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Medical oncologist, geriatrician, and physician scientist GJ van Londen and Chief of Genetic and Genomic Medicine at the University of Pittsburgh School of Medicine Gerald Vockley discuss the article “FDA delays could end vital treatment for rare disease patients.” GJ and Gerald explore the complex regulatory impasse where the U.S. Food and Drug Administration denied standard approval for elamipretide despite a positive advisory committee vote, creating a financial crisis that threatens to cut off supply for everyone. GJ shares his personal journey from treating cancer to living with primary mitochondrial myopathy, while the conversation emphasizes the critical need for the agency to use the flexibility granted by the Orphan Drug Act to save a treatment that has already proven its worth. Join us to understand the life-or-death stakes hidden behind administrative decisions.

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Transcript

Kevin Pho: Hi. Welcome to the show. Subscribe at KevinMD.com/podcast. Today, we welcome medical oncologist, geriatrician, and physician-scientist G.J. van Londen, and chief of genetic and genomic medicine at the University of Pittsburgh School of Medicine, Gerald Vockley.

Today’s KevinMD article is “FDA delays could end vital treatment for rare disease patients.” Josie and Jerry, welcome to the show.

Gerald Vockley: Nice to be here. Thank you.

Kevin Pho: Before we jump into the article, I am just going to ask each of you just to share a brief story and journey to where you are today. Josie, why don’t you go first?

G.J. van Londen: Thank you for having us, Dr. Pho. I am a medically retired medical oncologist because I am now living with a primary mitochondrial myopathy. As such, I have invited Dr. Vockley to join us to help me out if and when I should tire. Dr. Vockley is my own doctor at Children’s Hospital of Pittsburgh. He diagnosed me, and for the first time in history—correct me if I am wrong, Dr. Vockley—but he was able to offer me the first experimental treatment for my disease, primary mitochondrial myopathy. Dr. Vockley, I am going to give it to you.

Gerald Vockley: All right. Josie is correct. I was able to start her on an experimental drug. There is a clinical trial going on for primary mitochondrial myopathies, one of which she has (it is a group of disorders, not a single disease). It has been approved for one of those disorders, but not the one that she has. And so I was able to work with the company to help get her on that drug because she was not really in a condition to participate in the clinical trial.

I can tell you that doing things like that—having therapies available for rare diseases—is just a culmination of everything, all of the forces in modern medicine and science that have come together now closer to the end of my career. I am doing things that I could only have dreamed of when I got started. I have been doing this for 40-plus years, and we have moved from just figuring out what the diseases were to trying to understand the effects on cells and bodies, and now actually developing and using drugs to treat more and more of them.

Kevin Pho: The KevinMD article that we are talking about today is titled “FDA delays could end vital treatment for rare disease patients.” Josie, for those who didn’t get a chance to read that article yet, tell us what it is about.

G.J. van Londen: Basically, the article is about an experimental medication that Dr. Vockley started me on called elamipretide, which I am getting through expanded access for my indication, primary mitochondrial myopathy. But it was in the process of being approved for Barth syndrome. The idea was that if it would have been denied for Barth syndrome, that the stealth company who makes elamipretide will go under and everybody who is on expanded access for different indications would lose it. Which is why there was a huge advocacy effort for everybody concerned about this to try to raise awareness about the fact that Barth syndrome is an ultra-rare disease, and therefore elamipretide for Barth syndrome was awarded the Orphan Drug Act status.

The Orphan Drug Act status—probably Dr. Vockley can explain it better than I do, but there are many parts of that—but one part of that is that the FDA can review data of effectiveness beyond randomized control trials. This medication has been found to be helping in a very meaningful way for many individuals. Now I am going to give it to Dr. Vockley. So that is why I wrote the article: to explain the concept of the Orphan Drug Act, which I wanted to raise awareness for. Thank you.

Kevin Pho: Before I turn it on to Dr. Vockley, let me ask you, Josie: Tell me the effect that medicine has on your daily life. How does that medicine affect you?

