On this episode of the patient empowerment program is brought to you by ultragenyx. ultragenyx is on a mission to transform the lives of people living with rare and ultra rare diseases, and is a proud partner of the n-lorem Foundation. With multiple approved therapies and a deep pipeline of potential treatments and development. ultragenyx is going beyond everyday for the
rare disease community. Learn more about how ultragenyx is leading the future of rare disease medicine@ultragenyx.com That's ULTRAGNY x.com. Hello, and welcome to the n-lorem podcast series, a series that focuses exclusively on patients now referred to as having nano rare mutations. I'm Stan Crooke, and I'm the founder, chairman and CEO of n-lorem. And n-lorem is a nonprofit foundation that I initiated in January of 2020.
Our mission and enormous to take advantage of the technology we created at Ionas pharmaceuticals, Aniston's technology or ASO technology to discover, develop and provide experimental ASO treatments, to Nana real patients and to do that for free for life. Special guest today is Mo cactus. Emily is chairman and CEO of ultragenyx, one of the important companies that are involved in multiple new medicines for for rare diseases. And well, welcome. Thank you so much for joining us.
Thank you for having me, Stan. Happy to be here. Yes, it's great. And so I assume, since you went to Pomona and then UCLA and never seem to leave that you you're a California boy. Yeah, born and raised in California, and my parents were Greek. They emigrated the US and they love selling Southern California weather. And that's what we started there. And I stipulated around the bay that valley for school and ultimately laughed when I came to join bio Miranda in 1999.
Yeah. So it is I understand that your family is full of physicians of all sorts. So I guess you sort of were to the manor born as a physician scientist. Yes, my father is a neurologist. My uncle was a nephrologist. And they had a lot of their closest friend or physician. So a lot of the families and people coming over all physicians, me and two of my siblings are physicians and two of us married
physicians. So medicine became a core of kind of our life and living and became a way of life and a way of thinking in terms of caring for patients and taking care of them. And I'm really an old school approach, which is the all in type of care physicians, where you do whatever you have to do and how are related takes you to get it done. Right. Yeah. As physicians always used to do and still should do. Right.
Right. And so, after you finished undergrad, you then went to UCLA, and you did a joint MD PhD program, I think, right? Yeah. So that's the medical scientist training program. They had just opened that program at UCLA in 1982. And I was lucky enough to get a slot because it was hard to get slots at that time. And the great thing about that is it provided tuition and
fees and also gave you a stipend, which was great. Great, because otherwise seven years of medical school would be pretty darn expensive and a lot of that it still is and and were you always interested in pediatrics, or when did you become interested in neurology, pediatric neurology and all the well, I didn't can't go to it immediately i I became interested in genetic disease because of all the things that were going on at that time. During my PhD years in the
middle there the 80s. Every week, a Nature Genetics journal came out with new genes being cloned in a new dysmorphology syndrome being figured out the biology being nerved. And it was a really exciting time for genetics, that allowed me natural thinking about medical genetics as a specialty, which naturally is usually preceded by a pediatrics residency and so that was the direction I took to take advantage of the new discoveries in medical genetics.
So So you entered medicine you became interested in in pediatrics then genetics and then that led you to rare diseases? Is that sort of the progression of it? Well with medical genetics, your your always given rare diseases pretty commonly. And as an academic physician, I was thinking of Medical Genetics cases and situations as natural experiments of people have mutations and problems. And while we manage our problems, we're also learning about the
diseases to these natural experiments. At the same time, when I started my fellowship as a medical genetics fellow, I was looking around for a project, a research project. And at that time, Dr. Neufeld had just cloned the gene for MPs one, two, and it was just the fortuitous timing, the cloning had just occurred, I was needed a fellowship project. And she was willing to take me on as a fellow and that put me into studying MPs. One, I didn't know anyone with the disease, nor did
I know particularly much about it at all. And I had to get a crash course, learning about MPs and lysosomal diseases and meeting patients. And it was a great starting point. But I had no idea that I'd be spending the next 30 years working in that area. Yeah. Well, life is always a surprise, isn't it? And so, after you finished your residency and fellowship, then you joined the faculty at UCLA. So you sort of stayed home grown for a long while?
