Ask the Mito Doc March 2023
Clinical Trial Readiness and Emerging Therapies for Primary Mitochondrial Disease
Clinician: Dr. Mary Kay Koenig MD, University of Texas McGovern Medical School, Houston, TX
Watch the video: https://youtu.be/QLQuNM53xPk
Q: Would you advise on where the research stands in gene therapy treatments for nuclear DNA Mitochondrial disease (eg. Tk2d)? (if current trials have been promising and timeline when it may be a possible treatment.) 2) Are there clinical trials planned for treatments for TK2d?
A: Mary Kay Koenig, MD: Right now, Tk2 deficiency is the one that is under investigation with clinical trials. There’s also a clinical trial, I believe, happening out of Canada looking at some of the other DNA maintenance disorders. So off the top of my head I could list 5 or so. But again, I think most people who have a mitochondrial DNA maintenance disorder know that they have one. If you don’t, you could just look up your defect, and it should tell you, or you can ask your doctor if that’s what it is. But they’re really the disorders that affect the ability of the mitochondrial DNA to copy itself or to maintain its stability over time.
Q: Is LHON Plus with proven mitochondrial myopathy included in any of these trials, like it was in the previous Stealth MMPOWER trial?
A: Mary Kay Koenig, MD: Clinical trials are very specifically designed for a single purpose, and that is to test a therapy. And one of the things that’s so important about doing a clinical trial is making sure that you can answer the question at the end of the day. And so a clinical trial is not designed to be inclusive of everybody, so they will very frequently limit who’s allowed in, and who’s not. And so they have what’s called eligibility criteria, and exclusionary criteria. You can’t always predict what you will be eligible for, or what you won’t be eligible for, based on your diagnosis or your symptoms. You really just have to look at each individual trial to see whether or not you would be eligible for that, and almost all trials will have a coordinator or a study contact that you can reach out to. So step one is to identify a trial that you think you might be interested in and step 2 is then just to reach out to them and say am I eligible? And usually they’re going to ask you some questions, and they’re going to answer those questions, so you can’t ever answer in general about types of trials. It’s always specific for a clinical trial.
Q: Is there still petitions to sign to have funding for research and for insurance to pay for supplements?
A: Nicole Wilson UMDF: Yes – you can click here https://www.umdf.org/advocacy-central/ to learn more about asking your representative to join the caucus. You’ll also get updated emails about more opportunities as well.
Q: Our 19-year old-son was newly diagnosed with Mitochondrial Disease and all we know so far is that he has Respiratory Chain Deficiency. He can only qualify for clinical trials on a compassionate use basis. How do we know what clinical trials are available? We are in Pittsburgh.
A: Nicole Wilson UMDF: You can head to: Clinical Trial Finder – https://www.umdf.org/clinical-trials to use our clinical trial finder to see what trials you would be able to participate in. Hope to see you at the Pittsburgh Walk in June!
Q: Do these clinical trials require that everyone have a Mitochondria diagnosis? What about those who haven’t gotten a final diagnosis?
A: Mary Kay Koenig, MD: So most of them do require you to have a genetic answer, and in saying that, we know 30, 40, 50% of people with mitochondrial disease have a mitochondrial disorder do not have your genetic answer. I’m sad in a lot of situations that we cannot include people in clinical trials who don’t, and I work really hard with a lot of our families to try and continue to search for that genetic answer, so that we can include them in trials.
In the United States in particular, when you’re trying to prove that a drug works, there’s a lot of reasons to do that. One is because, as a patient, you don’t want to be taking a drug that doesn’t work. As a doctor, I don’t want to be prescribing a drug that doesn’t work. But probably the most important reason is, the FDA won’t approve a drug that we can’t prove to them beyond a reasonable doubt that it works. And in order to do that, there are very specific and rigid requirements that they have, and one of them is making sure that you have a very narrow and well-defined patient population that generally involves people of a certain age, people with certain symptoms, people with a certain diagnosis. They’re very strict on making sure that the patient population is as uniform as it can be.
For a lot of clinical trials, people all have to have the same genetic change, and one of the challenges in mitochondrial disease is that it’s so hard to find enough people with the same genetic change to do a trial that it would be exclusionary in a lot of situations. You couldn’t do it. And so the way that people have gotten around that is by saying, okay, what if we just take people with a genetic change and we stick with just that population. And so that’s the main reason, because of the rigor that’s required.
