Helping Regulators and Drug Developers Understand the Challenges of Living with Fabry Disease

Fabry disease is a progressive disorder that affects organs throughout the body including the heart, kidneys, and nervous system. People with the condition may suffer for years before obtaining a diagnosis. Jack Johnson, who co-founded the Fabry Support and Information Group, traced Fabry disease back more than five generations in his family. We spoke to Johnson about his own experience with the condition, his journey into advocacy, and a recent externally-led Patient-Focused Drug Development meeting to help regulators and drug developers understand the need for new therapies to address the challenges of living with the disease.

Daniel Levine: Jack, thanks for joining us.

Jack Johnson: Yes, thanks for having me on the episode.

Daniel Levine: We’re going to talk about Fabry disease, the challenges of living with the condition, and your efforts to change misconceptions about Fabry with regulators and others. Let’s start with Fabry itself. For listeners not familiar with it, what is it?

Jack Johnson: Fabry is a rare lysosomal storage disease that really results when the body is not able to make enough of, or any at all of a certain enzyme to break down a lipid substance. In our case this enzyme is α-galactosidase A and it breaks down a lipid material Gb3 that builds up in the cells throughout the body and causes damage. And this condition affects both males and females.

Daniel Levine: How does the condition manifest itself and progress?

Jack Johnson: Well, the classic form of the disease, the more severe form usually starts in childhood in school age children, and oftentimes its burning in the hands and feet. There can also be problems with reduced sweating, heat intolerance, even cold intolerance. Lots of kids miss school because of GI problems, diarrhea, stomach pain, and there are other symptoms, a lot of other symptoms that go along with it and can develop over time. These symptoms can interfere with school, sports, social activities, and work. It can lead to more severe organ involvement such as chronic kidney disease and lead to kidney failure requiring dialysis or transplant. Also, heart problems are a big issue and there are conduction arrhythmia issues with the heart and oftentimes cardiac enlargement, and these can, of course, lead to heart attacks. There’s also TIAs or mini strokes that can happen and full blown strokes. So there are other symptoms that go along, but oftentimes this can lead to an average for a shorter lifespan with women of about 15 years and men about 20 years.

Daniel Levine: You were diagnosed with the condition many years ago. How were you diagnosed with it and how is it generally diagnosed today?

Jack Johnson: Yeah, so my family’s story is my grandfather was diagnosed by a small town country doctor in a small rural farm town in Missouri, and that also allowed others in the family that were suffering to get a diagnosis. Fabry is rare and there is a lot of misdiagnosis associated with Fabry disease. My grandfather, he really got his diagnosis because he was going into kidney failure and the doctor just realized it didn’t fit other things. My mother saw the signs in me when I was four and I got my official diagnosis finally when I was seven. For getting other people today, oftentimes optometrists or dermatologists can spot the few outward signs, but there are two in the skin and in the eyes that can be spotted also. Nephrologists oftentimes will diagnose Fabry if they do a kidney biopsy on someone that’s having chronic kidney disease problems. And then when that first person in the family is diagnosed, it leads to others and some newborn screening is happening as well.

Daniel Levine: There are available therapies for Fabry disease, but it’s not a part of newborn screening in all states. What is the state of newborn screening and in any sense why some states don’t include it or what it will take to get them to include it if it’s not already part of their screen?

Jack Johnson: Sure. So, newborn screening is done on a state by state basis. Different states have their own ideas on what they would like to screen and it varies quite a bit. That’s kind of the status. Oftentimes when newborn screening for Fabry and other LSDs has been instituted, particularly with Fabry, they find boys but not the girls because girls can have normal levels of what they’re looking for. Oregon, Missouri, Illinois, Tennessee, Maryland, and New Jersey are currently screening. We have submitted to the states of Georgia and Utah requesting that they begin screening Fabry disease. And one thing that really helps to get states to screen for conditions is to get that condition listed on the recommended uniform screening panel or RUSP, which is a federal list of recommended conditions. And another thing that can help is states have started instituting rules that if a condition ends up on RUSP, they will automatically then start screening for it, and with Fabry disease, there’s about 10 states where that could help improve screening because of those rules. Some states have not included Fabry due to funding issues and resources to do proper follow up, but also Fabry is usually not treated in the newborn and is treated later in life. So that’s another issue with Fabry and some of the other lysosomal storage disorders.

