Ask the Mito Doc – Special Edition: FDA Approval of Kygevvi for TK2d
All answers today are based on personal experience of the participants. As always, please consult your personal physician prior to taking any action.
Ask the Mito Doc – Special Edition: FDA Approval of Kygevvi for TK2d
Topic: FDA Approve Drug for TK2D – Learn about KYGEVVI and What to Expect
Clinician:
- Michio Hirano, MD, Columbia University, New York, NY
Q: What is the status on the EMA application and expected approval date?
A: Yes, the application for the EMA approval was submitted, I believe even before the FDA application. However, in the case of the FDA, there was a priority review status. So that’s why it was approved more quickly, perhaps because of this priority review status. I know the EMA is actively reviewing the submission package from UCB and it may be approved sometime in the next weeks or months, but I don’t know for sure at this point when that will happen.
Q: When approved, what are the next steps and timeline for the medicine to be available to patients (e.g. Commercialization authorization, coverage by insurance or social security confirmation, production, etc.)?
A: So actually this is also relevant in the United States because although the drug has been approved, it’s not available at the moment because there’s no commercial supply, which will be available in the early part of 2026, probably in the first three months. So right now there is a company sponsored compassionate use expanded access program that can make it available for patients who need it urgently. So they can apply and go to the UCB or KGV website and find that information and work with their local physician to try to expedite treatment. Otherwise, in patients who are more stable, they may choose to wait until the commercial therapy is available. But there is a path to obtaining the therapy both in the United States and in Europe and other parts of the world earlier through the compassionate use program.
Q: I am an adult who was diagnosed with TK2d with genetic testing. What does my health care provider need to do or who does he contact?
A: Well, I think one important point is that the drug label specifies that the onset has to be before age 12. So you have to talk to your clinician and the patients and families will have to try to think back and see when they first noted the onset of disease, especially the adult patients. And it may be very subtle at the beginning and it may be that the children or when they were children, they tripped more than their peers or maybe they were slower runners than all their peers or they were not athletic because they had mild weakness. And those can be indications of early onset. And I think in order to obtain the therapy, one has to have some evidence of onset before age 12. But I think in most cases, if you thinking back carefully about your histories or you’re asking your parents if they notice something early on, you can find that information and justify the use of this therapy.
Q: I understand this is approved for patients with symptoms appearing before age 12. How well does that have to be documented? Is it just the patients recollections or doctor visits?
A: One would hope so. But if you can find your pediatrician’s notes or that document it, that would even be stronger evidence. So if you get the more evidence you have, the more likely will be approved by the insurance companies.
Q: As we see nucleotides therapies are already approved for TK2, is there any horizon or pipeline regarding trials or expanded access or any research to go further TK2 to other genes on the MDMD (Mitochondrial DNA maintenance defects) group like POLG, TWINKLl, RRM2B, etc? Which of the abovementioned gene/s is closer to be included in this treatment after the needed adaptations, if any?
A: With a medicine like this, it would have to go through a clinical trial with all the other different variants in order for somebody to be able to get it. And it really is designed specifically for TK2D. There are other disorders of mitochondrial DNA maintenance that are due to lack of building blocks. The nucleotides pools for mitochondrial DNA, but they may require specific combinations of nucleotides different from the TK, thymidine and deoxycytidine that are used for TK2. So really we need to have more evidence of efficacy in other disorders before we could consider similar sorts of therapies for other disorders of mitochondrial DNA replication.
Q: Is there any chance to make an off-label use of Kygevvi treatment on other patients with other mutations?
A: Well, this label is specific for TK2D only. It’s not approved for any other mitochondrial disease at this time. And this therapy has gone through a long process, starting with mouse models to prove that it works specifically for this disease. And so it’s not available and should not be used for other diseases without similar sorts of clinical trials to prove whether they will be effective. So for now, this therapy is restricted only to Tk2d.
Q: I know you said it’s not approved for other types of mito but I’m still getting side messages about “off label use.” Will docs have the ability to do that?
A: I do not encourage that, but in theory it can be done. But I would urge people to use it for Tk2 only at this point because we really don’t have evidence from any proper clinical trials that it’s useful for any other condition. Insurance may not cover it is another issue. And that is an issue for our adult patients who have onset after age 12. It’s an issue. But I think if you really dig carefully to your medical histories, you as the patients and neurologists may be able to find evidence that it started before age 12. So it’s something that you need to discuss with your clinician to really explore this issue carefully.