One of the things that as physicians we’ve recognized in the last 20 years is that a lot of people who have a clinical diagnosis of mitochondrial disease, as we are identifying their genetic change, we realize that it is not in a gene. It affects the electron transport chain or primary mitochondrial function, and they end up having a secondary mitochondrial functional defect, and those patients might not be appropriate to put in a trial. And so we don’t want to mix the population in the clinical trial without having that solid, confirmatory genetic piece. And so those are the main reasons that it is usually required to have that molecular or genetic diagnosis.
Q: Is mitochondria replacement therapy happening yet?
A: Mary Kay Koenig, MD: Augmentation therapy is under clinical investigation, and it is not commercially available anywhere. Mitochondrial replacement therapy is a treatment that’s being used for prenatal therapy for people who are trying to get pregnant, but it is not available in the United States. It is available in some other countries.
Q: I am often informed by our hospital that mitochondrial disease patients are not eligible for liver transplants. Is that not the case?
A: Mary Kay Koenig, MD: My colleague wrote a paper a few years ago now about the safety and efficacy of liver, of organ transplantation in patients with mitochondrial disease. So, having a mitochondrial disease in and of itself doesn’t, shouldn’t disqualify anyone from any sort of organ transplantation. We frequently have people come to our hospital for second opinions, because they have been told that they’re not eligible for some form of transplantation, and sometimes they are. There are times when they’re not because they’re not eligible for some other reason, but solely having a mitochondrial disorder should not disqualify you from any form of transplantation.
Q: Can you obtain USP or prescription grade NAD+, CoQ10 and Idebenone? If not, where can we obtain such supplements?
A: Mary Kay Koenig, MD: These are supplements that you can get over the counter at a variety of different vitamin stores. I would suggest talking to your doctor about whether or not there’s a particular formulation that might work for you better and talking about whether or not there’s side effects of certain ones, and whether or not they could interact with your medicines before you start any sort of supplement, because we tend to think of supplements as being benign but they’re still chemicals that we’re putting in our body, and so you do want to make sure you’re talking to your doctor about it.
Q: What are the mito DNA disorders that are being treated with the nucleotides?
A: Mary Kay Koenig, MD: Right now, Tk2 deficiency is the one that is under investigation with clinical trials. There’s also a clinical trial, I believe, happening out of Canada looking at some of the other DNA maintenance disorders. So off the top of my head I could list 5 or so. But again, I think most people who have a mitochondrial DNA maintenance disorder know that they have one. If you don’t, you could just look up your defect, and it should tell you, or you can ask your doctor if that’s what it is. But they’re really the the disorders that affect the ability of the mitochondrial DNA to copy itself or to maintain its stability over time.
Q: What does expanded access mean?
A: These are drugs that are approved by the FDA for use in the United States. So when a drug is approved for use by the FDA, they give you what’s called a label, and it tells you exactly who you can prescribe that drug for. So you can prescribe it to people with high blood pressure who are over 18 years of age. And as a doctor, if I have a patient who’s 16, who has high blood pressure, I am allowed to write a prescription for that patient, even though they’re not 18. Because that’s an FDA approved drug, and I believe that that patient would benefit from it, and so I can write it. That’s called off-label, and I’m allowed to do that.
What you can’t do is prescribe a drug to someone that has never been FDA approved for any indication. These drugs are called investigational products, clinical trials or under clinical investigation, but they’ve never been approved for any indication by the FDA, they are only investigational drugs and we are not allowed to prescribe those to patients in any way unless they are on a clinical trial or it expanded access program. So what we can do as a physician is ask the people who own the drug, which is the company and the FDA, if we are allowed to offer that drug to a patient who is not eligible for the clinical trial, because we believe that the patient would benefit from the therapy, and that’s called expanded access, or sometimes it’s called compassionate use.
So we say to the FDA, I have this patient that I think would benefit from this therapy, and there’s enough evidence that the drug is safe and that it might work and the patient is not eligible for the clinical trial, so there’s no way they could get access to it unless I put them on an expanded access program. Then we have to get the company to agree to give us the drug for free. They can’t charge for it and the FDA has to agree to allow us to use the drug in that situation. That’s an expanded access program, and it is an ungodly amount of paperwork but it has been a true benefit for a lot of patients. So I say the paperwork piece, because your GP down the street is not going to do this, this is going to be a specialist who is familiar with clinical trials, and who is familiar with genetic diseases and mitochondrial diseases, because it’s not something that just any physician can do.