Daniel Levine: You had gone through a recounting of your own family history with Fabry. It speaks to, I think, the importance of knowing a family history of health around genetic diseases. How did you come to know the history? Did it require a lot of work on your part? Was this something that was just shared with the family?

Jack Johnson: Yeah, it really was shared in the family. I’d heard the family stories of the individuals that really suffered with this condition and it was, of course, very mysterious in the beginning, but like I’d said, a doctor figured it out with my grandfather. And I had an uncle that did extensive genealogy work on our family so there were a lot of resources there. Also, my mother, who knew the stories, knew all the relatives and everything, and understood who was related to who. So, with all of that, she helped me to work to put together a family tree that followed, not a specific family name, but rather a condition, back through. And then we also found distant relatives that when we did the family tree, there was a connection, generations back is where the connection was made, and those family relatives that suffered from Fabry as well were related to us, we knew. So then, by looking back on the tree, we could verify how far back it actually went and we traced it back five generations.

Daniel Levine: People can talk about diseases from a biologic perspective. They can talk about, the symptoms and the manifestations, but what’s it actually like to live with Fabry?

Jack Johnson: Yeah, Fabry is a very difficult condition. It has a high impact on quality of life, like I discussed. You know, the pain can be a real problem. Temperature intolerances, hearing losses and dizziness or tinnitus, ringing in the ears, can be a problem. You can have dizzy spells, lots of patients suffer depression; fatigue can be a real issue. And there are other symptoms. Also, you never know really when you may get hit with a spell of severe pain, or pain in the burning in the hands and feet can really be distressing and cause a lot of impact. One of the things that might help people relate is they’ve probably heard about long Covid symptoms on media and just the general day to day things that many Fabry patients experience can be very similar to what I’ve heard long Covid is like. There are more severe symptoms such as a pain crisis that can hit and these can be very debilitating for hours. The stomach pain can really get severe for people. You can have fevers for no known reason. And lots of times if you have one of these fevers, it brings on a pain crisis or if you get a fever from an infection or catching the flu or something like that, that will start up a pain crisis. So, patients have trouble with throwing up shortly after eating and, of course, they can go into kidney failure, cardiac disease, and strokes. So, it has a large impact on people’s quality of life.

Daniel Levine: Enzyme replacement therapy for Fabry disease has been available for more than 20 years. How effective is this and is there a need for new or better treatments?

Jack Johnson: Well, ERT or enzyme replacement therapy certainly helps. It helps to stabilize many people for a period of time and it can help with pain and a number of the different symptoms, some of the GI symptoms and so forth. Unfortunately, it doesn’t help everybody the same. And one of the things that studies have shown is that it can slow disease progression but not necessarily stop it. There can be a point of no return essentially on kidney involvement so you may go into kidney failure, but it could take several more years or longer for that to happen. So, there are areas where it really helps, some areas where it doesn’t. Some patients don’t really notice a difference in symptoms after going on to ERT—that can be discouraging. There’s still continuing unmet medical need because of these symptoms and there can be infusion reactions. Most people can be worked through those, but not everybody. And some people have to discontinue ERT, they just can’t tolerate it. Also, these infusions can be rather burdensome. It can take anywhere from a couple hours to eight, possibly even 10 hours sometimes to receive an infusion. And you’re doing this every two weeks so it can make vacations and travel schedules and things like that rather difficult. And then because not everybody sees real benefit right away or what they were hoping for, they may start skipping infusions. And sometimes when patients go off of treatment and then start treatment back up again, they can have infusion reactions all over. So, that can be very challenging. And one of the things that people really want from treatment is just to feel like they’re normal, and unfortunately that doesn’t happen with a large enough percentage of the community.

Daniel Levine: When a patient finds they can’t tolerate the infusions or their schedule is overwhelmed and they put off getting one, or even if they discontinue because they feel they’re not seeing benefit, what’s the long term health consequence of that?

Jack Johnson: Well, one of the big problems is that disease progression starts back in. Some patients may have an increase in pain actually whenever they start. Some don’t, but some do, and that can lead to going off a treatment. And when you’re skipping these treatments infusion reactions, it’s always said it can be worse if they start to go back on. And the main thing is disease progression occurs and organ involvement can really catch up with people sometimes unexpectedly as a result.

Daniel Levine: You founded the Fabry Support and Information Group. How did you become involved in patient advocacy and what led you to create the FSIG?