G.J. van Londen: It is a daily injection in my belly subcutaneously. At that point, when I started taking it, I was unable to turn around in bed. I was heavily dependent on my husband for activities of daily living. But since I started taking this injection—and everybody responds differently; my response was a little slow, and my response is not as drastic as Dr. Vockley has seen it in other people—but I have now been able to regain my independence for most of my activities of daily living, so I can stay home alone and my husband can go to work. I was able to read a little bit again, and I was able to craft a little bit again to get some quality of life back which I hadn’t realized I had lost until I regained it. So for me personally, it has had a very drastic effect. But Dr. Vockley can probably share his experience with other patients.

Kevin Pho: Jerry, tell me about elamipretide and some of the obstacles that you are facing in terms of getting it approved for rare diseases like the one Josie has.

Gerald Vockley: It probably would help to just back up a second and do an overview of what is going on here and then come back to Josie’s case because it is illustrative of the field in general.

Rare diseases individually are rare. There are 10,000 of them, and there may be a handful of patients. There may be a thousand patients. But in general, these are things that most physicians aren’t going to see, and most pharmaceutical companies aren’t going to want to try to take on developing a drug for because the market is small; there is no financial incentive. So there is federal legislation that helps get those kinds of drugs to market. Although they are individually rare, together they are common. Three to 5 percent of babies born in this country have one of these diseases. And they might not show up right away; sometimes they are actually adult-onset conditions. But they are responsible for 40 percent of infant mortality. They are responsible for half of pediatric hospitalizations in tertiary care medical centers. So they are a big impact on the health system.

The process for getting one of these drugs approved is a little different than something for a common indication, you know, heart disease or diabetes or something like that. Part of that is due to something called the Orphan Products Act that has been passed to give the FDA flexibility in deciding how a drug can move forward. The ultimate goal is to provide something that is shown to be safe and effective. The definition of that is often in question though.

There is a standard that has been a longstanding one in the drug development field called the double-blind placebo-controlled trial. Neither you nor I know whether you are getting the real drug or essentially a sugar pill. And nobody knows that until the end of the trial when you unblind it and you do all your statistics and say: “Okay, patients who got the drug did a little better than patients who didn’t.” The problem is when you have a small population, when you are doing clinical trials with 10 or 20 or 30 patients, that is not a workable approach. So the FDA has the ability to modify that. All the law says is that a drug needs to be documented to be safe and effective. It doesn’t say that it has to have a particular approach. And there are approaches for proving efficacy in clinical trials for rare diseases that don’t require that standard double-blind placebo control or three or four-year kind of study. It doesn’t mean that FDA is lowering standards; they are using alternative statistical methods that have proven to be valid for rare disease.

Unfortunately, this comes down from the top. When you get into the trenches, the folks who are implementing that at the FDA sometimes seem to forget that. They come back and they say: “We haven’t done this. You haven’t done that. We don’t like your control.” They keep falling back into old habits. And that is a problem in general.

For elamipretide specifically, the first review of the drug by an expert panel that was assembled by the FDA to assess the clinical trial voted overwhelmingly to recommend it, saying that they had proven efficacy. For whatever reason, the FDA then elected not to approve it and said: “Sorry, you have to repeat it.” Well, there were maybe 40 patients in that trial. There were all of the patients in the United States very near anyway. To repeat it was essentially impossible. So this was a death sentence for those patients. “You can’t have your drug.”

Fortunately, the company that makes this drug was persistent and very savvy and continued to work with the FDA on it. Ultimately, the FDA did another deep dive on the data and said: “Okay, we are going to approve it for Barth syndrome.” Now remember, Josie doesn’t have Barth syndrome. She has primary mitochondrial myopathy. They have looked at the mitochondrial myopathy data and said: “Well, it looks like it is working for a bunch of these patients, but it didn’t work for these patients, so you have to do the whole study over again.”

Josie has one of the diseases where it worked, but at this point, we are still on compassionate use, and the company has been very good about continuing to make that available to patients like Josie. So either they have the bandwidth—and what I mean is the money—to redo that study or they don’t. We will find out as the days go on. But it is an example of the FDA either not following their own rules and regulations or changing them over the course of a study. Of course, if you change the rules, you can never win the game. I am hoping that with more and more examples like this where it is clear that the process backfired and they fixed it, we will get to the point where it doesn’t backfire in the first place.

Kevin Pho: Jerry, what does it mean that for patients like Josie, for the medicine to be used for compassionate use, it is approved for one disease which Josie doesn’t have, and the company can still produce it because it is approved for that one disease? So what does it mean for patients like Josie where it continues to benefit her but it is not specifically approved for her disease?

