Phase I study
In 48 subjects, all Japanese who received the study drug, no AEs were observed, and no clinically significant changes such as abnormal laboratory values were observed (range for patient recruitment and follow-up: November 14, 2014 to July 13, 2015). In addition, the plasma concentration of tipepidine was increased in a dose-dependent manner (data not shown) after a single administration of TS-141 15, 30, and 60 mg to the same subject with dose-up design, and there was almost no influence of diet. After a repeated administration of TS-141, the plasma concentration of tipepidine reached almost a steady state 3 days after the administration, and no accumulation was observed. When comparing the plasma concentration of tipepidine after the administration of Asverin, TS-141 functioned as a sustained-release preparation and was confirmed to be appropriately exposed and well tolerated. In phase I study, no protocol deviations were observed.
The exposure of tipepidine in both TS-141 and Asverin groups widely varied (CV of AUC, 164% in TS-141; 155% in Asverin) among individuals; however, Cmax and AUC were correlated between TS-141 (n=32) and Asverin (n=48) (Fig 2). As a result of genetic testing of 42 subjects, individual differences on the plasma concentration of tipepidine were correlated with CYP2D6 phenotype. The distribution of polymorphisms was not different from the results of Japanese general epidemiological studies with 35 subjects with EM, 5 subjects with IM, and one subject with both UM and PM (Table 1). Table 2 shows the pharmacokinetic parameters of tipepidine in TS-141 and Asverin groups for each CYP2D6 phenotype. Cmax and AUC0-∞ values when TS-141 was administered were high in the order of PM, IM, EM, and UM.
Table 1. CYP2D6 allele frequency at TS-141 Phase I study.
CYP2D6 Phenotype
|
N
|
(%)
|
allele
|
N
|
(%)
|
Total
|
42
|
(100.0)
|
|
|
|
PM
|
1
|
(2.4)
|
*5/*5
|
1
|
(2.4)
|
IM
|
5
|
(11.9)
|
*5/*10
|
1
|
(2.4)
|
|
*10/*10
|
3
|
(7.1)
|
|
*10/*41
|
1
|
(2.4)
|
EM
|
35
|
(83.3)
|
*1/*1
|
9
|
(21.4)
|
|
*1/*2
|
2
|
(4.8)
|
|
*1/*5
|
2
|
(4.8)
|
|
*1/*10
|
14
|
(33.3)
|
|
*1/*10A
|
2
|
(4.8)
|
|
*1/*41
|
2
|
(4.8)
|
|
*2/*10
|
4
|
(9.5)
|
UM
|
1
|
(2.4)
|
*1/*2A
|
1
|
(2.4)
|
A: Amplification
Table 2. Pharmacokinetic parameter of tipepidine in TS-141 and Asverin group.
TS-141 30 mg
|
All Phenotypes
|
PM
|
IM
|
EM
|
UM
|
N
|
29
|
1
|
2
|
25
|
1
|
Cmax (ng/mL)
|
|
9.90 ± 11.6
|
57.1
|
24.9 ± 16.8
|
7.17 ± 4.66
|
1.06
|
AUC0-∞ (ng・h/mL)
|
arithmetic mean
|
83.9 ± 138
|
728
|
213 ± 148
|
51.0 ± 35.1
|
4.69
|
|
geometric mean
|
45.9
|
728
|
185
|
40.3
|
4.69
|
|
CV (%)
|
164
|
-
|
69.5
|
68.8
|
-
|
MRT0-∞ (h)
