Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk, Episode 76 I'm your co host, Dr. Kane. I'm Dr. Patel, Speaker 1 00:36 and I'm Dr. Schuman, and I'm excited today to bring in a guest lecture with us. Dr. Shannon Furbish. Dr. Furbish is one of our PGY two psychiatric pharmacy residents at Captain James A Lovell Federal healthcare center. So she's gonna do is come in and talk to us a little bit about a topic that's near and dear to her heart, something that I believe you had done on a grand rounds presentation. Unknown Speaker 00:54 Yeah, that's right. Thanks for Dr. Sean Kane 00:55 having me here. So what is the title of today's presentation? Speaker 2 00:59 So today's presentation is the new move treating tardive dyskinesia. Dr. Sean Kane 01:03 So this is actually really interesting, because I don't see a lot of tardive dyskinesia, but I remember a lot about it from pharmacy school when we learned about neuroleptic so it sounds like there's some new movement in this area in terms of new drugs. Speaker 2 01:16 Yeah, that's right. Just last year, we got FDA approval for two medications, valbenazine and deutetrabenazine for tardive dyskinesia, and we'll be talking Speaker 1 01:25 about those today, right? So I guess, just to lead off, Dr. Furber, so can you tell, for the audience and maybe less familiar with those medications? So what exactly is tardive dyskinesia? Speaker 2 01:33 Sure. So tardive dyskinesia is a movement disorder that's typically induced from neuroleptics, so things like antipsychotics, which block dopamine, it's under the umbrella of EPs, so extrapyramidal symptoms, so it's one of the four EPS symptoms. So this Speaker 1 01:52 was something that originally was noticed back in the 1950s individuals were given these, we call them neuroleptics the time. Now we call them antipsychotics, or medications that block dopamine. Well, they noted it specifically was movements around the cheeks and the mouth. You see some grimacing or some puckering, or certain symptoms which were there and wasn't something just due to the medication. Because even when the dose was decreased or the medication was discontinued, these symptoms still occurred. So it wasn't quite the same thing as an adverse drug reaction, and it looked different than what we know about other disease states, like Parkinson's disease. Speaker 3 02:23 So you said that this kind of falls under the umbrella of extrapyramidal symptoms. What is an extrapyramidal symptom? Speaker 2 02:31 Sure, so it's a term that refers to the movement disorders that are brought on by medications. So one is Parkinsonism, tremor, bradykinesia, maybe postural abnormalities, and then dystonia, which is prolonged tonic contractions. So both of these are typically due to dopamine depletion. And then there's akathisia, which is typically described as inner restlessness. This is related likely to excess noradrenergic activity, and then there's tardive dyskinesia. Dr. Sean Kane 03:06 And just for the listeners who maybe don't work in the area of psych or neuro something like akathisia, we see with other medications outside of the arena that have some dopamine properties to them but maybe aren't used as neuroleptic so Reglan or metoclopramide, for example. We use that very commonly in my setting, in the ICU for nausea, and especially in younger patients, we can see some of this akathisia, where they feel like they just can't stop moving their legs, or they have this restlessness. Speaker 1 03:34 Dr. Kane, that's a great point. Is that's one of the things I want to pet peeve of mine with this is a lot of times we lump everything into something called extrapyramidal symptoms, and one of the things that's made it difficult to treat is the fact that they're so heterogeneous in terms of the way they look. So akathisia looks much different than a dyskinesia or Parkinsonism, and a lot of that is because of some of the mechanism of how they occur. And so when we look at rates of one versus the other, we have to be very clear about looking at each one separately. So that being said, Dr. Furber, so you know, we have some idea about, you know, Parkinsonism and what depleting a doping. So what's going on with tardive dyskinesia — how does it happen? Speaker 2 04:11 Yeah, so that's one thing that we haven't fully explained in the in the literature. So one hypothesis is that there's chronic dopamine blockade, which results in a response on the postsynaptic dopamine neuron. So we see an up regulation of those dopamine receptors, and then those dopamine receptors, because they're deprived of the dopamine, become over sensitive to dopamine when it actually binds. So that overreaction is what's, what we think is causing the movement disorder, Dr. Sean Kane 04:46 and that would partially explain why, once the drug is gone, that you're still seeing this tardive dyskinesia effect then, because it's not a drug effect per se, it's more up regulation of these receptors. It's more of a chronic, long