Yes, well, I took advantage opportunities, I actually did a fast track pediatric residency, so I only had two years to read, see, and then I went right into fellowship. And sometimes this happens in the university system, Stan, a faculty slot opened up at Harbor. And they said, I could do my first year of faculty in concurrently with my third year of fellowship. And so I said, Why would I say no to that? I said, Yes. So they need to fill the slot, because if they don't fill it, someone
might take it away. So I was I just got lucky. And I got started a year earlier as a faculty member and my wife was it has finished was a resident at Harbor, UCLA and OB Joanne. And so we had already established some routes in the area. That sounds sounds like it managed to condense a little bit of time for you, which is always important when you're, when you're thinking about all the time that is invested in just getting ready to do some work. Did you did you discover a drug
for MPLS? Or while you were at UCLA? Well, I wouldn't say I discovered it, I helped develop one the doctor knew how to clone the gene. And my first day of fellowship with her she said to me, I think you should work on enzyme replacement therapy for MPs. One, it was a lysosomal disease missing an enzyme called ionic days. And she thought we had never been able to make this enzyme in quantities, appropriate quantities with the right marker. Let's do that.
Now. I was most interested in doing gene therapies. And I really want to gene therapy was just starting with French Anderson and retroviral packaging. And I thought that was the sexiest science going on. And she crushed my spirit, right, that first meeting and said, No, you should do enzyme therapy. And I said, alright, I'll do enzyme therapy. Now, the reason is important part of the stories, Dan, is that we all get excited about things. But sometimes our excitement is not
well placed. Unfortunately, the retroviral stuff never really went very far. In the end, she put me on enzyme replacement, it had one distinct advantage over a sexy science. And that is an enzyme replacement actually worked. And therefore, the ability to change and treat someone make them better stand overtakes all the sexiness of science and fancy journal publishing and all the world you could think of disappear as important when you've actually been able to treat some patients and I
couldn't agree with you more. And I often talk about the fact that when people get excited about new drug discovery technologies, they forget time failures and dollars. And the fact that the vast majority of times you start out and it doesn't work and gene therapy now is what 40 years in and $50 billion in or something like that, and still a lot to be left to be done. And we'll we'll get to that in just a little bit Mo and so that sort of takes you into to the rare disease replay
enzyme replacement. Is that why you ended up then going to bio Moran and in 1980 98 or 99. I joined them officially 98 but moved to the Bay Area in 1999. I stayed down south for one more year but the transition to industry was a big change for me. I had planned to be an academic physician all my life, right? r1 grands do all kinds of studies become a member of the National She'll Khadem II, you
know, get the accolades of your peers and do great science. But when I treated patients and saw them get better and realized how important that was to me, and how important it was to have the adequate financial capability to do it, that I realized if I really want to make a difference in rare diseases, I'd be far better at going inside a company and advocating for them inside the company. And the reason I was born stand at those times,
and we're talking about, we're talking about 1990. At that time, rare disease was like Genzyme was like the only one or the few people making you know, taking generic products through but they're one people really doing rare disease focused. Even when I joined by Ameren, I was told by other executives, that there would never be another rare disease developed in pharma. And after the NPS, one, I was seriously told that but I thought, Stan, if I move inside the company, I can advocate for
those diseases. And I did step by step one by one. As we added product after product, they always succeeded stem and all the other stuff failed. barbering became a rare disease company because seven out of seven succeeded and all the other ones didn't like a lot of the rare disease companies. It didn't even Genzyme didn't start as a rare disease company, they staggered
their way into it. And then and you're 100%, right. The value of a drug is an incredible amount of leverage for good and more than you can do as a single practitioner or as a single scientist for sure. And I think too few people realize how much how much value is created out of the leverage of a good medicine. So then you went to bio Moran and and you you had successes with a number of products and the diseases are different, but the solution was the same which is enzyme replacement for MDS
and for phenol Kido. You're You're a an even battens disease, if I recall correctly, is that right? Yes. Several lies on diseases. MPs, one MPs, six MPs four a and ceiling two are late and late infantile battens also worked on Cauvin and peg Powell for PKU. And then, in addition to historic tide, which is this the new drug for a contemplation? Ya know, a Kandra. Pleasure wasn't a replacement therapy, was it?
