, is really, really huge. Um But that carries forward to so many aspects of translating therapies or changing, you know, care plans or um and all of that and, and understanding what are the important outcomes. I mean, how many times have we had clinical trials that, you know, in hindsight, those patients really did better, but we weren't capturing the right metrics, right? Some of the really key important things to families won't be considered any of our, our primary outcomes. Um so working with the patients and advocacy groups and, and you know, with clinicians and researchers altogether are key to understanding what, what is, you know, a a key outcome for an individual patient, what is acceptable, what's to say that this is enough to say that this therapy is doing good um because it may not end up being exactly what you think. Um And, and now I have, I have pictures on my bulletin board and I have, you know, thank you notes on and I think about them every single day and I think the more we get to tell these stories and the more we get to come together, the more we can, you know, affect change at the payer level at the regulator level, right? If we can, can really do that. So um it's been from my own personal career trajectory, really important to have had the opportunity to work side by side with all of these different types of individuals um from the patient to the clinician and to everyone in between. Um because it, it I I think it is a powerful force for change. Thank you doctor cousin. Perhaps patient communities um are perhaps even more powerful for rare diseases than they are for common diseases and seeing patient stories. Um not as a number, but as a person can definitely drive change. This question is for you, Doctor Dimes and and you reflected to us about where we are in terms of diagnostics for rare genetic disorders and accessibility or are we with therapeutics and what needs to happen to be ready for clinical trials for rare diseases? Yeah. Thank you for the question. Um So I think again, we have a long road for therapeutics for rare disorders. Um Some statistics, about 5% of rare genetic disorders have a therapeutic therapy that has been FD approved. Only about 10% of rare genetic disorders have a therapy under study. Um So vast majority of patients with rare genetic disorders actually do not have a meaningful therapy or a targeted therapy that's available. There are several routes that people or scientists and clinicians are taking. And one that has been discussed uh in this forum already is the ants o the therapy. So I think as a clinician or a geneticist sitting in the clinic, it's important to identify those patients that perhaps, um where that therapy could be tried or potentially tried. Um I think drug repurposing is something that has been actively looked in in this community. So new drug therapy is ex extremely expensive and takes decades and needs large numbers as you know, and over 90% of the time any novel drug therapy that's tried, it fails. And so, uh typically in rare disorder community, um you know, it's fraught with um a lot of expense in very small numbers, the less incentive for drug companies to work on it. But a drug repurposing, I think solves a couple problems here. First, the safety is studied and at least a subset of patients or, or or another disorder, plus it would be much less expensive to do that. And so I think drug repurposing has been done, studied and that opens again doors for several other rare disorders. And I think gene therapy, we, we have some examples now. Um I I is the future again, I think before we get to therapy, lots of steps need to happen for making a particular rare disorder, be ready for a clinical trial. And as a clinician, I think what we, what I think is very important is data sharing for the clinical phenotype. Each individual rare disorder is very rare. You know, some of them may only have few individuals worldwide. And I think we need to break barriers to be able to share data and then open up natural history studies. What do we want to study in this rare disorder? What is most meaningful as doctor cousin said from a patient standpoint and what is meaningful from, say, a science standpoint? Um um patient advocacy is extremely important and rare disorders as has been highlighted by two members on this panel. Um but uh since we're diagnosed more and more rare disorders, the orphan had actually list 800 patient registries. So there are at least 800 rare disorders where somebody has made an attempt to start a patient registry to collect clinical data to be ready for science um or therapeutics in the future. Um So I think again, we have a long way to go but we're all making, coming from different angles and making progress um in, in this group. Thank you. Um We have a question in the Q and A I think it's geared toward Erica. So I'll, I'll ask it of you. But if anyone else wants to add their thoughts, please jump in. Um The question is, is the FDA looking at this unique issue differently or is their drug approval path still quite cumbersome for these rare diseases? Um Julia might be able to answer this too but um I I can speak to it a little bit. Um I think that it's a little bit of a of a mixed bag with the FDA. I think sometimes they do recognize the need for some regulatory flexibility. Obviously, they have the um the um approval pathway, um the accelerated approval pathway. Um So that's, you know, shows a degree of flexibility. Um That one is probably one of the most problematic when you hit the formulary, you know, state formularies. Um So, but there's, there's some regulatory flexibility, but frankly, there's also um you know, times when they want placebo controlled trials and, and you know, um more clinical trial design that's a little more suited to larger patient populations. So there's, there's a long way to go. But Julie, I wonder if you could speak a little bit to that question as well. Maybe even more. Thanks. And I agree with everything that you said. Thanks. I mean, I would say the way I measure things is there are a lot of draft guidances. There's four that came out based on Miesen that are on individualized medicines and there's operation warp, speed and operation all sorts of different things to me. These are not translating into exponentially, more Children