Ultragenyx’s Post

Transcript

So. A lot of titles, but what it doesn't say is that you are really a pioneer. In the field of rear disease drugs going back before ultra genics. To Biomarin, maybe just very quickly give the audience a quick. A quick summary of that experience. Yeah, sure. Happy to I, I started my academic career as an MD, PhD, medical genesis at UCLA. And I got into a project to develop an enzyme 3rd for a rare disease. And I thought I'd finish that project handed off to a company and go on to the next project to, to, to hit the themes I know we want to hit. So that means that in this disease, the, the whole thing that was causing all sorts of problems for these kids was that there was some enzyme that's missing. You could make right they should get better MPs one patients are missing 1 enzyme and we can make it for them. We had cloned the genes that occurred in early 1990s. If we made the enzyme, could we give it back? And we we showed nano models you could do that. And I thought I didn't know much about the industry. I assumed, yeah, we'll just make the enzymes, show it works, hand it off to a company. And what I discovered is no one cared. And the the tragic reality is I figured you we've spent 30 years in age science to figure out what's wrong. We now know what to do. And we're going to write papers and leave them on the shelf and we're not going to do anything with it when the kids need it. There's a fundamental injustice in that. It's like, why are we doing all this if we're not going to do something? So that was the problem. While I was near giving up by a family, the Dant family found me. They had their son Ryan had MPs one and then they. They said, look, you're our only hope. Our sons, you know, five years old, this treatment, this enzyme is the only thing could save him. Can you save him? And that's when it turned from. You know, abstract basic science into life of this kid. And then the question is, are you gonna walk away from this kid right now? Walk away from a project? Are you walking from this kid? And honestly, I didn't have the courage to say I'm gonna walk away from this because my academic career didn't allow it. Side to side up, we're just gonna have to try to do this, and I have no idea what I'm doing and how to get there, but that's what we started. So what's the difference then between being a CEO and being an academic? Well, you know, as a, as a professor, you have sort of a, a narrow set of what you have to do and controls. And it's a, it's a small box you're in when and. There's also limits to what you can achieve when your CEO. Is now a wide open and you have so many more responsibilities, so more people and. Stakeholders than you do. They're immediate patients, of course, but investors, board members. Employees, his career and lives depend on you, so the stress level is much greater and you're trying to save kids at the same time. And so it is definitely and also it's high profile. Yeah. And when something doesn't work in the lab before you know, you just did another experiment when it doesn't work in a trial, you have a press release and and and Caterpillar public. So you the stock price the but so you created Ultragenyx with a specific thought around that issue that we just described around you have kids with diseases where you think having an enzyme replacement. Do you describe the thesis for people here? I'd spent eleven years at Fireman developing drugs and learning about the biotech industry and how to operate, and I left the company and. Was working on a foundation write a book. And I thought I was done, but then only families came to me and said we have these ultra rare diseases, we're trying to develop treatments, can you help us? And I realized that the work wasn't done. So we decided to form a company. And the thesis around Ultragenyx was, can we form a company that will focus on ultra rare genetic diseases where the science is very clear, the biology is just ready to be translated. There's people who are, like me, out in academic clubs that had the answer that no one cared about. And can we pick those things up, put in the clinic and develop them? More aggressively, more rapidly and get them through and that was the thesis I seed funded myself. So in 2010, I was me and my secretary and a couple $1,000,000. And so usually people or a lot of people argue that they don't like. Biomarkers as a way of approving drugs because they think that they want to see clinical data, they want to see clinical evidence. You actually think about this in rare diseases being the opposite, that in some diseases the biomarker is the better evidence. No, I definitely agree that in many ways, diseases where you know exactly the genetic cause and there's a material that builds up that's toxic. That toxic material builds up is a biomarker, but it's also the cause of disease. And if the treatment is replacing or fixing the underlying defect. That those are highly predictive situations, but we treat them like any other disease and we demand so much of them. And so in Ultragenyx, one of the goals was to push forth on using biomarkers for rapid approval. We started that with MPs 7. The map sevi product for MPs seven that disease effects 200 in the world and build sly the scientist that did the work had been It's been sitting foul for 20 years, but I wanted to make that a test case. OK. We're going to treat a disease with only 200 people, 20 people in the US affected. But can we use a biomarker, get it approved, demonstrate it works and do the work And we have still difficulty with FDA at that time, right. And in Europe was accepted, we did get the product developed in three