No, a contemplation was a very novel strategy. We're an academic physician, Bill Wilcox, came up with a strategy on how to treat a mutant immune receptor by using a hormone that had an equal opposite downstream signaling effect. It was like one hormone to counterbalance the abnormal receptor, which I thought was the coolest idea. And I had no way I had no idea how to treat contemplation. And I told you, we should try this. And people said, no one's done it before. I said, Yeah, but
there's no other way to treat that disease. So why not take the shot? And honestly, in a few months, we came up with a version of that or hormone that was stable, just got approved. Stan. Congratulations. So hormone treated contemplation, I think that's a fun disease, people thought would never get treated. I agree with you. And you know, I think it brings us to a general message one, and
is that that everything is a set of pathways. And as we understand the pathways, it opens up opportunities that were not obvious. And in the case of ICANN replays you an opportunity that was very far afield from what you had done before, right? Yeah, yes. We learned a lot about taking risks for really important results. And in this case, it wouldn't take long to stand to figure out if you could do it. And if you could, what a
great result that was. So it's been a guiding principle, all the work we've done since then is don't fear taking a small risks to figure out something will work but if it will, and have a huge impact, it's worth it. And I was very happy to see the SOAR tide approved and really getting utilized, like a lot of families are using it. So I think it's a great testament to the importance of the work. And that's wonderful. And just to make sure everybody
understands a condo replaces a former dwarfism. And so it's a lot of short stature, people with other isn't just stature it's also a bunch of other problems that they have and to be able to do something about that is a great achievement. And then, so tell me about why you founded ultragenyx and left your cushy job at bio Murrin for an even riskier opportunity. Well, Barbara and had grown into evolved. And there's a quaint 11 years in with three approvals that began to be different
company from the one I was joined. And I felt like there was time to do some other things I left to actually to start a foundation. The foundation was to focus on regulatory policy around rare diseases. And we worked for a number of years on the cure what it called the cure the process campaign. And that foundation in the every life foundation for rare disease still operates and goes, and I'm on the board. But after about a year of doing that, and getting it going, came up with the
thought of starting another company. I hadn't thought about it cm, but I realized there were so many parents coming to me trying to get help to treat their kids. As you know, from your experience with them warm that I felt like I couldn't not do more treatments. So I found it all projects to focus on ultra rare genetic disorders. And we started off with very simple small small molecules and simple proteins. And ultimately, the idea was to build a company treating each disease with the
right mode. And we've added over time, gene therapy and other things. But it was about doing a company that was built about rare diseases from the beginning with the right philosophical view of taking care of people before approval after approval, and assuring that whatever we develop becomes accessible to patients that need it. And that's a higher level responsibility and how we operate his company. Well. We hope you're enjoying the n-lorem patient empowerment
program podcast. We at n-lorem want to provide support to our podcast listeners the best way that we can. There's no better way for us to do that than to ask you directly. Do you have questions you want to ask Stan Crooke Stan, we'll be taking questions directly from you and other podcast listeners and dedicating an entire episode towards answering your questions ama style. If you're a nano rare disease patient, family member, friend, physician, rare disease advocate or you just enjoy the