term thing that happens. Unknown Speaker 04:59 Yeah. Exactly, exactly I Speaker 1 05:01 know when I try to talk it with students. For both of you, I know you're familiar with beta blockers, and so we know that what happens when you stop a beta blocker abruptly, tachycardia, right? So you kind of that rebound tachycardia. Now, with a beta blocker, it usually takes it usually reverts back after a period of time. Am I correct? Yeah. And so that's one of the issues here, though, is it doesn't quite that time period to revert back doesn't seem to be as quick as it would be with something Dr. Sean Kane 05:21 with a beta blocker. So in terms of the chronology of it, is this something where you'll have tardive dyskinesia for a couple days, a couple weeks, a couple months? Or could it be long term where it never goes away? Speaker 2 05:32 Yeah, typically, I mean, it's pretty late onset. So tardive means late, so late onset, and then it usually will last maybe forever. Sometimes it is irreversible. Speaker 3 05:44 And so what kind of symptoms or what kind of clinical signs and presentations are we looking for when we say somebody has TD or tardive dyskinesia? Speaker 2 05:53 Yeah, so we can see several different things. So oral buccal movements, so lip smacking, darting movement of the tongue, maybe some jaw movement, abnormal, like rapid movements of any area of the body. So it could be the arms, the legs, the trunk, rapid eye blinking. Sometimes we can see respiratory symptoms. So difficulty breathing, difficulty swallowing, difficulty speaking. So those can be pretty significant. Speaker 3 06:24 These are multifaceted symptoms and presentations that patients present with. And so as we talked about earlier, it's not as easy to diagnose, and I agree with that. Dr. Sean Kane 06:32 Now, is this something that a patient has any control over, where can they consciously make an effort to not move? Or is this completely involuntary, where they will continue doing it. There's no way to kind of blunt any of that movement that they're experiencing. Speaker 2 06:46 Yeah, it's completely involuntary. So they don't have any control over these movements. Speaker 1 06:51 And every once in a while, somebody that, if they do become aware, will attempt to try to control it. So actually, one of the things we talk about, there's a rating scale that can be used, and one of the things you do is you try to apply distractors, because sometimes an individual will try to minimize and we want to be aware of what's going on, but a lot of individuals really have no insight into it, and so it may not even bother them. So that's an important thing as we look at talking about treatment options, is, does it bother the individual? Obviously, as a healthcare provider, I would never, for the first time I saw it in in a in a patient setting, and seeing somebody just just lean back and yawn and freeze that way and kind of this unusual movement. And so seeing my first kind of EPS episode, patient had no insight into it at all. So as providers, you may have a more negative approach to it than then the patient does well. Dr. Sean Kane 07:33 It sounds like it can be fairly severe, especially if it is chronic, to the sense of a lifelong side effect that you experience, I would hope that this isn't very common. But do you have any sense of what the incidence rate is? Speaker 2 07:44 Yeah, so it's it's pretty rare. So two to 5% annually, although those who are on chronic antipsychotics, the incidence is a little bit higher, so 15 to 30% maybe. Speaker 3 07:57 And I believe then there are some individual factors that also take place in designing who would be more prone to having TD versus the other. So I'm assuming people with older age, because of the regulation on these neurotransmitters, is one of the individual factor. Speaker 2 08:12 Yeah, generally age over 55 is a risk factor. There's several risk factors that they've seen in the literature. So female gender tends to be a risk factor. African American ethnicity patients who are taking first generation antipsychotics, and this is related to how tightly these medications bind to the dopamine receptor. Yeah. Speaker 1 08:36 So the first notice with those original again, we think about things like like Thorazine, or man's like Haldol. There's old school medications, and especially something like Haldol, it hits that dopamine receptor and bind to it really strongly, and then the more it binds, and the tighter it binds, the more that up regulation. And so it's less likely with some of these second generation and newer rates. So for those kind of practicing really more in this this newer in the last 1015, years, may see very little of those order medications outside of like a PRN, but so something like Seroquel (quetiapine), Clozapine (Clozaril), or Abilify (aripiprazole) are generally much less likely to cause it, although you may still see it there may be partially as a remnant from when they were on one