Clinical development of valbenazine for tics associated with Tourette syndrome

Figures & data

Table 1. Valbenazine studies in Tourette syndrome

	Population	Design	Treatment Duration	Treatment Groups (n)	Select Outcomes
OL Dose-Finding Study
T-Force (NCT02256475) Phase 1b	Pediatric (6–18 years)	OL, multiple, fixed dose	14 days	Children (6–11 yrs): VBZ 5 mg (6), VBZ 10 mg (5), VBZ 25 mg (0)^a Adolescents (12–18 yrs): VBZ 10 mg (6), VBZ 25 mg (6), VBZ 50 mg (5)	Safety/tolerability Pharmacodynamics
DBPC Studies
T-Forward (NCT02581865) Phase 2	Adult (18–64 yrs)	DBPC, randomized, parallel group, fixed dose	8 wks^b	PBO (40), VBZ 40 mg (42), VBZ 80 mg (42)	YGTSS TTS (primary endpoint) CGI-TS Improvement CGI-Tics-Severity
T-Force GREEN (NCT02679079) Phase 2	Pediatric (6–17 yrs)	DBPC, randomized, parallel group, fixed dose	6 wks^b	Children (6–11 yrs): PBO (15), VBZ 10 mg (14), VBZ 20 mg (15) Adolescents (12–17 yrs): PBO (18), VBZ 20 mg (18), VBZ 40 mg (18)	YGTSS TTS (primary endpoint) CGI-TS Improvement CGI-Tics-Severity
T-Force GOLD (NCT03325010) Phase 2b	Pediatric (6–17 yrs)	DBPC, randomized, dose optimization	12 wks^b,c	PBO (64), VBZ 20–80 mg (63)^d	YGTSS TTS (primary endpoint) CGI-TS-Improvement CGI-Tics-Severity
OL Extension Studies
T-Fusion (NCT02879578) Phase 2	Pediatric (6–17 yrs) & Adult (18–64 yrs)	OL, fixed dose, extension^e	24 wks	Children (6–11 yrs): VBZ 10–20 mg (33) Adolescents (12–18 yrs): VBZ 20–40 mg (40) Adults (18–64 yrs): VBZ 40–80 mg (79)	Safety/tolerability (primary endpoint) Pharmacodynamics
T-Force GOLD+ (NCT03444038) Phase 2b	Pediatric (6–18 yrs)	OL, dose optimization, extension^e	24 wks	VBZ 20–80 mg (85)^d,e	Safety/tolerability (primary endpoint) Pharmacodynamics

^aThe final cohort (25 mg in children) was not enrolled, as sufficient data were obtained from the first 5 dosing cohorts to confirm a priori, population-PK model predictions for pediatric exposures and to provide the initial safety profile of the 5–50 mg doses in pediatric patients with TS.

^bDoes not include a 2-week, no treatment follow-up period.

^cIncludes a 6-week VBZ optimization period and a 6-week maintenance period.

^dSubjects <50 kg were optimized to 20, 40, or 60 mg VBZ; subjects ≥50 kg were optimized to 40, 60, or 80 mg VBZ.

^eSubjects from T-FORCE GREEN or T-Forward could enroll in T-Fusion; subjects from T-Force GOLD could enroll in T-Force GOLD+.

CGI-Tics-Severity, Clinical Global Impression of Tics-Severity; CGI-TS-Improvement; Clinical Global Impression of Change-Tourette Syndrome-Improvement; DBPC, double-blind, placebo-controlled; OL, open-label; PBO, placebo; VBZ, valbenazine; wks, weeks; yrs, years; YGTSS TTS, Yale Global Tic Severity Scale Total Tic Score.

Figure 1. Change from baseline in YGTSS TTS by visit and treatment group in double-blind, placebo-controlled studies (primary outcome)

*P< 0.05, **P< 0.01 for valbenazine versus placebo. Y GTSS TTS, Yale Global Tic Severity Scale Total Tic Score. (a) T-Forward (b) T-Force GREEN (c) T-Force GOLD.

Table 2. Primary and select additional efficacy outcomes in double-blind, placebo-controlled studies