podcast. We want to hear questions from you. Please don't be shy. All questions are important and may end up helping other listeners. So don't miss a great opportunity to get your questions answered by the patient empowerment program host CEO of M n-lorem. And the father, antisense technology himself, Dr. Stan Crooke to submit a question for the upcoming q&a Episode email podcast at n loram.org. That's
podcast at n l o. R e m.org. With the subject line podcast question, if you wish to be identified mentioned your name and email. If not, we'll keep your submission anonymous. We can't wait to hear from you. Now back to the episode. So let's that brings us to every life, which is an interesting Foundation. And you know, I'm familiar with it, because some of the publications and you know, for example, the the publication that describes the economic impact of rare diseases
and so on in the US. And it to my mind is first and foremost, a foundation that engages in relevant scholarship on these diseases and and obviously, you and others have participated in the revolution in treating rare diseases, which I'm interested in. The way I look at it in the patient voice was the key event here. And it really began with AIDS. And then the recognition that that patient voice matters and getting that in front of the
FDA and other companies and so on. Is that is that your view of the history of it? Or do you have a different perspective? I think the patient voice piece is very important in the the rehabilitation of the patient's role, because the patient's had been reduced to being emotional and non rational people somehow and no one bothered to actually ask them and that harmed drug development. And I think now, we're much more working with rare disease patients as partners in the process,
continuing to evolve and improve that model. But I think it's the regulators also are starting to connect and realize that they are an important contributor to the whole process. I think the other piece, though, is on the regulation, the raw law and and that the FDA applies and their guidance is an approach are an important part of what the foundation was working on. A lot of this is maybe technical about the details of how accelerated approval is evaluated or how biomarkers are qualified or
study designs and other technical pieces. So at foundation we Did a little bit of that work to trying to move the ball forward on the quality of the development strategies and the regulation, building the patient voice in was just part of that bigger picture of improving the quality of drug
development. And it involved a lot of workshops, a lot of investigation reports and analyses, as you were talking about, and to some extent, discussing on Capitol Hill, what are the needs of rare disease patients and having the patients come to the Hill, during rare disease week where hundreds of patient advocates come together, and we send them out on the hill to talk to their congressmen on the very same day, give them the kind of bulk that a common disease has, but with all the
individual rare disease patients gathered together as one team? Yeah, I think, of course, I've been in industry long enough to remember way before you. And there was no question voice. And then I think the industry has benefited tremendously. And the FDA has benefited tremendously by integrating the perspective of the patient. And, and, obviously, you've spent a lot of time thinking about clinical trials and what endpoints ought
to be and how we should go at that. But I think we'll leave that for another conversation, because that does get pretty technical. And you, if you were to pick one thing that every life did that you're really proud of? What would what would it be? I think it's gathering together the rare disease community, truly, during rare disease week, where we actually bring hundreds of people together from all different segments, we, and help
all them actually find a common vision and a common voice. I think that's what we've been, has been most important, because they then don't feel alone, they feel empowered, and rejuvenated. And I think it propagates across the country. So I think it's bringing the whole community together, it's been really important, and in that enabling and empowering them to actually take action on behalf of their disease area.
