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Evaluating the Long-term Efficacy and Safety of Deutetrabenazine
In this video, Joohi Jimenez-Shahed, MD, explains a 3-year, open-label study which evaluated the long-term efficacy and safety of deutetrabenazine, a treatment for the movement disorder tardive dyskinesia. The study was presented in a poster at Psych Congress 2020.
Dr. Jimenez-Shahed is a movement disorders neurologist at the Icahn School of Medicine at Mount Sinai in New York, New York.
Reference
MORE: Deutetrabenazine Effective for TD Across Age Groups
Read the transcript:
Thank you for the opportunity to present this poster to you which is entitled "Long-Term Treatment With Deutetrabenazine Is Associated With Continued Improvement in Tardive Dyskinesia: Results From the Completed 3-Year Open-Label Extension Study."
My name is Joohi Jimenez-Shahed. I'm a movement disorders neurologist at the Mount Sinai School of Medicine. I was an investigator on this particular study.
By way of background, tardive dyskinesia is an often irreversible, debilitating, and iatrogenic movement disorder that typically results from exposure to dopamine receptor antagonists.
Deutetrabenazine is a VMAT2 inhibitor, a vesicular monoamine transporter type 2 inhibitor, that is approved by the US FDA for the treatment of both chorea associated with Huntington's disease as well as for the treatment of tardive dyskinesia in adults.
This approval was based on two 12-week pivotal studies called ARM-TD and AIM-TD, which we'll talk about in a moment. In those particular clinical trials, deutetrabenazine showed statistically significant improvements in AIMS scores with a favorable safety profile as well as a tolerability profile and low rates of discontinuation.
Patients who were enrolled in these pivotal studies were eligible to then enroll in a 3-year, single-arm, open-label extension study that was designed to evaluate the long-term efficacy and safety of deutetrabenazine.
The objective of this poster was to present the results of that open-label extension study in terms of both the long-term efficacy and safety of deutetrabenazine in patients with tardive dyskinesia.
The study design is that patients who were in one of the parent studies, ARM-TD or AIM-TD, were required to conduct a 1-week washout of their assigned treatment in the parent study and then had to undergo a final evaluation before being able to enroll in this open-label extension.
Now, in figure 1, you can see the study design. Patients in ARM-TD were either assigned to placebo or to deutetrabenazine using response-driven dosing. In AIM-TD, subjects were randomized to receive either placebo or a fixed dose of deutetrabenazine at 12 mg/day, 24 mg/day, or 36 mg/day.
As I said, the patients had to wash out of that treatment assignment for about a week. Then they entered into a 6-week titration phase in the open-label extension study. This titration phase was also conducted using response-driven dosing similar to the ARM-TD study.
Patients were started at 12 mg/day and then titrated once per week until one of the following occurred. Either they achieved adequate dyskinesia control, or they experienced a clinically significant adverse event, or they reached a maximum dose of 48 mg/day.
As you know, deutetrabenazine does have a CYP2D6 metabolism. For patients who were receiving a concomitant strong CYP2D6 inhibitor, that maximum dose was 36 mg/day.
Once they completed the titration phase, the patients entered into the long-term treatment and monitoring which, as we mentioned, went on for about three years.
The primary analyses in this report are related to efficacy and safety. Efficacy was assessed based on several outcomes. The first was, of course, the improvement in the AIMS score compared to baseline. This was assessed by the local site raters, which was different from the parent studies in which the ratings were performed by a central reviewer.
Another efficacy measure was the percentage of patients that achieved either a 50 percent or a 70 percent improvement in the AIMS score from baseline.
The last efficacy analysis was the percentage of patients achieving treatment success measured by the clinician on the Clinical Global Impression of Change. Those individuals who were identified as being much improved or very much improved were analyzed.
Safety was assessed in terms of both adverse events and adverse events of interest using what's called an exposure-adjusted incidence rate. We'll talk about what that is in a moment.
The adverse effects of interest in this particular study were akathisia and restlessness, somnolence and sedation, parkinsonism, and depression. These are all particular adverse events that can occur with dopamine blockade and have been previously reported with other drugs with similar mechanisms of action.
There were 343 patients that enrolled into the open-label extension study. This is shown in Table 1. Six patients were ultimately excluded from the analyses. The final reporting is based on a total of 337 individuals. Of that patient population, 227 of those patients had previously received active treatment with deutetrabenazine, and 110 had received placebo.
Overall, you can see the patient characteristics in table 1. 56 percent of these individuals were female. 78 percent were Caucasian. The total mean AIMS score at baseline was 10.7. The total duration or the mean duration of tardive dyskinesia at the time of enrollment was about 5.7 years.
