RARE Daily

Forging a New Path for Medicine

April 27, 2023

Amy Dockser Marcus, in her new book We the Scientists, tells the story of a group of parents of children diagnosed with the rare and fatal genetic lysosomal storage disorder Niemann-Pick disease type C. When they were confronted with the fact that no treatment existed or would likely be developed in time to save the lives of their kids, they began collaborating with themselves, researchers, and physicians to accelerate the path to a treatment. We spoke Marcus about the lessons learned from the experience of the Niemann-Pick disease type C community, how these parents took an active role in the drug development process as citizen scientists, and how their efforts reflect a broader change in the way biomedical research is conducted.


Daniel Levine: Amy, thanks for joining us.

Amy Marcus: I’m happy to be here.

Daniel Levine: Oh, first, congratulations on the publication of We the Scientists.

Amy Marcus: Thank you.

Daniel Levine: We’re going to talk about your new book, what happened in the Neiman-Pick disease type C community, and how rare disease patients and their families are changing the way medical research is being conducted and by becoming a citizen scientist and taking an active role in research and drug development. You began reporting on the story in the course of your work at the Wall Street Journal. How did that come about?

Amy Marcus: I think the origin story really also has a personal root. My mom was diagnosed with a rare cancer, gallbladder cancer, and I tried to help her. I did a lot of research. I went to her doctor appointments, and I suddenly found myself immersed in this world of rare diseases. There wasn’t a lot of work being done in her type of cancer. It didn’t have a lot of patients who were diagnosed every year. And I started experiencing some of the frustrations that family members and patients often face when they realize that there’s just not a lot going on with drug development in an effort to try to save their loved ones. My mother passed away, unfortunately, but I continued to immerse myself in this world of rare diseases and patient advocacy and decided to focus my research and writing in that area. I took some time off from the Wall Street Journal. I got a grant and traveled around the country trying to meet individuals who were trying to change the way rare disease drug development was done. And during the course of that research, I got introduced to some parents, parents whose children had a very rare disease called Neiman-Pick type C. And I had been told that they were trying to form a kind of innovative collaboration that would accelerate drug development for this particular disease. I was intrigued. I got introduced to them and I started following their story and continued to do so even after I went back to the Wall Street Journal and started up my regular reporting again.

Daniel Levine: I think many listeners will be familiar with Addi and Cassi Hempel and their parents, Chris and Hugh. Hempel is a board member of Global Genes, which is the publisher of this podcast. How did they come to the world of rare disease?

Amy Marcus: I mean, they came the way a lot of people come, which is their children were diagnosed with a rare disease and they wanted to do whatever they could to help save their children’s lives and started doing research in the disease, meeting people, connecting with people. I mean, it’s a root that many parents and many families and many patient advocates end up following you. You see that there’s not a lot going on in the disease that is affecting the people you love most and you jump in.

Daniel Levine: At the time their children were diagnosed, what was known about Neiman-Pick type C? Tthis is a rare lysosomal storage disorder that’s progressive and fatal. What was the drug development landscape like for potential treatments?

Amy Marcus: Neiman-Pick type C is part of this larger umbrella group of lysosomal storage disorders. And, you know, Tay-Sachs disease is disease is one. Those are more familiar names maybe than Neiman-Pick type C, but they’re all part of this larger group. And Neiman-Pick type C is a cholesterol metabolism disorder. There was a lot of interest in basic science and research because the disease affected cholesterol, which is clearly something that a lot of people have interest in. But the drug development landscape wasn’t that robust. There was a trial that was underway using a drug that had already been approved for use in Gaucher disease called Zavesca. But there, it was moving relatively slowly and there wasn’t a lot going on. But there had been some recent papers that gave some thought that there might be some promising drugs in the works. And I think when Chris and Hugh got the diagnosis for their children, they were interested in trying to explore some of those options and trying to work in a collaboration that might accelerate drug development in some of the more promising compounds.

Daniel Levine: The Hempels are not trained scientists. How did they respond to what they saw?