of these older medications in the past. And that's another thing to look at better too. Is because we see this transitioning to a newer medication as well. So if somebody was on an old medicine that caused an up regulation now they switched to a newer medication, you may actually see a worsening of symptoms initially, not that the new medication is causing it, but again, they're essentially going into that rebound because the dopamine is not as tightly bound. And so again, why it becomes so difficult to treat is because it's going to take time and process to get those receptors back in a homeostasis, Dr. Sean Kane 09:45 and I would assume, based on the proposed mechanism, that bigger doses for longer periods of time are going to increase your risk. In addition any other agents that you take that may also block dopamine. We mentioned metoclopramide (Reglan) earlier, but even prochlorperazine (Compazine) for nausea, if you're kind of doing these other things, or having high doses of your typical antipsychotic or your first generation, it seems like that would be a risk factor as well. Speaker 3 10:08 Yeah, absolutely. And so we talked about some of the presentations and clinical symptoms. But how easy is that to diagnose somebody with tardive dyskinesia? Speaker 2 10:18 So typically, we use the AIMS test to kind of give us a clue as to whether or not they may have tardive dyskinesia, gives us an idea of the severity of the symptoms. So what is the AIMS? Exactly sure. So it's the Abnormal Involuntary Movement Scale. So it was first developed for research purposes, but it was so easy to use that now we just use it all the time in clinical practice. So it's a five point rating scale looks at seven different body areas and kind of rates how significant the movement is. So rating from zero meaning none to four meaning severe. So you essentially have a and with Speaker 1 10:56 those seven items, so up to like 28 points, for example, would be a max score. And it's something that's actually pretty straightforward, because you have a sheet, you can kind of go through and go through and assess the questions. So it's actually something we teach in our second year students, in our in their lab practice. We're actually getting ready to do it in about two, three weeks, to teach our students. So the one thing I've noted with it is that there's a lot of inter rater variability, and so because you are rating something like mild or moderate or extreme normal. What I say is, you know, an extreme normal for a symptom, you know, dr, Dr. Kane, doctor. For any one of you know, you may say, Well, I see that as more severe. So a lot of it comes to being internally consistent. So again, as you look at studies, as you look moving forward, making sure that you what you see as a two in severity is the same for every patient. So the consistency as you see one patient over a continuum of time that you're you're kind of controlling for that. But going back to what was your last score, for Speaker 2 11:49 example, yeah, I would, I would definitely agree with that. Speaker 3 11:52 So let's say we know that a lot of the TD symptoms come from use of either first generation or even second generation antipsychotic use. Are there any recommendation as to we should be performing this AIMS test and those patients who are taking this antipsychotics, or is there any recommendation at all? Speaker 2 12:09 Yeah, the American Psychiatric Association has monitoring guidelines or recommendations. So they recommend monitoring every six months for those taking first generation antipsychotics, and then annually for those taking second generation antipsychotics, Dr. Sean Kane 12:25 is that what you actually do in your clinical practice, Dr. Furbish, it is Speaker 2 12:28 actually it's one thing that I look at with all of the patients that I have in clinic. Speaker 1 12:34 We have a Clozapine treatment team, for example, and that's one of the things we're very clear on, is making sure that we're doing that minimum yearly monitoring for that medication. We have a few that are due right now, so we try to, as we come into our clinic, try to do a few of those with the students and the right chance for them to see that this is not something we just teach you in lecture, but you actually going to see it in clinical practice, the pharmacist doing Dr. Sean Kane 12:54 these things now. Is there a specific score that rates at? Yes, you have TD, or is it more based on previous scores or the change in score? How do you know that someone actually has it based on the AIMS test? Speaker 2 13:07 So the AIMS test isn't diagnostic on its own, so we use the Schooler-Kane criteria, which is typically used in clinical practice. So there's three different criteria for it, and then the AIMS is part of it. So typically, you know, looking at trends and their aims scores, that can be helpful, the higher the score, the worse the symptoms. And then just talking to the patient, is this