Jack Johnson: Yeah, so I was participating in the research program and the doctor there who was studying Fabry disease, he really is the one that pushed me to do this. It wasn’t something I ever saw coming or ever thought about. I was doing computer work and he really pushed, saying that there was no community or no organization for Fabry. So, finally I decided that maybe we could try and get something going, but we weren’t given any idea of what or how to do it or anything. So, we thought, well, maybe we could gather information and do a newsletter and get that going. And then I was able to put together a website because my computer background and my family really helped me out. And we got that website going and that’s when people started really finding us. We started out with less than 20 people we knew. It just really grew from there.

Daniel Levine: In September you spoke with the FDA at an externally led focused drug development meeting. What’s the purpose of these meetings and why do they matter?

Jack Johnson: Yeah, the patient focused drug development meetings are a really important means for organizations to get with the FDA and actually have patients speak directly with members from the FDA. And they get to hear the needs and the wants from the patient community directly from a number of different people. So, this is a very important pathway and can be very powerful in getting a community’s needs communicated to the FDA and also to drug companies that listen in on these things and can hear about different aspects of the disease that are not being addressed appropriately and can hopefully develop drugs and treatments that will do a better job of targeting those aspects. That’s a really important aspect as well as the FDA working with the pharmaceutical companies to help design trial protocols that are going to address these needs and hopefully reach trial endpoints that will then lead to drug approvals and improved therapies for patients.

Daniel Levine: In the world of rare diseases, this is one that’s generally better known. There are two approved therapies for it in a longstanding and established patient community. Nevertheless, when you spoke to the FDA, you talked about common misconceptions about Fabry disease. What are some of the common misconceptions?

Jack Johnson: Right, so yes, Fabry is well known within the rare disease community, but that’s a fairly small community. You get out of there and most doctors have never heard of Fabry or maybe remember it was on a test question they had to take going through school, and that’s all they knew. So, there’s still old information that doctors were taught that females with Fabry disease don’t really suffer because it’s an x-linked condition, but that’s just totally wrong. We know today that most women with Fabry disease will suffer from the disease, will have disease impact, and some of those can be just as severe as what’s seen with any male. And also, you know, patients know more than their doctors usually about the disease so we need to get more information out there.

Daniel Levine: What’s the consequence of having these misconceptions?

Jack Johnson: Well, patients go into a doctor’s office, they’ve never heard of Fabry Disease, then they have to teach the doctor, they have to explain what Fabry disease is and they feel that it should be the other way around. But that’s an issue with many of the rare diseases also that many doctors just don’t get how I much of an impact the disease can have on one’s quality of life because that’s what patients live with most of the time: they don’t feel their kidneys getting worse; they don’t necessarily feel their heart getting worse; you don’t feel that a stroke may be coming on, but you feel all of these other quality of life issues, the pain, the GI problems, the fatigue, dizziness, hearing loss, all of these types of things—and they hit you. That’s what you live with day to day. And then finally the organ involvement becomes a big issue, but much later in life normally. So, those are constant battles for the community.

Daniel Levine: And what were the takeaways from the meeting?

Jack Johnson: Well, the takeaways were that the community’s voice is really being heard, the FDA is listening. There’s still significant unmet medical need that needs to be addressed with these continuing symptoms. Even though treatment does help, it doesn’t eliminate these. And the patient community really wants more convenient treatment options in the future. And the fact that females suffer with the disease and have significant impact is very important. And since there’s so much misunderstanding of the disease and it’s not well known, there’s a lot of misdiagnosis and even underdiagnosis. Lots of patients go many, many years and never get a correct diagnosis. So, those were all significant issues that that came from the meeting.

Daniel Levine: And what are you doing to leverage the outcomes from the meeting and ensure that others see it and act on it?

Jack Johnson: Well, one of the things that will come from the meeting that hasn’t been released yet is a voice of the patient summary report and sharing that with the patient community and with the physician and research community and the pharmaceutical industry will help spread the message of the Fabry disease [community] and the needs that they have. Also, on the female side of things, we’re going to be having our first Fabry Women’s Summit in November this year. And we’re looking forward to that and helping spread information within the female patient community to address the special needs that they have. And we will be continuing our advocacy work, of course, with the medical professionals and pharmaceutical industry and the general public whenever we can. And so the outcomes from this meeting will be a big part of the message that we share.

Daniel Levine: Jack Johnson, founder and executive of the Fabry Support and Information Group. Jack, thanks so much for your time today.

Jack Johnson: Thank you very much. It’s been a pleasure.

This transcript has been edited for clarity and readability.