Amy Marcus: They joined other people who weren’t trained scientists. There was a group of parents that have long been interested in trying to advance the study of Neiman-Pick type C. And they found other like-minded people who said to themselves, “What can we do? How can we work together?” And at the time there were also a group of scientists who were coming at it from the other direction. They were saying, we’ve been trying to develop drugs and it hasn’t really been all that successful. Is there a different way of doing this? Is there a way where we can really partner with parents and work together to prioritize drugs, to think about what should be done to move things more quickly? I mean, it was kind of this evolution in thinking of all the different partners and a way of approaching this in a novel manner. Let’s be partners instead of like doctors or scientists doing experiments on people, could they work together with people, with parents, with advocates, with others and approach it in a more collaborative way.

Daniel Levine: Many listeners may be engaged in a world where they’ve become accustomed to rare disease patients and their families being engaged in funding research, helping forge a research agenda, and even doing work themselves. Can you remind listeners what the landscape was like a decade ago? How did scientists view patients’ role in research?

Amy Marcus: You know, I think one of the biggest transformations was that the internet started to really get popular and allow patients to connect with each other. And I think it also allowed scientists to connect with patients in novel ways too. I mean, a decade ago you were starting to see chat groups. You were starting to see social media emerging. Patients who were far flung geographically were able to more rapidly see one another, and meet up with one another online. They were able to forge collaborations. There were rare disease conferences, and parents started showing up at them. Patients started showing up at them. They started meeting and greeting with scientists. They started thinking, we have some thoughts, we have some ideas, and we’d like to work together. And the internet also helped accelerate this revolution in another way because it allowed groups and parents to disseminate information they were finding to one another and build on what other groups were doing. So, you just had a lot more synergy. You had a lot easier way of finding things over time. But when the NPC group—the parents that worked on this collaboration—started meeting up with one another, some of these things that are now commonly done were more in their infancy.

Daniel Levine: There’s a tension between the slow and deliberate pace of science and the urgency felt by parents with a child that has a progressive and deadly disease. How much tension did this cause between the patients and scientists and the patients themselves who may have differed on best approaches?

Amy Marcus: I think that there’s always tension in any kind of collaborative effort that involves drug development and science and trying to save lives. I think one of the things that all of the parents seemed to agree on when I was there during their discussions was that they of course wanted to save the lives of their children, but they also wanted to gather information about their children that would be useful to all other children as well. They wanted to save everyone’s lives as well as the lives of their children. Not everyone agrees on the kinds of risks they’re willing to take. Some people feel more comfortable being enrolled in a clinical trial. Other people feel more comfortable trying to access drugs that might be more widely available and then working with doctors on a more individual basis. So, there’s always different points of view. Some of the children progressed more quickly than others. Some of the children were slower in the progression, some people just had a different risk-benefit profile. I think in any kind of collaborative effort, different people are going to disagree on how things should get done, but I think where there was general agreement was how can we produce scientific knowledge that’s going to save our children’s lives or extend our children’s lives, and how can we make sure that that scientific knowledge is widely available to others and can also be built upon for the future?

Daniel Levine: There are a few key figures who emerged from the book. Chris Austin, the former director of the National Center for Advancing Translational Sciences and Mark Patterson, a scientist working on NPC research. How did they understand the challenges of researching and developing therapies for conditions like NPC and the need for scientists to not only collaborate with each other, but with patients?

Amy Marcus: So, I think what’s unique about Mark and Chris and some of the other doctors and scientists that were involved in this project is that in addition to doing research, they also had or were treating patients. So, they brought both a clinical side as well as a research side to thinking about the problems. I think that many of the scientists who got involved recognized that there was a need to try to do something different. You know, basic research is so essential, it helps advance understanding of diseases and disease process, but it it’s not designed to immediately come up with drugs that can be translated and brought into a clinical setting right away. And I think there was a recognition that the traditional way of looking at things just wasn’t going to yield drugs that would save the current generation of children who were diagnosed. And there was a recognition that they wanted to do something different. I think that they brought some of their own expertise and previous experiences with failed efforts to get drugs to patients. And that fueled their desire to work with patients on a more partnership basis. Nobody really had a roadmap on how to do it. You know, everyone arrived at Chris Austin’s lab at the NIH thinking we want to try something different, but we’re not exactly sure what it’s going to look like. It really was not only a scientific experiment, but really a social experiment. And that’s what I focused on in the book too, like there’s so much science involved, but what was really novel was the social experiment that they were trying to do.