significant enough to where it's impacting your ability to attend to your activities of daily living. So is it difficult for you to eat? Is it difficult for you to walk? Dr. Sean Kane 13:45 So those kinds of things. So it sounds like you would have kind of a clinical diagnosis that would be made after the screening tool in terms of treating tardive dyskinesia. What is the typical approach prior to these new medications that came to the market recently? Speaker 2 13:59 So typically, prevention is key. So we want to avoid first generation antipsychotics, if possible, generally, using the second generations more often, using the lowest effective dose, shortest duration. Speaker 3 14:15 Or if there are those PRN medications like metoclopramide, we want to make sure patients are not on those medications for a very long period of time. Speaker 1 14:22 Certainly, we have to think holistically about the mechanisms of action. So again, if we're trying to treat migraines and somebody who has bipolar source schizophrenia, being aware of those that extra effect that they may not be on a first generation anti psychotic, but they're on a second gen and they're on medical provide so again, that combined effect, you may be still getting a lot of bit a lot of that binding to dopamine. So yeah, like with anything at pharmacy review for polypharmacy, minimum effective doses, this goes back to a lot of what we're doing the elderly is really making sure that if we're using, you know, antipsychotics in the elderly, we have a good indication for it, and not part of this overall. Well, I just want you to be quiet. So here's your medication. Dr. Sean Kane 14:59 So prevention is. Great. But what do you do, especially part of these new medications? What would you do for a patient who definitely has tardive dyskinesia, has a high enough score that it kind of necessitates some amount of treatment or a clinical approach? Sure? Speaker 2 15:16 Yeah, so, switching patients from first generation to second generation antipsychotics, eliminating any medication that may be exacerbating tardive dyskinesia. So getting rid of those anticholinergic medications, if possible, sometimes we can switch a patient to Clozapine. There's no reports and evidence of in the literature of Clozapine causing tardive dyskinesia. So that may be a viable option for some patients. Speaker 3 15:44 So I hate to treat a symptom or a side effect of a medication with another medication, and you take necessary steps to remove the offending agent or switch them to something else. But sometimes it's not possible. You have to keep the patient on that medicine, even though we know it's causing the TD, what do we do? What do we add? What do we treat of it? Speaker 2 16:05 Yeah, so according to the 2013 American Academy of Neurology guidelines, they recommend four different medications, clonazepam and ginkgo biloba, which both have level B evidence, and then amantadine and tetrabenazine, which have level C evidence. Dr. Sean Kane 16:21 It sounds like now we have two new agents that probably weren't on the market at the time of those guidelines. Speaker 2 16:25 Yeah, exactly. So now we have valbenazine and deutetrabenazine. Speaker 1 16:30 So again, if we had four agents that are with level BC evidence, why does it really matter that we have two new ones? Speaker 2 16:35 Well, these in particular, have the FDA labeled indication. Dr. Sean Kane 16:40 So what you're saying is we've gone above and beyond just what the guidelines recommend, but it's actually been evaluated by the FDA, probably to a higher level of criticism, to receive the stamp of approval from the FDA, saying this medication is safe and effective for tardive dyskinesia, right? Okay? Speaker 1 16:55 And then Dr. Furbish, I know that kind of from your journal clubs and your grand rounds, you've really focused on looking at these two agents. So let's, let's let's go into, let's start talking first with Ingrezza or valbenazine. What exactly? What is it? What's it different than these other ones? What's the evidence like? Speaker 2 17:10 We'll start with valbenazine. So it's a potent, selective VMAT2 inhibitor, so it has a longer half-life than tetrabenazine, but still has a similar mechanism as tetrabenazine. Dr. Sean Kane 17:22 I'm gonna have to back you up here. V mat two. You lost me there? Sure. Speaker 2 17:27 So V mat two is a protein in the brain, and it transports mono amine neurotransmitters, so things like dopamine, serotonin, norepinephrine, so it packages up these neurotransmitters for release into the synapse. So what V mat, two inhibitors do is prevent the uptake into these vesicles of the neurotransmitters. Therefore, there's less neurotransmitters available for release into the synapse. So then we have less dopamine in the synapse binding to these hypersensitive dopamine receptors. Dr. Sean Kane 18:02 No, it sounds like that's not specific to dopamine. Then correct, no. Speaker 2 18:06 And that's the difficult