being treated. So it actually doesn't matter to me how many draft guidances or meetings or zebra stripes there are. And like it's frustrating for me, Milo was treated, began treatment six years ago. There's hardly any Children have been able to be treated. So how can we learn and improve if we can't even treat? So, the real pattern we need to start is we have significantly more access, not just draft guidances so that we can um treat, learn, improve, treat, learn, improve, not like talk, talk, talk, talk, talk. And then every like few years we like are magically able to treat a patient. Um And so I would say that, you know, recently a senator asked me to list the batten treatments and where they were and I knew that that many of them had been shelved. But until I made that list about a week and a half ago, it didn't really hit me how many, every single seal in one seal in two seal in three seal in six seal in seven seal in eight, all of them gene therapies. A so all of them have been, you know, meal since different had been shelved. And one of the reasons I am not part of these companies, but I know the CEO S a lot of these companies, I know the academics involved. I have yet to hear a single person for any of those trials say that they were unsafe. And in fact, I've heard from many of the parents that they were, some of them were helping a little, some of them medium and some of them a lot. The FDA is requiring massive amounts of NHP studies for repurposed drugs that are in Children in the United States and other indications for years that are perfectly safe. Just a few weeks ago. One of those for dying Children with another form of Baton Disease. The company after years of doing this, they gave up. They're like, we give up the FDA is requiring so much of us and, and, and there's placebo groups for dying Children. Nhps for drugs that have been around for years that are safe. I mean, this is insane. So my answer would be very clearly that the FDA may have flexibilities but they are not pulling from them. And I'm not convinced that I think some of the high level people in the FDA truly do want the change. But I'm not convinced that um the FDA is able to make the drastic amount of change that's needed unless there's legislation which I hope that we're able to. So Erica good job for everything that you're doing on a state level. I think on a national level, we need to really help. The FDA is a better way of putting it to have the resources to pull from their flexibilities to be able to change Julia if I might just ask quick. Um If you could speak just a quick second, I know we're probably at about time here but on um risk tolerance, you talked about what your risk tolerance was about Mila and the many family conversations you had. That's a big topic and how disparate, you know, or how different that is from regulators and payer models, not addressing what that risk tolerance is. Thank you, Margaret for asking that. Actually. Is a really good point. And I think it's particularly interesting actually because it's mayo clinic that is listening to this right now in the sense that you are a leader in, not only just genetic disease, but also in, in cancer and oncology and the way that I have thought about this, which just drives me crazy is that Mila, let's call Mila having end stage genetic disease. Watch how the topic changes. I've been doing it in the last six months and it completely changes the discussion. So Mila had end stage genetic disease. There was no option for her. And if you look at a child, her exact same age as end stage cancer, the society has accepted in a massive amount of risk that we're willing to take for a child that's dying of cancer that is not responding to other treatments. And this is not even just car t this could be, you know, you, you are the experts, it could be high experimental cancer treatments of which have enormous risks and these are Children and we all know someone that has cancer. My mother died of cancer the same year as um as, as Mila. And I couldn't believe yes, she was older, but I couldn't believe the difference in risk tolerance between the two. So if Mila had end stage cancer, we'd be as a society, completely willing to do whatever it could obliterate her system if that would just give her a shot, even if it meant buying her a few months of life. Now we have 30 something years of experience with just A S OS and many more coming down the pipeline and we're the, the, the, the risk tolerance is like the Grand Canyon. We're unless it's perfect and we're really sure that it's gonna be perfectly safe and magically gonna help her, then, then we're not gonna risk ever hurting me. And in fact, people in the FDA have said we, we wouldn't ever want to expedite Mila's death. And I'm sorry, but like, yes, you have to consent parents. And if all parents don't agree, like no problem, that's fine. But there are millions of parents who have dying Children who are very eager to give their Children a chance. And I think if we don't think about risk um correctly and thank you Margo for bringing that up, I think it actually creates the wrong foundation of the house that we're building. And so we can't really actually build the house correctly. And I don't know Erica, you what your thoughts are on that I could not agree more. Um I, I think also another observation I've seen is, you know, to your point using the cancer paradigm, also the the um threshold for clinical benefit uh seems to be quite a bit higher for some of these rare diseases and the expectation uh for approval clinical benefit, especially in terms of gene therapies. Um We need that. You're right. I think to build the foundation and, and yes, that the um safety is so important. But the, the risk tolerance we have because these are diseases that are, you know, so devastating and there's just no hope for our community. We have much the, the risk tolerance needs to at the FDA level needs to change. For sure. I agree. Thank you all so much for a robust discussion. And we have another question to Chad, but perhaps we can table that there may be a communication via email if that's possible. Thank you for your time. Thank you for sharing your passion. Um And again, instilling in us a a drive for positive change. Thank you. Thank you all. Thanks for having us. Thank you.