Yeah, that's very much what this podcast series is about. For the even less, even more poorly served or non served, and an n of one people literally don't have anyone to talk to. And, and, and, again, I think that's a matter of providing a forum a place to be heard, but also a place to be taught. Because certainly my experience is that parents and patients are doing remarkable things with no training, what could they do if they had some training? And I know you've thought a lot about
that too. And, and at at ultragenyx, you have what you call a boot camp, which I spoke out this year. But why don't you tell our folks about what that is and how that's how that's working? Well, one of the philosophies underpinning ultragenyx, as a rare disease company was that we would use our knowledge to help everyone around us do work on their disease, or the idea that we won't work on every disease, but we can help others be
successful. That involved a lot of individual one on one consulting and with time, wise one of our employees felt that we could be even more effective by grouping together some people and creating a bootcamp a several day in persons, a place where a small group of selected family foundations or small nonprofits, could come with their drug development questions, and get trained and insight from experts in the field and build real camaraderie among themselves as well as make
relationships with others that would help advance the development of treatments for their care. And the bootcamp followed follows up with some consulting and help that we do pro bono for families and we think it's kind of camaraderie and shared ecosystem to solve rare diseases. It's an important part of being a rare disease company. How do you measure the value that you create a bootcamp? Well, I measure it because of the number of families have
actually helped to drive and treat their kid. Right. One of the early ones Laurie seems has has a kid with Gam and she got her kid treated. I was such a great thing to see. And you of course familiar with, you know, the other end of one cases that are out there, most recently, Terry Pribyl latkes, developed a gene therapy for his, his SPG 50 affected child and got him treated and sends me pictures of that. So I measure it in another disease after disease actually getting a treatment to a few
patients. And that is, you know, it's priceless in terms of what it means for your career to know you've helped make that happen. Yeah, I've had the privilege of putting a lot of drugs on the market. And, and having that experience and of course, in Lorem, is, I describe it as much more like practicing medicine. For me, it's one patient at a time, it's that intimacy that that you don't get when you're developing drugs commercially.
And, of course, your pipeline has small molecules that his enzyme replacement says antibodies, it has genes and as antisense. Early on, I talked with you and all the gene therapy companies about whether gene therapy was ready to sort of be industrialized take on the Nano rare patient, I think most everybody concluded that no, not yet for a variety of reasons. What do you think needs to happen for gene therapy to get to the place where it can be applied as as as innocence technology is today?
I think the biggest challenge is manufacturing, scale and costs. That is where I think it's challenged. Now, because we're talking about single dosing, it does help. But it's very hard to develop a manufacturing process that may take 10s of millions of dollars and have only one kid get treated, right. And while there can be ways to leverage and simplify, the truth is, hasn't really dramatically altered the cost structure of getting there. I think that is the biggest number one issue.
More and more, though, there are people focused on CNS, intrathecal, CNS strategies for gene therapy, like Terry did for his son with SPG 50, where they're just plugging and playing another vector and an AV nine and, and are able to get a few million dollars put together to do the manufacturing. And so there may be some improvements, if you can narrow this what you're doing. And if you're using a particular IV strategy, intrathecal strategy, the amount of vector you need less. So
manufacturing can is the biggest issue. And I think getting to high quality, lower cost manufacturing would have the biggest impact. Yeah, I think there's still a lot to be learned too. And, and where we have nearly zero cell turnover in the central nervous system, that's not the case to the rest of the organs. And so I think when you move out of the brain, it becomes even more
challenging. But obviously, at enlarged, we are anxious to see gene therapy progressed to the place where it can help because we can't fix mutations. So let's move on then to end Lorem. And first of all, I want our listeners to know that you and ultragenyx have been incredibly supportive, and we appreciate that and and, of course, you add in yourself and ultragenyx, you have plenty of places to put your money. That's, that's never
the issue. What is it about in n-lorem, that convinced you that investing in Enmore made some sense. But definitely a large number of ultra rare, there's so rare that the traditional drug development path, it's just not going to be plausible. And I've worked on some very rare ones. But when you have a few dozen or less, it's just, there's just no way
to get the traction with a company to invest. And therefore then you start looking at strategies in which you can customize the development of a treatment and do it at scale appropriate for that and get it done. And I think the use of antisense oligonucleotides. And the n-lorem approach is that you can custom create therapies that would actually address very
small population. And unlike, let's say making an enzyme or biologic, you can kind of plug and play the sequence in this chemistry, you don't have to create a whole huge manufacturing system to produce it. So be ability to plug and play the sequencing chemistries means that you can make small lot drugs and make that work and a timeframe and a cost structure that I think is plausible for approaching some of the rarest of the diseases. Yeah, we're
doing it. I mean, we've already proven it can be done and now the now the the next step is to prove that as sustainable as a charitable endeavor and with support from you Many others in the industry, I think we're well on our way to doing that. So, Li, I want to thank you very much for for participating. Is there a question I should have asked you that I didn't?