part of these medications, is that it's depleting not only dopamine, but also serotonin norepinephrine, which can cause problems. Speaker 1 18:17 Yeah, because again, as we have all these others easily say something, oh, you're depressed. We think it has to do something with these neurotransmitters or with Parkins. We have our low energy and so we say, Oh, we're gonna fix it. We're gonna deplete you of these. So yeah, I think we maybe have some concerns here. Yeah. Speaker 2 18:32 In fact, tetrabenazine has a black box warning for depression and suicidality. So deutetrabenazine has that same black box warning, but valbenazine does not, which is interesting. Dr. Sean Kane 18:44 So before we get into some of the clinical data, you mentioned tetrabenazine a couple times. It's kind of an analog to this and isn't as long acting. What do we use tetrabenazine for? What is it FDA approved for? Speaker 2 18:56 It's FDA approved for chorea, associated with Huntington disease. Dr. Sean Kane 19:00 So very specific kind of niche population. Okay, so what kind of data do we have for valbenazine? Speaker 2 19:07 So the phase two trial was the KINECT‑2 trial. It's a six‑week, double‑blind study. It had 102 patients with moderate to severe tardive dyskinesia, and they were either treated with valbenazine or placebo, and the primary outcome, which is the same for all these studies, was the mean change in the total AIMS score. So what they found was a difference of 3.6 — a decrease in the AIMS score of 3.6 for the valbenazine group, and then a decrease of 1.1 for the placebo group, and they found that this was statistically significant. Speaker 3 19:46 So somebody who is not practicing how to do aim score, how to assess the patient, I wouldn't know whether the 1.1 versus 3.6 holds any clinical significance, does it? Speaker 2 19:58 Yeah, and that's the that's the difficult. Part to determine so a decrease of 3.6 or three points may be significant for one patient, but you may not even be able to tell a difference in another patient. So it really depends on which body movement improved and how much it could have been three body areas that improved just slightly, or one body area that improved a little bit more Speaker 1 20:26 significant, yeah, and that's where the nuance of it is. So if you have somebody who, again, has this puckering motion, this neck movement and these kind of hip movements, and they all decrease slightly, the individual may not see a great benefit. But if somebody has maybe one or two areas that are the more I guess, the individual feels stigmatized about, or more self conscious about, you could see a bigger increase in that one area. So it's there's, it's going to be such individual specific. Dr. Sean Kane 20:51 This is fascinating to me, because I teach an elective here at the University called deconstructing landmark clinical trials, and one of the things we talk about is something like this, where you have this continuous endpoint that may or may not have clinical significance, and if you aren't sure that your drug is going to prove clinical significance, it's often a very smart move to have this continuous variable, like an aims score, where numerically, you might show a difference, but clinically it may not actually Be different. And it's safer to have this, you know, statistical significance on this continuous variable, as opposed to, yes, no, did you see improvement in whatever symptom you want to look at. This is a smart move from the drug manufacturer to get FDA approval. But again, the question is whether it will be clinically relevant to the patient or not, or Speaker 3 21:38 even collecting humanistic outcomes and asking patients, Hey, are you noticing a difference? Are you feeling better? Speaker 1 21:45 And so then the second piece of it was they kind of went on and did the connect three trial, which was very similar in a larger population. They looked at two different doses, 40 and 80 milligrams. Same here, the same outcome. So you looked at the sum of those items, one to seven on the aims, really, you could have up to a score of 28 points up to four on each one. Average in this study, individuals had a score of about 10. And then the mean change from baseline to week six was a reduction of about two to three points in the valbenazine group, depending upon which dose (it did seem the higher dose was a little bit better), and then a very slight 0.1‑point decrease in the placebo group. So here again, you had a very large difference in terms of the decrease in aims. But again, it comes to is, is that clinically meaningful for the individual, based upon these numbers, we can't make that claim. Dr. Sean Kane 22:31 So if I'm understanding the typical clinical course of tardive dyskinesia, it would seem that you would be taking this medication for a long period of time. How long did these trials run for Speaker 2 22:41 these trials were six weeks long, so they were pretty short in duration. Dr. Sean