|
|
11.8 ± 4.70
|
17.0
|
9.86 ± 0.764
|
11.8 ± 4.93
|
11.0
|
Asverin 40 mg
|
All Phenotypes
|
PM
|
IM
|
EM
|
UM
|
N
|
42
|
1
|
5
|
35
|
1
|
Cmax (ng/mL)
|
|
30.7 ± 28.5
|
125
|
58.2 ± 26.2
|
24.9 ± 21.6
|
1.05
|
AUC0-∞ (ng・h/mL)
|
arithmetic mean
|
114 ± 177
|
1080
|
248 ± 126
|
70.5 ± 57.9
|
3.62
|
|
geometric mean
|
61.9
|
1080
|
220
|
51.6
|
3.62
|
|
CV (%)
|
155
|
-
|
50.8
|
82.2
|
-
|
MRT0-∞ (h)
|
|
4.67 ± 1.67
|
12.3
|
5.76 ± 0.578
|
4.33 ± 1.13
|
3.54
|
PM: Poor Metabolizer, IM: Intermediate Metabolizer, EM: Extensive Metabolizer, UM: Ultrarapid Metabolizer
Phase II study
Study population and characteristics
Of the 227 patients who participated in the study (range for patient recruitment and follow-up: May 12, 2016 to August 16, 2017), 216 were randomized for treatment into 4 groups (Fig 3): 211 received at least one dose of study medication (FAS population), and 195 were followed up based on the study protocol (PPS). Baseline patient characteristics in all treatment groups were similar and summarized in Table 3. Mean age for each group was between 9 and 10 years with male predominant. The mean IQ was 95.3 ± 13.5. The most common type was mixed (58.3%), followed by inattentiveness (41.2). Only one patient had hyperactive-impulsive type (TS-141 120 mg). About 22.7% of patients had ASD, without significant difference between the groups. About half of patients had history of previous treatment use for ADHD. The baseline ADHD RS-IV-J:I score (total score) was 33.8±6.8. The percentage of CYP2D6 phenotype for each group is also shown in Table 3. Only one patient with PM was assigned to the 30 mg group. Baseline scores and changes in the primary end-point, ADHD RS-IV-J:I total score, are shown in Table 4.
Table 3. Demographic characteristics at baseline (FAS).
|
Placebo
|
TS-141
30mg
|
TS-141
60mg
|
TS-141
120mg
|
Total
|
|
n=52
|
n=54
|
n=52
|
n=53
|
n=211
|
Gender, n (%)
|
|
|
|
|
|
|
|
|
|
|
Male
|
44
|
(84.6)
|
47
|
(87.0)
|
46
|
(88.5)
|
42
|
(79.2)
|
179
|
(84.8)
|
Female
|
8
|
(15.4)
|
7
|
(13.0)
|
6
|
(11.5)
|
11
|
(20.8)
|
32
|
(15.2)
|
Age, years
|
|
|
|
|
|
|
|
|
|
|
Mean ± SD
|
9.6 ± 2.1
|
9.8 ± 2.3
|
9.2 ± 2.2
|
9.7 ± 2.5
|
9.5 ± 2.3
|
Median
|
9.0
|
10.0
|
9.0
|
10.0
|
9.0
|
Min - Max
|
6 - 14
|
6 - 16
|
6 - 16
|
6 - 16
|
6 - 16
|
Intelligence Quotient
|
|
|
|
|
|
|
|
|
|
|
Mean ± SD
|
96.5 ± 14.5
|
96.6 ± 15.0
|
93.7 ± 12.6
|
94.4 ± 11.7
|
95.3 ± 13.5
|
Median
|
95.5
|
94.0
|
92.0
|
93.0
|
93.0
|
Min - Max
|
71 - 142
|
72 - 145
|
73 - 137
|
76 - 126
|
71 - 145
|
ADHD Subtype, n (%)
|
|
|
|
|
|
|
|
|
|
|
Combined
|
31
|
(59.6)
|
28
|
(51.9)
|
34
|
(65.4)
|
30
|
(56.6)
|
123
|
(58.3)
|
inattentive
|
21
|
(40.4)
