Jerry Walter
Gerald Hladik, MD

Galafold (migalastat) was approved in August 2018 for the treatment of Fabry disease. Jerry Walter, a patient who has Fabry, and his nephrologist, Dr. Gerald Hladik, discuss how the drug works, and common concerns and questions patients have about the treatment. Dr. Hladik is the Doc J Thurston Distinguished Professor of Medicine and Chief of the UNC Division of Nephrology and Hypertension.

“Migalastat, or Galafold, is the first oral medication available for the treatment of Fabry’s disease in individuals with amenable mutations. It’s dosed every other day, which is much more convenient than the intravenous enzyme replacement therapy.”

– Dr. Gerald Hladik

Ron Falk: Hello, and welcome to the Chair’s Corner from the Department of Medicine at the University of North Carolina.

We are beginning a new series talking about novel therapies. We’ll get to hear from experts in several divisions in our department, who will tell us about treatments that have recently been approved by the Food and Drug Administration, otherwise known as the FDA. We’ll explain the drug’s effectiveness, side effects, and concerns and questions that people have raised.

Today we will discuss Galafold, a new treatment for Fabry disease. We recently discussed Fabry in our last episode, so if you haven’t checked that out, you may want to do so before you listen to this podcast. In it, we talked with a patient who has Fabry, Jerry Walter, and his kidney doctor, Dr. Gerald Hladik.

We welcome them both back today: Jerry Walter, who is a retired United States Army Colonel, has Fabry disease. He also is the founder and president of the National Fabry Disease Foundation.

We also welcome back Dr. Gerald Hladik, who is the Doc J. Thurston Distinguished Professor of Medicine and Chief of the Division of Nephrology and Hypertension at UNC.

Thank you both for talking with us again.

Walter: Thanks, Dr. Falk.

Hladik: Thank you.

How Galafold works

Falk: Dr. Hladik, please tell us a little bit about Galafold and when it was approved.

Hladik: On August 10 of 2018, the medical and Fabry community were excited to learn that the FDA finally approved Galafold, or migalastat, as it’s known, for the treatment of Fabry’s disease.

Falk: And how does that medicine work?

Hladik: Well, it’s a chaperone molecule. So, you know that a chaperone on a date is somebody who comes along as a guide and to observe, and in this case, the drug is the chaperone. With Fabry’s disease, there’s an abnormal enzyme, and that abnormal enzyme is chaperoned into the lysosome—that part of the cellular machinery where it needs to localize to be effective in breaking down fatty molecules.

Falk: In the last episode, we learned that Fabry’s disease is caused by a deficiency in an enzyme. Remind us what that enzyme is called?

Hladik: The enzyme is alpha-galactosidase A, and the gene that encodes this protein is called GLA. Remember that the level of this enzyme is quite low in Fabry patients, leading to impaired clearance of GL3 (globotriaosylceramide).

Falk: The chaperone helps alpha-galactosidase now get into the cell?

Hladik: It stabilizes the enzyme so that it can more readily enter into the “digestive system” of the cell, the lysosome, where can effectively break down GL3.

Falk: Even if you have a very small amount of the enzyme, whatever amount of enzyme you have now works better than it did by itself.

Hladik: Precisely.

Falk: This molecule then joins forces with the enzyme to get into the cell, to have the enzyme work.

Hladik: That’s right.

Falk: What patient will this drug be best used for?

Hladik: Well, unfortunately it turns out the drug is not effective in every patient with Fabry disease. About thirty to fifty percent of people with the disease are candidates for this drug. This is determined by the specific mutation a person has, or in the case of novel mutations, a bioassay can test whether or not the drug will be effective in clearing GL3.

Falk: Are there any side effects associated with this drug?

Hladik: There are. Now, one of the big breakthroughs of this medicine is it’s the first oral medication available for the treatment of Fabry’s disease. It’s dosed every other day, so that’s much more convenient than the classic treatment, which is treating by replacing the missing enzyme. Remember, that’s an infusion that patients have to receive every two weeks.

Enzyme replacement therapy

Falk: There is an enzyme replacement therapy. Can you tell us a little bit about that?

Hladik: Yes, well there are two products on the market. One is called Fabrazyme, the other is Replagal. Fabrazyme is available in the US. It’s an infusion, basically the enzyme – alpha-galactosidase A, that’s infused every two weeks.

Falk: And the advantages and disadvantages of that molecule, for that drug?

Hladik: Well, the advantage is you’re replacing what’s defective, and there’s good evidence showing that it’s quite effective, particularly when started early.

Falk: The downside is you have to have an intravenous infusion, every two weeks throughout your entire life.

Hladik: That’s right. How long does that infusion take, Jerry?

Walter: Mine takes about four hours at the moment. I’ve gotten down as quick as three hours and fifteen minutes. I started out in clinical trials in 2002, and you start with a five to six-hour infusion, then you progressively step up the rate. According to the label, you can get down to about a two-hour infusion, but everyone’s body doesn’t like it that fast.

Side effects and effectiveness of Galafold

Falk: The advantage of Galafold, is that it’s an oral medication. You take it by mouth. What are the side effects of Galafold?

Hladik: The most common one is headache. It can also cause nose and throat irritation. There are some reports of urinary tract infection and febrile reactions.

Falk: How effective is it for the individuals for whom it’s going to work?