Kane 22:46 Okay, that sounds like that might cause some issues with external validity in terms of how we actually use the drug versus what they studied it for, especially something like longer term side effects. You guys mentioned some depression concerns and things like that, Speaker 2 22:59 absolutely, and we probably weren't. They probably weren't able to capture those long term effects in just six weeks. So there's a lot that we still don't know about, valbenazine, and Speaker 1 23:10 actually, to that point, there is a 42 week extension trial coming, because that's one of my initial and Dr. Furbish, we have discussed this in the clinic multiple times. Is you have a drug that's structurally similar to one in the past that caused crippling depression and suicidality. But we say, all right, six weeks of data says you didn't see a safety signal for suicidality and depression. So I guess it's not gonna, it's gonna be not a problem, right? And then let's put this on you, and maybe 1020, years down the road now we'll see. And so that's, that's my big concern with these Dr. Sean Kane 23:39 medications, and especially considering the sample size, we have basically 100 and a 200 patient study. I'm sure they have other data, but that's not a lot to be able to detect a even a reasonably small ADR, like suicidality in patients. Speaker 3 23:54 Yeah, and think about adding this medicine on the slew of other meds that they are already on. So what's the cause impact? Speaker 2 24:00 Obviously, this is a new medication, so it's going to be quite expensive. So a 30 day supply of the 40 milligram tablets would be just over $6,000 and then for the 80 milligram dose, a 30 day supply is about 7500 a month. Speaker 3 24:16 It's pretty impressive. That is very impressive, especially when you compare to Level B ginkgo biloba, which is available as over the supplement. These drugs are pretty expensive, Speaker 1 24:26 and I believe we just added ginkgo to our list of medications at our facility, right? Speaker 2 24:29 We did. We did? We have one patient who's on treatment with ginkgo right now. Unknown Speaker 24:34 Have you seen any benefit yet? We Speaker 2 24:36 have, actually, he still has the oral buccal movements that was the most significant thing, and he has improved. Dr. Sean Kane 24:44 And of course, when we think about cost is to kind of wrap that section up. We always have to worry about cost effectiveness, right? So it goes back to the original question we said, is it clinically relevant in terms of the benefit that we see? And if it is measuring that clinical benefit is really. Difficult because it's, you know, a continuous variable on a scale, right? Like, what does two points mean on the aim scale? So then, just if you were to do a cost effective analysis, it becomes really difficult to just say, like, what is a meaningful difference, and how much do you have to pay to get that meaningful difference, and is that too expensive, or is it a good cost? And all of those things, I would assume, are questions that a, no one knows, and B, someone will try to answer, but will probably be sponsored by the drug company in doing so. Speaker 1 25:27 And one, I think another fascinating thing is looking, as I said, most individuals, or number of individuals, have no insight into the nature of it, and so it's difficult to then do a an impression about the patient if the patient's not even aware of it. In fact, one of the questions you ask them as part of the rating is whether or not it capacitates them or if they're aware of it. So you can almost bias the aims itself, not the seven they discuss, but other pieces of the questionnaire. You can bias it even, even as you ask them, Oh, do you notice your symptoms are better? What symptoms? And so I think there's even a little bit of that confounder there, simply as far as do you introduce it to them, and thus, do you make it more stigmatizing? Just to answer some questions about how the drugs working interesting. Dr. Sean Kane 26:05 So what about the other new agent on the market? It's kind of unique that we have two new agents for a fairly rare disease, and it sounds like they came out about the same time. So what is the second agent? Speaker 2 26:14 Yeah, so deutetrabenazine. So this is a pretty unique formulation. So the 'deu' refers to deuteration. So this is a deuterated tetrabenazine. Deuteration is a process where they replace the hydrogen atoms with deuterium, which is a much heavier atom. Speaker 1 26:33 It's not radioactive, though. That's just for anyone else looking at that we checked yes. Speaker 2 26:37 Good point. Thank you. Dr. Schuman, so the carbon‑deuterium bond is much stronger than the carbon‑hydrogen bond, so it slows the metabolism. So basically, what we have is an extended‑release tetrabenazine. And so Speaker 1 26:52 I think this is something that's, for me, fascinates from the drug design aspect, is you can take a drug and instead of, you know, making it go