Well, I guess the biggest question right now is what what can we do to help rare diseases get treated, and I am working on one thing, Stan, I'm I'm working on us improving the ability to accept primary disease activity, biomarkers, that's a type of biomarker that really affects reflects the underlying disease, as clinical endpoints to get approval, that we need to change the paradigm of drug development. And a lot of these ultra rare diseases, if you wait for clinical endpoints, it takes
so long, there's so much variation. And many diseases will have irreversible symptoms, by the time you treat, that you'll never get to the end. And we as a country have to get smarter about using the primary cause of disease as a true measure of disease. And understand that we can develop drugs better than you can any other way. Just like HIV drugs
and viral load. Stan, can you imagine developing a quad, quadra, Vaillant combination, highly active retroviral therapy, using clinical endpoints impossible, it's time to enter the 21st century, and use the proper disease activity biomarkers as the true measures of disease and transform our drug development system into an a really effective, efficient system. And that's getting past our limitations and our angst about biomarkers and starting to realize, we need a precision
medicine equivalent for the measurement of disease. My big question and answer and and as you know, I've strongly agree, I think you call it the tyranny of statistics in the end, and you know, it goes well beyond rare diseases, the bigger problems are in the large diseases where you have to treat a massive number of people, each of whom probably has a different disease that just got categorized as diabeetus, or whatnot. And I think there's a
great deal of work to be done there. And I think the lessons that will be learned from n-lorem, and ultra rare rare diseases, eventually will be applied. And I would assume that you also strongly agree that among the things we all have to work toward is adoption of, of of genomic sequencing as as a standard part of newborn screening, or at least symptomatic patient evaluation. Minimum, right. It's happening in other countries. And you know, the
cost is coming down. And if you think about what costs you would say, by getting to these patients, actually understanding what the prevalence of natto rare and other kinds of mutations isn't getting them to them before they've progressed to the place that they're almost impossible to treat. So I think, what's encouraged me and in doing it n-lorem Is the tremendous momentum behind this and in the regulatory community, in the office sides, technology, the President and throughout the
industry. So we all recognize that there's a desperate need here. And if we the only way we're going to get it done, is band together and, and work together. So, again, thank you very much for the opportunity to interview you and all your support in the past, and I'm sure we'll have opportunities to work together again in the future. So with that, thank you, Mr. Lan. And thanks, everyone, for joining us and look forward to the next podcast. That's coming up real soon.
Thanks for having me. This episode of the patient empowerment program is brought to you by ultragenyx. ultragenyx is on a mission to transform the lives of people living with rare and ultra rare diseases. And as a proud partner of the n-lorem Foundation, with multiple approved therapies and a deep pipeline of potential treatments and development. ultragenyx is
going beyond everyday for the rare disease community. Learn more about how ultragenyx is leading the future of rare disease medicine@ultragenyx.com That's ULTRAGE n y x.com.
And n-lorem is a nonprofit committed to discovering and providing personalized experimental treatments for free for life to patients with genetic diseases that affect one to 30 patients worldwide, referred to by n-lorem and As nano rare, many of these patients progress and die without ever achieving a diagnosis, this is where n-lorem comes in. They do the impossible by providing hope, and for those
that they can help free lifetime treatment. For more information about n-lorem or today's episode, visit n-lorem dot org. Any questions can be sent into podcast at and n-lorem dot org, search and n-lorem on Twitter, Instagram, YouTube, LinkedIn and Facebook to connect with us. Please rate and review the podcast on Apple Spotify or wherever you listen. This truly helps us climb the charts and allows others to find the show. This podcast is hosted by Dr. Stan Crooke, our videographer is
John Magnusson of Mighty One productions. Our producers are John Magnuson and Kira Dineen of DNA today. Thank you for listening