Austedo (Page 6 of 10)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No carcinogenicity studies were performed with deutetrabenazine.

No increase in tumors was observed in p53+/– transgenic mice treated orally with tetrabenazine at doses of 0, 5, 15, and 30 mg/kg/day for 26 weeks.

Mutagenesis

Deutetrabenazine and its deuterated α-HTBZ and β-HTBZ metabolites were negative in in vitro (bacterial reverse mutation and chromosome aberration in human peripheral blood lymphocytes) assays in the presence or absence of metabolic activation and in the in vivo micronucleus assay in mice.

Impairment of Fertility

The effects of deutetrabenazine on fertility have not been evaluated. Oral administration of deutetrabenazine (doses of 5, 10, or 30 mg/kg/day) to female rats for 3 months resulted in estrous cycle disruption at all doses; the lowest dose tested was similar to the maximum recommended human dose (48 mg/day) on a body surface area (mg/m2) basis.

Oral administration of tetrabenazine (doses of 5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation, resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day. No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine at doses of 5, 15 or 30 mg/kg/day prior to and throughout mating with untreated females.

14 CLINICAL STUDIES

The studies described below establishing effectiveness for Huntington’s disease and tardive dyskinesia were conducted with AUSTEDO tablets. The efficacy of AUSTEDO XR is based on a relative bioavailability study comparing AUSTEDO XR tablets administered once daily and AUSTEDO tablets administered twice daily [see Clinical Pharmacology (12.3)].

14.1 Chorea Associated with Huntington’s Disease

The efficacy of AUSTEDO as a treatment for chorea associated with Huntington’s disease was established primarily in Study 1, a randomized, double-blind, placebo-controlled, multi-center trial conducted in 90 ambulatory patients with manifest chorea associated with Huntington’s disease. The diagnosis of Huntington’s disease was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including an 8-week dose titration period and a 4-week maintenance period, followed by a 1-week washout. Patients were not blinded to discontinuation. AUSTEDO was started at 6 mg per day and titrated upward, at weekly intervals, in 6 mg increments until satisfactory treatment of chorea was achieved, intolerable side effects occurred, or until a maximal dose of 48 mg per day was reached. The primary efficacy endpoint was the Total Maximal Chorea Score, an item of the Unified Huntington’s Disease Rating Scale (UHDRS). On this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for 7 different parts of the body. The total score ranges from 0 to 28.

Of the 90 patients enrolled, 87 patients completed the study. The mean age was 54 (range 23 to 74). Patients were 56% male and 92% Caucasian. The mean dose after titration was 40 mg per day. Table 5 and Figure 1 summarize the effects of AUSTEDO on chorea based on the Total Maximal Chorea Score. Total Maximal Chorea Scores for patients receiving AUSTEDO improved by approximately 4.4 units from baseline to the maintenance period (average of Week 9 and Week 12), compared to approximately 1.9 units in the placebo group. The treatment effect of -2.5 units was statistically significant (p<0.0001). The Maintenance Endpoint is the mean of the Total Maximal Chorea Scores for the Week 9 and Week 12 visits. At the Week 13 follow-up visit (1 week after discontinuation of the study medication), the Total Maximal Chorea Scores of patients who had received AUSTEDO returned to baseline (Figure 1).

Table 5: Change from Baseline to Maintenance Therapy in Total Maximal Chorea (TMC)* Score in Patients with Huntington’s Disease Treated with AUSTEDO in Study 1
Motor Endpoint AUSTEDON = 45 Placebo N = 45 p value

Change in Total Chorea Score* from Baseline to Maintenance Therapy

-4.4

-1.9

<0.0001

* TMC is a subscale of the Unified Huntington’s Disease Rating Scale (UHDRS) Primary efficacy endpoint

Figure 1: Total Maximal Chorea Score Over Time in Study 1

figure-01.jpg
(click image for full-size original)

Figure 2: Distribution of the Change in Total Maximal Chorea Scores in Study 1

figure-02.jpg
(click image for full-size original)

Figure 2 shows the distribution of values for the change in Total Maximal Chorea Score in Study 1. Negative values indicate a reduction in chorea and positive numbers indicate an increase in chorea.

A patient-rated global impression of change assessed how patients rated their overall Huntington’s disease symptoms. Fifty-one percent of patients treated with AUSTEDO rated their symptoms as “Much Improved” or “Very Much Improved” at the end of treatment, compared to 20% of placebo-treated patients.

In a physician-rated clinical global impression of change, physicians rated 42% percent of patients treated with AUSTEDO as “Much Improved” or “Very Much Improved” at the end of treatment compared to 13% of placebo-treated patients.