through the liver for a first pass issue, which they've done with some medications. Or instead of binding it in a, you know, encapsulating it, or putting in a little granules to slow their release, you can actually make it just delay the kinetics of and so this is something that's actually going to be applied to a number of other medications in the future. So we're actually going to be doing a future episode with one of our basic sciences faculty who kind of looks at the drug design aspect. And we're going to look and see going to look and see is, does this hold water to douch, or is this something then maybe in the future? Well, can it be applied to other medications? And it Dr. Sean Kane 27:30 sounds like this is going to be ripe for extending patents and things like that for other drugs. We've seen this classically for a number of different things, in terms of isomers of drugs, or using a pro drug that gets converted to a parent drug, and things like that. So this could be a whole new avenue for drug companies to start coming up with, kind of me too, or patent extending formulations of existing products. Speaker 3 27:53 So I believe this drug has an FDA indication for treatment of tardive dyskinesia, but also chorea associated with Huntington disease, correct? Unknown Speaker 28:01 Yeah, that's correct. Yeah. And Speaker 1 28:03 then in the Dr. Furbish, you mentioned, the one big difference off the bat between this medication of albanism is that that warning. So what was that black box warning again? Speaker 2 28:11 Yeah, so it's a warning for depression and suicidality. Dr. Sean Kane 28:14 And did we see that in the data, or was it just because of the history with tetrabenazine? Speaker 2 28:20 It was because of the history with tetrabenazine. So we didn't actually see this in the studies. They did test for if there was any suicidality, but they didn't find that in the studies. But again, these studies were only 12 weeks long, so probably not long enough to detect that. Speaker 1 28:37 Yeah, you had like, a 1.7% depressed mood versus none and placebo 1.7% depression, suicidality, so there was a small signal, but again, was not major, but it's kind of grandfathered in from that serious concern about tetrabenazine. And wanted to be very, very, and I agree, be very, very, very careful before getting this one into routine clinical practice. Dr. Sean Kane 28:55 So why don't you tell us a little bit about the clinical trials that were conducted? It sounds like there are 12 week trials, again, kind of short, given that this is a likely lifelong medication for many patients. But how did they design them and what did they show? Speaker 2 29:08 So pretty similar study to the valbenazine studies, the first phase two trial was the ARM-TD study. It had just over 100 patients, and they were randomized to placebo or deutetrabenazine, they looked at the change in the AIMS score, and they found an average decrease of three for the deutetrabenazine group, and then 1.6 for the placebo group. So we're seeing pretty similar results to what we saw with the valbenazine studies. Dr. Sean Kane 29:38 Let me guess they did another trial. They called it something different. They ran it very similarly, and they just had more people, Speaker 2 29:45 yes, this is the AIM‑TD study, and again, very similar results. So they did different dosing for deutetrabenazine, and they found pretty similar decreases in the AIMS score for 36 mg/day and 24 mg/day — about a 3.2–3.3 point decrease. Speaker 1 30:07 And then, as far as safety, again, it was, it was fairly similar. You had a little bit of a signal for depressed mood. A couple of patients, you know, didn't seem to be necessarily dose dependent, but was seen with a few of the doses of the, you know, for example, three to four patients in each of the different groups, and then three patients with suicidal ideation in one dose, one in the other dose, not dose dependent, but was there as a little bit of a signal? So again, that's, I think, something that gives us a Speaker 3 30:33 little bit of pause. And I know this, we're not like head to head trials, and the results are pretty similar. But was there any difference between how the patients were in the deutetrabenazine trials versus patients in the valbenazine trial, Speaker 1 30:47 not really. One of the things they did is they tried to either some of the studies, they either said your aim score needs to be six or higher to get into the study. And they did that with valbenazine. And I believe, for deutetrabenazine, they had where they would kind of go and do a modified intention‑to‑treat analysis, where they would exclude certain patients from efficacy analyses; so that's a little methodological difference. But overall, they were really focusing on those with more severe symptoms. Study‑wise, they seemed to keep the designs pretty close. Dr. Sean Kane 31:20 So I'm gonna go out on a limb here and say this is not a cheap medication, given that