Q: Does this help ptosis at all?
A: Slight improvement in ptosis, but not as consistently as some of the other motor functions.
Q: Will routine labs and EKGs still be ordered? Do you have any idea on the cost of it and/or would Medicaid cover this? How did it gets its name Kygevvi?
A: So treatment under a clinical trial is different from commercial clinical treatment. In a clinical trial, there are many more measurements that are performed both to assess both safety and efficacy. And once those safety issues are identified in the clinical trial, they can be reduced for commercial clinical use. So in the case of Kygevvi, the label recommends only monitoring of liver function tests once a year and does not specify that EKGs or other safety monitoring tests need to be done. So it’s much simpler for the commercial use to monitor patients.
Q: Have any patients also experienced daily nausea accompanying the condition?
A: The most common side effects from the new therapy for TK2D were diarrhea, abdominal (stomach) pain, vomiting, and increased liver enzymes. While nausea was not specifically named, vomiting and several gastrointestinal issues were discussed as side effects.
Q: What is the approximate cost of the approved medicine and 2nd gene therapy update?
A: No, I do not. And I suppose that will become apparent when the commercial product is available. And of course it’s likely to be expensive, but as all rare disease therapies are these days. But pro companies work with insurance companies and try to get prior authorizations alongside with the clinicians. And also sometimes in the case of ucb, I understand there’ll be perhaps some patient assistance programs as well to help offset some of the costs. So I think this is such an important therapy for the patients that we really need to work very hard to make sure that it’s affordable for the patients and they get the support they need to make it possible.
Q: Is there a scheduled pipeline to broaden the genes on primary myopathies that could benefit from this treatment, adapted to the specific genes?
A: So that’s a very interesting topic for me because we’ve used gene therapy in the mouse model and it works very well. And what works even better is the combination of gene therapy with the pharmacological therapy. So our mice normally live about, let’s say 14 days without any treatment. And if we give the therapy, the pharmacological therapy the mice live, let’s say, 30 days or 45 days, depending on the dose. But when we give the gene therapy in combination with the pharmacological therapy, we’ve had a mouse live 450 days. So in theory, our evidence in the mouse model indicates that the gene therapy in combination with the pharmacological therapy is synergistic. They work better than either therapy alone. So we’re very excited about the possibility of gene therapy, but it will take years to, to get that through clinical trials and approved if we can do that. But for now, I think we’re very happy to have the KVY therapy available and hopefully eventually we’ll get to G therapy, but we’re not there yet.
Q: Will studies continue on the positive effects it has on patients and will studies continue on these patients to look at them over time and see what kind of changes you might see as outside of the clinical trial?
A: Well, I think that in many cases companies are obliged to do some additional studies afterwards to address issues that aren’t necessarily assessed during the clinical trial. For example, most clinical trials require patients to use some sort of birth control, so we don’t know the effects of the therapies on pregnancy. So often there’ll be some monitoring of patients to see if the drug has any effects on pregnancy. Then that’s usually a formal requirement by the FDA after a drug is approved. But also I think academic physicians will continue to monitor patients and be very interested and will probably report on the longer term outcomes of patients. We have the unusual situation where the patients have been in the phase two trial for more than six years, so that’s a very long follow up. But we don’t know what’s going to happen 10, 20 years on this therapy or longer. So I think that there’ll be continued interest and people will continue to monitor patients and report if there’s something unusual that’s happening with them.
Q: What is the possibility of having the test available to diagnose it worldwide?
A: TK2D. Well, everywhere in the world. I don’t think it’s quite available everywhere around the world, but in most countries it is available in various ways, including gene panels for biopsies or whole exome sequencing. And if you think, if your clinician thinks it’s TK2 and wants to test just that single gene, that’s theoretically possible, there are some pre-genetic testing programs that also can make this available to people.
Q: For patients that travel out of state to see their mito doc, is there a benefit to finding a local clinician in their state for Medicaid approval purposes?
A: Oh, yes, absolutely. Because, yes, many, many times the Medicaid plans which are administered at the state level will only approve prescriptions that are written by a local physician within the state. And also, frankly, it’s a lot easier for the patients and their families to work with a local physician rather than travel across state lines. And it’s particularly difficult for patients on ventilators to do so. We encourage patients to work with local physicians who have the capacity to learn about this new disease if they’re not familiar with it or work with local mitochondrial disease experts and get the therapy written as a prescription locally and with close monitoring. And I think that would be best for the patients and their families.