years, got it approved. But in the US they were looking at the clinical data, they wouldn't accept the buyer marker, so. That case didn't get U.S. Open the door, but what is the difference? In this situation, the biomarker is not a random thing, it's not a blood test. That doesn't mean anything. It is the toxic material. It is the cause of disease. And I think we need to think about designing treatments to affect the cause of disease rather than think about treatments affecting the outcome of disease. The cause is what you really want to fix. The outcome of disease are clinical things that happen many years later and our combination effect of the disease plus a number of other variables and the way I try to describe this man. Is like in a car example. Hmm. It's like you have the brakes broken on your car. Well, if your brakes are broken in your car, you will have crashes. But how you crash or how often may depend on who your driver. If you're driving in Manhattan or if you're driving out in the Iowa corn farm, right? The risk of crash depends on a lot of other factors, but if you have brakes are not working well, you're going to crash. But you can measure the brakes accurately. But measuring crashes is variable. It's inconsistent. It's it's hard. Medical example I think was helpful was the example of HIV. Yeah. And HIV, you measure the viral load, that's the disease cause if you get rid of the disease cause, the outcomes will improve. If you try to measure the outcomes like an HIV, if you talk about opportunistic infection, hospitalization and death. It takes years for those things to develop and they're highly variable with different secondary outcomes. You never figure out the way. So what I want to be clear about is the biomarker based approval for HIV. Is not just speeding the approval of drug a little bit, That's what acceler approval means to people, is a transformation of treatment for the underlying cause, meaning drugs that really get it the virus so that we end up developing a treatment that actually fundamental. If we develop only clinical endpoint driven, we focus on outcomes. You would develop immune stimulants which would make their immune system a little better for 12 weeks and maybe help them with an infection, but they're going to die anyways. Does this sound familiar? Are a lot of the drugs? Developing helping your symptoms late and chronic and never fixing them. This is the paradigm of depending on clinical outcomes. If we start depending looking at disease caused biomarkers, we're now gonna develop drugs that actually fix underlying problems and we'll we'll fix the clinical outcomes in in a much more profound way just like a disapproval work. Do you think that you're barriers in doing that in creating? A paradigm that is something like an HIV for at least some rare diseases where you really understand what's wrong, it's obviously not all of them, right? Right. Do you think the barriers are more regulatory or science based? I think it's primarily, it's primarily regulatory and it's a little bit political too, because there's been so much written negatively about Excel. Your approval is being drugs that are experimental and not really proven, but the truth is. That biomarker based drugs can be more potent, more specific, more effective. Then drugs are just affect downstream disease issues. So the regulatory issue has been that the level of of evidence required to allow qualified biomarker is so great that for many ultra rare diseases you can never meet the standard. And therefore for the last decade we haven't had accelerated approvals for neurologic genetic diseases even though the biochemistry is very clear. The science is sound. It's not about science. But in the last couple of years, through a number of efforts, we were able to pull together. A coalition of companies and academics around one particular disease area, MPs brain disease and held a Reagan Udall conference, which is the FDA's Regulatory Science Foundation and showed the world without compilation of data that heparin sulfate this material that accumulates in in San Filippo and other MPs to brain diseases. Can predict outcome, Mm-hmm. And we're able to shift FDA's view of that marker. And now because of that, five programs for MPs brain disease that we're going to be cancelled or lost potentially are now getting accelerated and surviving. And so that's a step forward for the science. And we're very pleased that the FDA's change in view is put us in position now of treating not just MPs brain diseases, but so many other rare diseases that the new technology we have. Gene therapy, gene editing and other drugs can finally address. But if we don't, if we didn't adopt that, we wouldn't be able to solve those problems. But I think now this first step I'm hoping will lead to more steps. And a resurgence in the use of gene therapy, editing other strategies to tackle some of these diseases that affect only a few 1000. Where we know what's happening now, you might think that's only a few 1000 people. What does it matter? Well it feels too rare to matter, but I guarantee you if it's your family, doesn't feel so rare. And there's a whole lot of them. A lot of them. Sitting out there waiting. And they're waiting for us to get out of our own way. Cut through red tape, believe the science and start pushing forward and getting drugs approved that need to be approved. And I think the FDA has made a great push forward. Real excited about the possibilities of changing things the next few years. All right, we're going to have to end there. But. Thank you very much and thank you for sharing. Good. Thanks for having me. By the way, yeah.