it's a new way to kind of do the right molecule. In addition to that, is a new molecule period. So where does this price compare in terms of the AWP? Speaker 2 31:34 So six milligram tablets, a 30 day supply, would cost you about $4,000 the 12 milligram dose, month supply would be about $6,000 so again, expensive. Speaker 1 31:48 One thing to note, though, other than some of the safety signals, the few other comparisons Dr. Patel made with it are that deutetrabenazine is a little bit better tolerated than, certainly, tetrabenazine. And that's one thing to notice as far as some of the suicide but again, what does that mean moving forward, that's going to be something that we need to be very careful of. And again, mechanistically, I always like to know why. Why would deuterating the molecule create a much stronger safety signal than simply tetrabenazine? And again, I'll bring on other individuals to discuss this, but I don't see that making sense. So then I have some concern about just making sure. Then, was it the population in the study. And then we need to be very careful then that when we use patients and put it on patients, make sure that they're the right kind, so we don't see this massively, you know, this suppress smaller states in here. And then in the global population, we're back into the back into the stratosphere, as far as you know, depression, Dr. Sean Kane 32:38 and I would guess that they had pretty stringent exclusion criteria for patients with a history of suicidality and basically risk factors for severe depression and things like that, that perhaps those exclusion criteria weren't present on the original tetrabenazine studies because they didn't know it at that time. Or there could have been a lot of study design things that allowed the study to not demonstrate this crazy amount of suicidality. Yeah. Speaker 1 33:03 So they, again, they look at under, you know, untreated or either untreated or under treated psychiatric illness. They were very explicit in a number of these exclusion criteria. So they really wanted to make sure that we had a safe patient population to use it in. But again, is, is that going to be the population which is being used in clinically so, to kind of Dr. Sean Kane 33:21 wrap up what we've discussed today, tardive dyskinesia is a one of the elements of EPS. It's fairly common as a consequence of long term anti psychotic use, although there are other medications that, especially when used concurrently with some of these earlier, first generation anti psychotics, we did see a fairly good incidence rate of tardive dyskinesia. Speaker 3 33:44 And up to this point, the management was largely related to maybe prevention or even removing the offending agents or switching them to a different medication, or adding agents such as ginkgo biloba or some of the older available agents that were we had. Speaker 2 34:00 And so we talked about the two new medications that we have, valbenazine and deutetrabenazine, and how these are the only two FDA‑approved medications for treatment of tardive dyskinesia. These medications are quite costly. We're not quite sure about the clinical significance of these, and there may be some concerning side effects in terms of depression and suicidality with these and hopefully with further studies, we'll we'll learn a lot more about them. Speaker 1 34:26 So I think in terms of clinical practice, you know, it's something, again, they certainly can be useful for patients with serious symptoms, for those that we may be the patient is not bothered by or they're clinically borderline, as far as whether it warrants treatment, I think really minimizing symptoms, realizing the risk factors before you prescribe are the two main pieces of it. So for example, before you utilizing long term antipsychotic use, make sure that you talk to the patient the risk and benefit. Make sure you've looked at these other medications that do block dopamine and try to mitigate risk by minimizing these of those medications and. Then also being aware of those risk factor populations, whether it's it's older age, whether it's it's female African American, being aware of the populations at higher risk, again, weighing that risk versus benefit before we even prescribe in the first place. Dr. Sean Kane 35:11 I think that sounds like a great review of tardive dyskinesia and these two new medications. For those that want to get more information, we'll have links and some content on our show notes at HelixTalk.com you can touch base with us at HelixTalk on Twitter, and we love the five star reviews in iTunes, so keep those coming so that we can climb the iTunes rankings and other listeners are more apt to find us. So with that, I'm Dr. Kane, Unknown Speaker 35:35 I'm Dr. Schuman, I'm Speaker 3 35:36 Dr. furbisch, and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 35:41 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 35:52 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.