Daniel Levine: One of the potential treatments to emerge during this time was cyclodextrin, a type of sugar that was used in drug formulations. How did it emerge as a potential treatment?

Amy Marcus:

Scientists were experimenting with a promising drug and cyclodextrin had been used as part of those experiments. This was done in mice and they started to recognize that mice that were receiving cyclodextrin were living just as long as the mice that were getting the drug that they were initially interested in. You know, it was a serendipitous finding. And then as more scientists joined forces and did experiments, it emerged that cyclodextrin might be a promising compound that could be tried in humans as well as in mice. And that’s what a number of scientists and families started to focus on. How can we advance this specific drug into trials?

Daniel Levine: The Hempels were not part of a clinical trial, but did go through the FDA and did gather data on treating Addi and Cassi. Can you explain what they did to treat their children?

Amy Marcus: Yeah. The FDA allows people who have life-threatening diseases and don’t have any available therapies to come forth with a doctor’s assistance and apply for compassionate use permission. It’s done pretty routinely nowadays. And Chris and Hugh and a number of other parents eventually also decided that the effort to create a formal trial was very important, but wasn’t going to be quick enough to help their children. And so, because cyclodextrin was available and because doctors were willing to work with them and help them, they went to the FDA and they sought permission to set up an individual clinical trial where they would gather data on their children with the use of cyclodextrin. And the FDA signed off on this and allowed them to move forward.

Daniel Levine: There seemed to be a surprising amount of sophistication about the importance of their data, not only their own family, but from other families pursuing compassionate use. Are there lessons here about patient data people should note?

Amy Marcus: You know, one of the things that has happened very often in developing rare disease drugs is that it’s very hard to get a very clear answer on whether a drug works or it doesn’t work. Formal clinical trials may end up having positive results and the FDA may even say that’s great that there’s positive results, but we’re still not totally certain that this drug is effective and you may need to do another trial. It’s really hard in rare disease drug development to get drug approval. And so compassionate use trials offer families, scientists, doctors, and sometimes drug companies and the FDA another source of data that can buttress conclusions that are reached in a formal clinical trial or can allow for the analysis of hypotheses that might not get to a clinical trial. It’s just another data stream. And I think that there was really early recognition by a number of the families, including the Hempels and some of the scientists, that there is value in compassionate use data. And I think that’s one of the important lessons that emerge from this collaboration, that when you’re trying to advance drugs for rare diseases, in particular, where the number of patients is so small and where it’s so hard to get a trial up and running, and where you’re not sure that the first trial is going to work, that every scrap of data possible should be collected. You never know where a promising idea is going to come from. You never know what’s going to help buttress whatever conclusion emerges from the formal trial. And they really pushed hard on that idea. Compassionate use data is important, and they made headway with FDA in getting recognition from FDA that the data could potentially be useful, maybe not to approve the drug solely with that data, but at a minimum to allow them to weigh whether the drug was safe and effective, along with the other package of information.

Daniel Levine: The book is perhaps a bit polite at times in touching on conflicts between patients and each other, between patients and scientists, and patients and drug developers. I know there have been some legal battles let alone many heated discussions. Are there any lessons learned today on how to better navigate conflicts or put into place mechanisms for resolving disagreements early on as more patient groups take a central role in research and development?

Amy Marcus: I think today there’s greater recognition among researchers, scientists, and parents and advocates that it’s important to set up the terms of engagement at the beginning of any collaborative effort. In the book, I do cite how there are ethicists and scientists and researchers who realize that the current regulatory and ethical framework really has evolved over decades of work, based on the concept that scientists and doctors are going to come up with the ideas, that patients are going to be the research subjects, that they are going to be the consumers of scientific information and not the producers of scientific knowledge. And I think that what’s emerged in recent years is an understanding that patients themselves and advocates and families also have ideas for experiments to run—that they are going to be the producers of scientific knowledge, not only the beneficiaries or the consumers of scientific knowledge–that they’re going to experiment on themselves, that they’re going to devise ideas, collaborate with one another, set up models and all of that. This notion that the patients and the advocates are going to drive science and initiate science requires new thinking, potentially requires new ways of regulating things, or ensuring that there’s ethical protections, requires new thinking about how to negotiate when people disagree, whether it’s patients and advocates among themselves or scientists with each other. And I think that’s such a fascinating and important lesson that the book focuses on and that other groups are focusing on as well, even today. One of the things I mentioned in the book is that some of these same notions of like, how can we do this better? How can we be better partners? How can we adjudicate things when we disagree for whatever reason are merged? also occurred during the Covid 19 pandemic, when you had long Covid patients who also wanted to study themselves and be the initiators of experiments. This is something that we’re going to keep seeing over and over again. And there is growing calls for more attention to be focused on how can we create contracts guidelines, frameworks to make collaboration more equitable, more effective, and address any disagreements that may inevitably arise when people are trying to do work together.