Hladik: For patients who have what are called “amenable mutations,”—those are the patients for whom the drug is going to work—it appears to be very effective. There are now two trials showing equal efficacy with enzyme replacement therapy, at least in the short term.

It’s important to note that this drug was approved by the FDA’s accelerated approval pathway, so it’s emerged from clinical trials relatively early, which is great for patients, but we do need further confirmatory studies to document efficacy in the long term.

Falk: How do you as a physician know that this drug is doing what it’s supposed to do?

Hladik: Well, you can follow symptoms. For example, if a patient was having painful crises in the past and they went away with enzyme replacement therapy, and the symptoms return after changing to Galafold, that would be a concern.

Falk: What would be a reason that a patient would stop taking Galafold?

Hladik:The most obvious reason would be if they’re having intolerable side effects, such as headache. Next would be evidence of treatment failure, such as an acceleration in their symptoms, or signs of progressive organ injury.

Falk: Colonel Walter, could you tell us about all the therapies you have had for Fabry’s?

Walter: Well, for myself I’ve only had enzyme replacement therapy personally. I started on my birthday in 2002. So, I’ve been on enzyme replacement therapy every two weeks for almost sixteen years. For me, I think it’s saved my life. I think it’s kept my kidneys stable, I think it has improved my heart clinically—I don’t think, I know it has improved my heart clinically. Even though I still have heart issues, I didn’t start therapy until I was forty-eight years old. In my case I had been very fortunate.

I’ve lost several family members to Fabry disease before treatment was available, under the age of fifty, which is the statistical prediction. When I learned I had Fabry disease, I the average death of an untreated male was only forty-one. Later on, through dialysis and transplant, it became fifty. Now it’s cited as fifty-eight years old for average age of death—but not for untreated, because now we have so many people getting treated. Average age of death in general is fifty-eight.

Concerns and issues

Falk: When you heard that Galafold was approved by the FDA, what were your reactions?

Walter: Well, my reaction from a community standpoint is it’s very exciting and great news. Personally, I have a deletion mutation, which means I’m missing part of the gene and Galafold won’t work on people who have deletion or insertion genes, an extra part or a missing part, but it will work on a certain type of mutation, that of Dr. Hladik spoke of, it will only work for a certain percentage.

But for those people, it’s exciting because it’s easier to take. You take a capsule every other day, in lieu of biweekly IVs, which is tremendous. Travel time, and convenience of not having to leave work or leave school for an IV infusion are definitely huge benefits. We’ll just wait and see how effective it is for those taking it. It’s very promising.

Falk: Have you heard any concerns from any individuals in your foundation, or patients?

Walter: The biggest concern is that everyone can’t take it. We have this new product on the market and it’s only good for a certain percentage of our population. Everyone wishes they could take a shot at it and see if they would be better.

But in terms of the medication itself, I haven’t heard any concerns about serious reactions or problems. We’ll learn, even though it seems simpler, whether compliance taking the medication is an issue or not. There are some restrictions, like not eating two hours before or after, of taking it every other day, so we’ll see how all that turns out.

Falk: What suggestions do you have for someone with Fabry’s disease who is just starting enzyme replacement therapy, or other treatments, including Galafold?

Walter: Well, I think we’ve learned that it’s not a one-size-fits-all disease or one-size-fits-all treatment, so I think enzyme replacement therapy is going to work very well for many people. They may choose it over the easier one—or they may not have a choice if they can’t take it—but even some people have elected to continue taking enzyme replacement therapy. That may be because it’s so new they’re not ready to make that switch.

I think everyone just has to figure out what best works for them. We know there are people who can’t take enzyme replacement therapy, due to infusion-related reactions or other problems. We know already that there may be some people who can’t take Galafold for various reasons. We think it’s just something we’ll learn over time.

Falk: What other questions or issues do you think people would want us to talk about, about Galafold?

Walter: What we hear a lot, and the questions we hear are, “How can I get my mutation tested?” Or, “How do I take the first step in getting treatment?” Some people are having problems with insurance. Insurance, for one reason or another, doesn’t want to make the change to pay for Galafold. So, all of those issues have to be worked out, so that everyone gets what works best for them.

New drugs on the horizon

Falk: Are there new drugs that are on the horizon?

Walter: In addition to the two treatments that we now have, and three in Europe—a second enzyme replacement therapy, in other countries, we’ve got two substrate reduction therapies being worked on, where the drug would make your body produce less substrate, produce less GL3, and therefore you don’t have to get rid of as much.

Then, there’s three gene therapies in progress right now—three different solutions. We still have a lot to look forward to. The gene therapy solution, is in theory, a one-time deal. You take the medication and you’ve cured Fabry disease in that sense.

Falk: Wouldn’t that be wonderful?

Walter: It would.

Falk: Especially in children.

Walter: We have so much to look forward to. We’re fortunate as it is, to have treatments available. As I’ve said before, our prognosis is so much brighter.

Falk: Thank you, Jerry Walter and Jerry Hladik, for joining us today.

Walter: It’s really been a pleasure. I’m always anxious to further our cause and spread awareness of Fabry disease and its treatments.

Hladik: Thanks so much.

Falk: Thanks so much to our listeners for tuning in. Our next episode in this series will be on new diabetes treatments with Dr. John Buse.

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