75 percent of patients were receiving a concomitant dopamine receptor antagonist as baseline. As we talked about, this was something that was allowed in the parent studies, and also shown to be safe and, therefore, was continued in the open-label extension as well.
The reason for dopamine receptor antagonist use was psychotic disorders in about 61 percent of patients, mood disorders in about 34 percent of patients.
In this study, 48 percent of patients discontinued early. You'll see that in the attrition rates over time. The reasons for discontinuation included withdrawal by subject in about 23 percent of cases without other further explanation. Twelve percent of these discontinuations occurred because of adverse events. Seven percent occurred because of patients being lost to follow-up. Only 3 percent were reported to be related to lack of efficacy.
Figure 2 shows the dosing that was achieved in these patients over time. By week 54, the mean daily dose was 38.7 mg for all patients, so not necessarily the maximum dose. We don't here have the information about the proportion of patients who were taking concomitant strong CYP2D6 inhibitors which, as we talked about already, limited the maximum dose.
This dose was essentially maintained over the 145 weeks of follow-up with only a minimal increase to 39.4 mg by week 145.
From an efficacy standpoint, this is shown in Figure 3, the change in AIMS score from baseline. You can see in this study that patients that were treated with deutetrabenazine in the open-label extension experienced sustained improvement in the AIMS score over time.
The most significant improvement or the most dramatic change occurred in the first 6 weeks, as expected, during the titration phase. Then, over time, the efficacy was maintained without any loss of control over tardive dyskinesia symptoms as measured by the AIMS score.
Keep in mind here, you can see at the bottom of this particular figure that the attrition rate certainly needs to be factored into interpretation of these data.
Another measure of efficacy that we talked about was the percentage of patients who achieved at least a 50 percent or a 70 percent improvement in the AIMS score. What is shown here in Figure 4 in the light green is the proportion of patients who had at least a 70 percent improvement in the AIMS score. You can see how this changes over time.
In fact, there's an increase of this proportion of patients over the course of the study. That's seen not only in just the percentages of the population. Eighteen percent of patients at week 15 were identified as having at least a 70 percent improvement in their AIMS score. This increased to 42 percent by week 145.
You can also see this borne out in the absolute numbers of patients where at week 15 that represented 55 patients. By week 145, that was increased to 67 patients. This is certainly suggestive about a potential for increased efficacy over time.
By week 145, 73 percent of patients achieved treatment success based on the Clinical Global Impression of Change. That's shown in figure five.
From a safety standpoint, deutetrabenazine was generally well tolerated across the subjects in this open-label extension study. There were 8 patients who died during the course of the study. None of those deaths were assessed to be related to the study drug by the site investigator.
You can see in Table 2 the exposure-adjusted incidence rate. What does this mean? This represents the number of patients who had an adverse effect divided by the total exposure time amongst patients in the treatment group. What this really gives us is a sense of whether or not the duration of exposure seems to have an impact on the occurrence of these adverse events.
Adverse events, in general, were reported to have an exposure-adjusted incidence rate of 1.22 in all subjects across the study. Serious adverse events occurred at a rate of 0.11 and severe adverse events at a much lower rate of 0.09. Treatment-related adverse events were identified at 0.34. Very low proportions of these were adverse events that led to dose reduction, dose suspension, or to withdrawal.
If you look at specifically the adverse events of interest, these, as we talked about, were akathisia and restlessness, somnolence and sedation, parkinsonism and depression. The exposure-adjusted incidence rates for all of these were quite low throughout the course of this open-label extension.
In conclusion, deutetrabenazine treatment for tardive dyskinesia was associated with sustained improvements in symptoms as assessed by the AIMS scale. These were maintained over time. This efficacy was achieved using response-driven dosing, which means that patients were able to be titrated to the dose that was effective and well tolerated for them.
The measured treatment response indicated that there were clinically meaningful long-term benefits in tardive dyskinesia symptoms. We can see that deutetrabenazine was well tolerated over its long-term use. In fact, there were no new safety signals that came out over this long-term exposure.
Really, just the known safety profile of the drug was reiterated in the long-term extension. This also included, of note, the low incidence of depression, which is a particular side effect of concern with this drug.
The possibility of increasing benefit over time was also seen in this open-label extension report. This occurred without an associated increase in dose of the medication. I think that's of particular interest for clinicians when they're considering when or whether to initiate treatment for tardive dyskinesia.
Thank you very much for your attention.