|
26
|
(48.1)
|
18
|
(34.6)
|
22
|
(41.5)
|
87
|
(41.2)
|
hyperactive-impulsive
|
|
|
|
|
|
|
1
|
(1.9)
|
1
|
(0.5)
|
Complication: ASD, n (%)
|
|
|
|
|
|
|
|
|
|
|
Absence
|
40
|
(76.9)
|
45
|
(83.3)
|
37
|
(71.2)
|
41
|
(77.4)
|
163
|
(77.3)
|
Presence
|
12
|
(23.1)
|
9
|
(16.7)
|
15
|
(28.8)
|
12
|
(22.6)
|
48
|
(22.7)
|
Prior medication, n (%)
|
|
|
|
|
|
|
|
|
|
|
Absence
|
20
|
(38.5)
|
27
|
(50.0)
|
27
|
(51.9)
|
31
|
(58.5)
|
105
|
(49.8)
|
Presence
|
32
|
(61.5)
|
27
|
(50.0)
|
25
|
(48.1)
|
22
|
(41.5)
|
106
|
(50.2)
|
ADHD RS-IV-J: investigator
|
|
|
|
|
|
|
|
|
|
|
Mean ± SD
|
34.7 ± 6.4
|
33.4 ± 7.4
|
34.9 ± 7.1
|
32.3 ± 5.8
|
33.8 ± 6.8
|
Median
|
34.0
|
32.0
|
35.0
|
32.0
|
33.0
|
CYP2D6 Phenotype, n (%)
|
|
|
|
|
|
|
|
|
|
|
PM
|
|
|
1
|
(1.9)
|
|
|
|
|
1
|
(0.5)
|
IM
|
9
|
(17.3)
|
9
|
(16.7)
|
10
|
(19.2)
|
11
|
(20.8)
|
39
|
(18.5)
|
EM
|
43
|
(82.7)
|
44
|
(81.5)
|
39
|
(75.0)
|
40
|
(75.5)
|
166
|
(78.7)
|
UM
|
|
|
|
|
1
|
(1.9)
|
2
|
(3.8)
|
3
|
(1.4)
|
Unknown type/Unable to be determined
|
|
|
|
|
2
|
(3.8)
|
|
|
2
|
(0.9)
|
Table 4. Mean changes in ADHD RS-IV-J:I over time for all treatment groups (FAS).
|
Placebo
|
TS-141 30 mg
|
TS-141 60 mg
|
TS-141 120 mg
|
|
(N=52)
|
(N=54)
|
(N=52)
|
(N=53)
|
ADHD RS-IV-J:I
|
|
|
Difference with placebo
|
|
Difference with placebo
|
|
Difference with placebo
|
Start of the study (Mean ± SD)
|
34.7 ± 6.4
|
33.4 ± 7.4
|
-
|
34.9 ± 7.1
|
-
|
32.3 ± 5.8
|
-
|
Change from Baseline(Point estimate [95%CI])
|
Week 2
|
-3.8
[-5.6 - -2.1]
|
-3.6
[-5.3 - -1.9]
|
0.2
[-1.8 - 2.2]
|
-3.1
[-4.9 - -1.3]
|
0.7
[-1.3 - 2.7]
|
-4.2
[-5.9 - -2.4]
|
-0.3
[-2.3 - 1.7]
|
Week 4
|
-6.0
[-8.4 - -3.6]
|
-4.7
[-6.9 - -2.5]
|
1.3
[-1.3 - 3.8]
|
-3.9
[-6.2 - -1.5]
|
2.1
[-0.4 - 4.7]
|
-6.2
[-8.5 - -3.9]
|
-0.2
[-2.8 - 2.3]
|
Week 8
|
-9.1
[-11.9 - -6.2]
|
-6.9
[-9.6 - -4.2]
|
2.2
[-0.8 - 5.2]
|
-5.4
[-8.1 - -2.6]
|
3.7
[0.6 - 6.7]
|
-9.0
[-11.7 - -6.3]
|
0.0
[-3.0 - 3.0]
|
End of the study
|
-8.0
[-10.6 - -5.4]
|
-6.0
[-8.5 - -3.5]
|
2.0
[-0.9 - 4.8]
|
-4.9
[-7.5 - -2.3]
|
3.1
[0.2 - 6.0]
|
-8.5
[-11.0 - -5.9]
|
-0.5
[-3.4 - 2.4]
|
Efficacy: Primary analysis
The score decreased over time from week 2 to the end of period, week 8, in all groups. In any of the TS-141 treatment groups, no significant improvement in ADHD RS-IV-J:I total score change was observed at the end of the study as compared with the placebo group (placebo: −8.0 [−10.6 to −5.4], TS-141 30 mg: −6.0 [−8.5 to −3.5], TS-141 60 mg: −4.9 [−7.5 to −2.3], and TS-141 120 mg: −8.5 [−11.0 to −5.9] at the end of the study), and no dose response was observed. Similar results were obtained for secondary end-points (data not shown).