	T-Forward (18–64 yrs)			T-Force GREEN (6–17 yrs)			T-Force GOLD (6–17 yrs)
	PBO	VBZ 40 mg	VBZ 80 mg	PBO	VBZ 10/20 mg^a	VBZ 20/40 mg^a	PBO	VBZ 20–80 mg
YGTSS TTS (Primary Endpoint)
Baseline
n	39	41	40	31	32	32	61	58
Mean (SD)	32.1 (6.5)	31.6 (7.8)	30.0 (6.3)	30.4 (7.2)	32.8 (6.8)	32.9 (6.2)	31.2 (9.0)	29.3 (8.7)
Change from baseline to end of treatment
n	37	35	27	29	30	31	54	43
Mean (SEM)	−6.1 (1.1)	−7.4 (1.7)	−8.0 (1.1)	−8.3 (1.6)	−7.6 (1.4)	−9.7 (1.6)	−6.9 (1.1)	−8.8 (1.3)
LS mean (SEM)	−5.8 (1.3)	−7.2 (1.3)	−8.3 (1.4)	−8.8 (1.5)	−7.3 (1.4)	−9.1 (1.4)	−6.8 (1.0)	−8.9 (1.1)
LS mean difference (SEM)^b	-	−1.4 (1.8)	−2.5 (1.9)	-	1.5 (2.1)	−0.3 (2.1)	-	−2.1 (1.5)
95% Confidence interval	-	(−4.9, 2.1)	(−6.2, 1.2)	-	(−2.6, 5.6)	(−4.4, 3.8)	-	(−5.2, 1.0)
P value	-	0.433	0.184	-	0.467	0.888	-	0.177
CGI-TS-Improvement
n	37	36	27	29	30	31	61	43
Mean score (SEM)	3.2 (0.2)	3.0 (0.2)	2.6 (0.1)	3.3 (0.2)	3.5 (0.2)	2.9 (0.2)	3.1 (0.1)	2.7 (0.2)
LS mean score (SEM)	3.2 (0.2)	3.0 (0.2)	2.6 (0.2)	3.4 (0.2)	3.5 (0.2)	3.0 (0.2)	3.2 (0.2)	2.7 (0.2)
LS mean difference (SEM)^b	-	−0.2 (0.2)	−0.7 (0.3)	-	0.1 (0.3)	−0.4 (0.3)	-	−0.5 (0.2)
95% Confidence interval	-	(−0.7, 0.3)	(−1.2, −0.1)	-	(−0.5, 0.8)	(−1.0, 0.2)	-	(−1.0, −0.1)
P value	-	0.381	0.015	-	0.669	0.212	-	0.025
CGI-Tics-Severity
Baseline
n	39	41	40	31	32	32	61	58
Mean (SD)	4.5 (0.7)	4.6 (0.7)	4.6 (0.7)	4.3 (0.6)	4.7 (0.8)	4.4 (0.7)	4.4 (0.8)	4.4 (0.7)
Change from baseline to end of treatment
n	37	36	27	29	30	31	54	43
Mean (SEM)	−0.8 (0.2)	−1.0 (0.2)	−1.0 (0.1)	−1.0 (0.2)	−0.7 (0.2)	−0.9 (0.2)	−0.8 (0.1)	−1.0 (0.2)
LS mean (SEM)	−0.8 (0.1)	−1.0 (0.1)	−1.0 (0.2)	−1.1 (0.2)	−0.5 (0.2)	−0.9 (0.2)	−0.7 (0.1)	−1.0 (0.1)
LS mean difference (SEM)^b	-	−0.2 (0.2)	−0.3 (0.2)	-	0.6 (0.2)	0.2 (0.2)	-	−0.3 (0.2)
95% Confidence interval	-	(−0.6, 0.2)	(−0.7, 0.2)	-	(0.2, 1.1)	(−0.3, 0.7)	-	(−0.6, 0.1)
P value	-	0.307	0.205	-	0.009	0.413	-	0.110

^aThe VBZ 10/20 mg group includes children randomized to VBZ 10 mg and adolescents randomized to VBZ 20 mg; the VBZ 20/40 mg group includes children randomized to VBZ 20 mg and adolescents randomized to VBZ 40 mg.

^bVBZ vs PBO.

CGI-Tics-Severity, Clinical Global Impression of Tics-Severity; CGI-TS-Improvement, Clinical Global Impression of Change-Tourette Syndrome-Improvement; PBO, placebo; VBZ, valbenazine; YGTSS TTS, Yale Global Tic Severity Scale Total Tic Score.

Table 3. Treatment-emergent adverse events in double-blind, placebo-controlled studies