Daniel Levine: And what’s happened to cyclodextrin and have treatment options emerge for NPC?

Amy Marcus: So, there are a number of efforts to advance compounds. Cyclodextrin has not yet been approved by the FDA. The trial that was run did not result in data that allowed the FDA to approve it. The compound has been licensed by a different drug company now, and there are efforts to continue to study it and to potentially bring it to the FDA again in the future. There are other trials that are underway, but as of now in the United States, there is not yet an FDA-approved drug for NPC disease. The parents and the scientists haven’t given up hope that eventually there will be, and you know, they continue to work at this.

Daniel Levine: You recently earned a master’s degree in bioethics. I’m wondering how your studies may have changed the way you thought about the issues around patients’ changing role in biomedical research.

Amy Marcus: One of the reasons why I decided to go back to school is because I was spending so much time writing about groups like the NPC parents and the collaborative that they ended up forming with the scientists and other families and advocates who were trying to change the way science was done. One of the things I realized is yes, they seem to be trying to do something that’s different, and I wanted to better understand, well, what is the typical way that things are done? What are the traditional rules and regulations? I wanted to immerse myself in understanding where the potential pressure points are for the existing system. I had to understand how that worked before I could truly understand the revolutionary impact that parents and advocates were having by saying, we don’t want to follow the traditional system. We don’t think it fits with what we’re trying to do. It was really exciting to think about all the experiments that were being driven by families and advocates and to set them against the larger, more traditional research landscape. It made me have even greater appreciation for what the families were doing and what advocates continue to do today. The system that’s in place has emerged over decades and decades. It’s firmly entrenched and there is movement but it requires a lot of effort to go against a traditional system. So, my studies enabled me to think again on the need and the necessity for creating frameworks and guidelines that will allow partnerships that are patient-centric to flourish. And I think that’s what’s needed to really move things forward to the next step.

Daniel Levine: And how would you say the rare disease research and drug development landscape has changed and what lessons do you think we can take away from the NPC story?

Amy Marcus: I think that the NPC story, as well as other stories that are chronicled in the book and that are emerging in recent years are what is driving this notion that patient-centered drug development, patient-centered collaborations, are truly essential. I don’t think that we’re there yet, but I think that it’s in the landscape, it’s in people’s minds. Parents still have to bear such a burden of advancing science. I was talking about the book at one of the bookstores that I had been invited to give a discussion about the book. And one mom who is involved in a different disease stood up and said, it’s so hard on parents to have to do this while we’re also raising our children and taking care of children that really need our attention and have life-threatening diseases. And many times, there’s other children and they’re working. The burden on these families is just huge and it just seems unfair that they have to do so much. And yet what they have done is really revolutionary in that you can see change happening. There are parent and family driven groups that are starting to get FDA drug approvals after years of effort. They are sharing their findings with other parent groups. They are forming coalitions with each other to try to get best practices out there. They’re posting things online so that people don’t have to reinvent the wheel so that if they wake up with a devastating diagnosis for their children one day, they don’t have to start from nothing. They can build on what’s been done. And I think that there’s more to be done. And I think that the NIH and the FDA and funders should think of parents and families as scientists and try to help fund them and train them and make them even better scientists than they are even now. And I think if all of these things happen, if how to help patients now and do good science as equal partners, if those notions take hold in the way they have, I think you’re going to see more and more families getting involved with this and really pushing forth and changing the drug development landscape as well as the rare disease landscape.

Daniel Levine: The book is We the Scientist. Amy Docker Marcus, Pulitzer prize-winning reporter for the Wall Street Journal. Amy, thanks so much for your time today.

Amy Marcus: Thank you so much.

This transcript has been edited for clarity and readability.


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