Gerald Vockley: Well, it means that her insurance company won’t pay for it. If I were to go to them and say, “I want to prescribe this,” one of the benefits of having an approved drug is as a physician, you can prescribe it for anything. It doesn’t have to be the approved indication. But the insurance companies don’t have to pay for it if it is not approved for that condition. For most of these rare disease drugs, they are relatively expensive. It is a lot of investment, and it ends up only getting into a very small number of patients. So the companies have to charge enough money to get their investment back; otherwise, there are no investors and there are no more future drugs.

So that is the difference with a compassionate use protocol. What you can do is go to a company and say: “I am convinced your drug will work in this patient.” And you write them a protocol that explains why, and then they either say: “Great, we agree with you, we are going to provide you that drug at no cost and let you treat your patient.” So that is what is going on here.

Kevin Pho: And quickly, Jerry, in terms of cost, when you say it is expensive, just give us a ballpark range of the dollars we are talking about.

Gerald Vockley: So we don’t know what elamipretide is going to cost in Barth syndrome. Most of these rare disease drugs hit six figures and some of them hit seven figures on a yearly basis.

Kevin Pho: Josie, so where are we with elamipretide? If the FDA doesn’t approve it for your particular condition and it has to be continued to be given to you on a compassionate use basis, tell us what that potentially could mean to you and the impact it has on your life.

G.J. van Londen: Well, I continue to be hopeful that the company will continue to provide me elamipretide through expanded access, which they have promised they will. If they stop doing that for some reason, then my medicine will be put on hold. Dr. Vockley and I are concerned that my decline will go faster. I had to put it on hold for a week a little while ago for reasons that are not relevant, but I already noticed a decline in that one week. Meaning the medicine by personal experience only works when you take it.

Now there are other medications in the pipeline, but not necessarily for my particular condition. I don’t know how in detail you want to go, but maybe Dr. Vockley can make a comment on that. Overall, the field is having a huge moment right now.

Kevin Pho: Josie, let me follow up. Are you in contact with other rare disease patients as it relates to that specific drug? Tell me what kind of advocacy efforts that you are pursuing in order to hopefully get the FDA to perhaps change its mind.

G.J. van Londen: Yes. For Barth syndrome, I was part of a big advocacy effort through the Barth Syndrome Foundation. At the moment, I am part of different advocacy efforts that are merging together by the UMDF (that is the United Mitochondrial Disease Foundation, which is one of the relative patient advocacy groups that deals with these diseases) as well as MitoAction and the POLG Foundation. There are some smaller ones, but yes, there is a big effort—research-wise, advocacy-wise, patient support-wise—that these organizations do. They are collaborating more and more to synergize, which I find very heartening to see.

I wanted to tell you four things that are very important to me. Yes, these are rare diseases, but somebody has to fit in these small percentages. So don’t automatically write it off. Next take-home message is you are never too old to have a rare slash genetic disease. Because it is a spectrum. Everybody gets diagnosed at a different age with different symptoms. They progress differently. And so that makes it hard to do research on it, but not impossible.

And my last take-home message is: There is hope. There is a huge momentum in the scientific community, which I find very encouraging to see. I want to thank everybody in my private life, but also in my advocacy family and my provider family. Dr. Vockley has sort of become my extended family member, and he knows that it is really good that you do this, Dr. Pho. You raise awareness for this. Thank you for letting us talk.

Kevin Pho: Jerry, I am going to give you the last word. Just why don’t you leave us with some take-home messages that you want to share with the audience.

Gerald Vockley: Hard to top that. I will also point out or finish with the thought that I had earlier, which is that rare diseases are individually rare but together are common. If something is going on with you that you or your care providers don’t understand, think about them and get yourself referred to someone who can investigate for one of these rare diseases.

The technology for identification of these diseases and the development of new drugs for them has increased exponentially. It is a thousand-fold higher than it was 10 years ago. This is really a moment that the field has to continue to push for better therapies and earlier identification of patients who have these diseases. Hopefully, what that means is earlier identification, earlier therapy, better life, longer life.

Kevin Pho: Well, thank you both for sharing your stories, time, and insight. Thanks again for coming on the show.

Gerald Vockley: My pleasure. Thanks for having us.