	T-Forward (18–64 yrs)				T-Force GREEN (6–17 yrs)				T-Force GOLD (6–17 yrs)
	PBO n = 40	VBZ 40 mg n = 42	VBZ 80 mg n = 42	All VBZ n = 84	PBO n = 32	VBZ 10/20 mg^a n = 32	VBZ 20/40 mg^a n = 33	All VBZ n = 65	PBO n = 62	VBZ 20–80 mg n = 59
Total TEAEs	21 (52.5)	31 (73.8)	40 (95.2)	71 (84.5)	17 (53.1)	19 (59.4)	24 (72.7)	43 (66.2)	38 (61.3)	43 (72.9)
SAEs	1 (2.5)	1 (2.4)	2 (4.8)	3 (3.6)	1 (3.1)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.6)	0 (0.0)
Discontinuations due to TEAE	1 (2.5)	3 (7.1)	13 (31.0)	16 (19.0)	2 (6.3)	0 (0.0)	2 (6.1)	2 (3.1)	3 (4.8)	8 (13.6)
Deaths	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Common TEAEs by preferred term^b
Somnolence	1 (2.5)	8 (19.0)	9 (21.4)	17 (20.2)	1 (3.1)	4 (12.5)	3 (9.1)	7 (10.8)	0 (0.0)	11 (18.6)
Headache	2 (5.0)	6 (14.3)	2 (4.8)	8 (9.5)	3 (9.4)	6 (18.8)	3 (9.1)	9 (13.8)	5 (8.1)	11 (18.6)
Fatigue	1 (2.5)	5 (11.9)	7 (16.7)	12 (14.3)	0 (0.0)	1 (3.1)	2 (6.1)	3 (4.6)	5 (8.1)	6 (10.2)
Akathisia	0 (0.0)	1 (2.4)	10 (23.8)	11 (13.1)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.6)	0 (0.0)
Vomiting	0 (0.0)	0 (0.0)	3 (7.1)	3 (3.6)	1 (3.1)	2 (6.3)	1 (3.0)	3 (4.6)	4 (6.5)	6 (10.2)
URTI	3 (7.5)	3 (7.1)	2 (4.8)	5 (6.0)	0 (0.0)	1 (3.1)	5 (15.2)	6 (9.2)	0 (0.0)	1 (1.7)
Suicidal ideation	0 (0.0)	1 (2.4)	1 (2.4)	2 (2.4)	0 (0.0)	0 (0.0)	2 (6.1)	2 (3.1)	1 (1.6)	5 (8.5)
Insomnia	0 (0.0)	0 (0.0)	5 (11.9)	5 (6.0)	1 (3.1)	2 (6.3)	3 (9.1)	5 (7.7)	2 (3.2)	1 (1.7)
Sedation	1 (2.5)	1 (2.4)	4 (9.5)	5 (6.0)	0 (0.0)	2 (6.3)	3 (9.1)	5 (7.7)	0 (0.0)	0 (0.0)
Irritability	1 (2.5)	1 (2.4)	1 (2.4)	2 (2.4)	3 (9.4)	2 (6.3)	2 (6.1)	4 (6.2)	2 (3.2)	3 (5.1)
Anxiety	1 (2.5)	1 (2.4)	4 (9.5)	5 (6.0)	1 (3.1)	0 (0.0)	2 (6.1)	2 (3.1)	2 (3.2)	3 (5.1)
Nausea	1 (2.5)	1 (2.4)	4 (9.5)	5 (6.0)	2 (6.3)	0 (0.0)	1 (3.0)	1 (1.5)	2 (3.2)	3 (5.1)
Lethargy	0 (0.0)	2 (4.8)	3 (7.1)	5 (6.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Pain in extremity	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	2 (6.3)	1 (3.0)	3 (4.6)	0 (0.0)	3 (5.1)
Abdominal pain upper	1 (2.5)	0 (0.0)	1 (2.4)	1 (1.2)	1 (3.1)	2 (6.3)	0 (0.0)	2 (3.1)	2 (3.2)	3 (5.1)
Restlessness	0 (0.0)	0 (0.0)	2 (4.8)	2 (2.4)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	3 (5.1)
Influenza	0 (0.0)	0 (0.0)	1 (2.4)	1 (1.2)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.6)	3 (5.1)
GERD	1 (2.5)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	3 (5.1)

^aThe VBZ 10/20 mg group includes children randomized to VBZ 10 mg and adolescents randomized to VBZ 20 mg; the VBZ 20/40 mg group includes children randomized to VBZ 20 mg and adolescents randomized to VBZ 40 mg.

^bReported in ≥5% of all valbenazine-treated subjects in any study at an incidence greater than in placebo.

GERD, gastroesophageal reflux disease; PBO, placebo; SAE, serious adverse event; TEAE, treatment-emergent adverse event; URTI, upper respiratory tract infection; VBZ, valbenazine; yrs, years.

Figure 2. Secondary/exploratory efficacy outcomes by visit and treatment group in T-Force GOLD

*P< 0.05, **P< 0.01, ***P< 0.001 for valbenazine versus placebo. CGI-Tics-Severity, Clinical Global Impression of Tics-Severity; CGI-TS-Improvement, Clinical Global Impression of Change-Tourette Syndrome-Improvement. (a) Change from Baseline in CGI-Tics-Severity (b) CGI-TS-Improvement Score.

Figure 3. Change from baseline in YGTSS TTS by visit in 24-week, open-label, extension studies

YGTSS TTS, Yale Global Tic Severity Scale Total Tic Score. (a) T-Fusion (b) T-Force GOLD+.

Data availability statement

The datasets generated during and/or analyzed during the current study are not publicly available due to valbenazine being a product that has not been approved for the treatment of patients with Tourette syndrome but available from the corresponding author on reasonable request.