14.2 Tardive Dyskinesia

The efficacy of AUSTEDO in the treatment for tardive dyskinesia was established in two 12‑week, randomized, double-blind, placebo-controlled, multi-center trials conducted in 335 adult ambulatory patients with tardive dyskinesia caused by use of dopamine receptor antagonists. Patients had a history of using a dopamine receptor antagonist (antipsychotics, metoclopramide) for at least 3 months (or 1 month in patients 60 years of age and older). Concurrent diagnoses included schizophrenia/schizoaffective disorder (62%) and mood disorder (33%). With respect to concurrent antipsychotic use, 64% of patients were receiving atypical antipsychotics, 12% were receiving typical or combination antipsychotics, and 24% were not receiving antipsychotics.

The Abnormal Involuntary Movement Scale (AIMS) was the primary efficacy measure for the assessment of tardive dyskinesia severity. The AIMS is a 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this study. Each of the 7 items was scored on a 0 to 4 scale, rated as: 0=not present; 1=minimal, may be extreme normal (abnormal movements occur infrequently and/or are difficult to detect); 2=mild (abnormal movements occur infrequently and are easy to detect); 3=moderate (abnormal movements occur frequently and are easy to detect) or 4 =severe (abnormal movements occur almost continuously and/or of extreme intensity). The AIMS total score (sum of items 1 to 7) could thus range from 0 to 28, with a decrease in score indicating improvement.

In Study 1, a 12-week, placebo-controlled, fixed-dose trial, adults with tardive dyskinesia were randomized 1:1:1:1 to 12 mg AUSTEDO, 24 mg AUSTEDO, 36 mg AUSTEDO, or placebo. Treatment duration included a 4-week dose escalation period and an 8-week maintenance period followed by a 1-week washout. The dose of AUSTEDO was started at 12 mg per day and increased at weekly intervals in 6 mg/day increments to a dose target of 12 mg, 24 mg or 36 mg per day. The population (n= 222) was 21 to 81 years old (mean 57 years), 48% male, and 79% Caucasian. In Study 1, the AIMS total score for patients receiving AUSTEDO demonstrated statistically significant improvement, from baseline to Week 12, of 3.3 and 3.2 units for the 36 mg and 24 mg arms, respectively, compared with 1.4 units in placebo (Study 1 in Table 6). The improvements on the AIMS total score over the course of the study are displayed in Figure 3. Data did not suggest substantial differences in efficacy across various demographic groups. The treatment response rate distribution, based on magnitude of AIMS total score from baseline to week 12 is displayed in Figure 4.

The mean changes in the AIMS total score by visit are shown in Figure 3.

In Study 2, a 12-week, placebo-controlled, flexible-dose trial, adults with tardive dyskinesia (n=113) received daily doses of placebo or AUSTEDO, starting at 12 mg per day with increases allowed in 6-mg increments at 1-week intervals until satisfactory control of dyskinesia was achieved, until intolerable side effects occurred, or until a maximal dose of 48 mg per day was reached. Treatment duration included a 6-week dose titration period and a 6-week maintenance period followed by a 1-week washout. The population was 25 to 75 years old (mean 55 years), 48% male, and 70% Caucasian. Patients were titrated to an optimal dose over 6 weeks. The average dose of AUSTEDO after treatment was 38.3 mg per day. There was no evidence suggesting substantial differences in efficacy across various demographic groups. In Study 2, AIMS total score for patients receiving AUSTEDO demonstrated statistically significant improvement by 3.0 units from baseline to endpoint (Week 12), compared with 1.6 units in the placebo group with a treatment effect of -1.4 units. Table 6 summarizes the effects of AUSTEDO on tardive dyskinesia based on the AIMS.

Table 6: Improvement in AIMS Total Score in Patients Treated with AUSTEDO in Study 1 and Study 2
Study Treatment Group Primary Efficacy Measure: AIMS Total Score
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Treatment Effect (95% CI)

Study 1

AUSTEDO 36 mg*

(n= 55)

10.1 (3.21)

-3.3 (0.42)

-1.9 (-3.09, -0.79)

AUSTEDO 24 mg

(n= 49)

9.4 (2.93)

-3.2 (0.45)

-1.8 (-3.00, -0.63)

AUSTEDO 12 mg

(n= 60)

9.6 (2.40)

-2.1 (0.42)

-0.7 (-1.84, 0.42)

Placebo (n= 58)

9.5 (2.71)

-1.4 (0.41)

Study 2

AUSTEDO

(12-48 mg/day)*

(n= 56)

9.7 (4.14)

-3.0 (0.45)

-1.4 (-2.6, -0.2)

Placebo (n= 57)

9.6 (3.78)

-1.6 (0.46)

*Dose that was statistically significantly different from placebo after adjusting for multiplicity.

LS Mean = Least-squares mean; SD = Standard deviation; SE = Standard error; CI = 2-sided 95% confidence interval

Figure 3: Least Square Means of Change in AIMS Total Score from Baseline for AUSTEDO Compared to Placebo (Study 1)

figure-03.jpg
(click image for full-size original)

SE = Standard error

Figure 4: Percent of Patients with Specified Magnitude of AIMS Total Score Improvement at the End of Week 12 (Study 1)

figure-04.jpg
(click image for full-size original)

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.