Efficacy: Subgroup analysis
The ADHD RS-IV-J:I (mean±SD) changes in the placebo and 120 mg treatment groups were −6.1±11.1 and −11.2±9.5 in CYP2D6 IM group (the slow metabolizer group), but no difference in the CYP2D6 EM group (the rapid metabolizer group) (Table 5). The total score change tended to increase from UM to PM when considering each dose curve. Moreover, each dose curve has a different slope (Fig 4).
Table.5 Mean changes in ADHD RS-IV-J:I by CYP2D6 phenotype in the subgroup analysis (FAS).
CYP2D6 phenotype
|
UM
|
EM
|
IM
|
PM
|
Placebo
|
|
-8.5 ± 8.4 (43)
|
-6.1 ± 11.1 (9)
|
|
TS-141 30 mg
|
|
-5.5 ± 7.0 (44)
|
-5.6 ± 5.6 (9)
|
-23.0 (1)
|
TS-141 60 mg
|
-6.0 (1)
|
-5.5 ± 6.9 (39)
|
-3.9 ± 5.0 (10)
|
|
TS-141 120 mg
|
-2.0 ± 4.2 (2)
|
-7.6 ± 7.1 (40)
|
-11.2 ± 9.5 (11)
|
|
Mean ± SD (N)
Safety
The safety of TS-141 was examined in 211 patients who received at least one dose of the study medication. The incidence of AEs was 36.5% (placebo), 51.9% (30 mg), 46.2% (60 mg), and 49.1% (120 mg), and the incidence of side effects was 3.8% (placebo), 5.6% (30 mg), 17.3% (60 mg), and 3.8% (120 mg), but no significant difference was observed between the groups (Table 6). No death occurred, and only one serious AE was reported in the placebo group. Although three patients in the TS-141 group stopped treatment because of AEs, all of them recovered and the consequence of study drug was denied. The most common side effect was somnolence, one of the side effects of Asverin, which occurred (frequency of occurrence) in 2 (3.8%), 2 (3.7%), 5 (9.6%), and 0 (0%) patients in the placebo, TS-141 30 mg, 60 mg, and 120 mg, respectively. No clinically significant changes in laboratory test, body weight, and vital signs were observed. An ECG abnormality was observed in one patient in the placebo group, but not in the TS-141 treatment groups. As a result of C-SSRS, suicidal ideation was observed in one patient in the 30 mg group after the study drug administration, but bullying from a classmate was reported and the event was clearly associated with suicidal ideation without causal relationship with the study drug and with mild symptoms. Therefore, the trial was continued. There was no clinical difference in any safety data between CYP2D6 polymorphism, including the patient with CYP2D6 PM.
Table 6. Summary of overall safety and adverse drug reactions during the 8 weeks treatment.
|
Placebo
|
TS-141 30 mg
|
TS-141 60 mg
|
TS-141 120 mg
|
|
N=52
|
(%)
|
N=54
|
(%)
|
N=52
|
(%)
|
N=53
|
(%)
|
AE
|
19
|
(36.5)
|
28
|
(51.9)
|
24
|
(46.2)
|
26
|
(29.1)
|
AE leading to death
|
0
|
(0.0)
|
0
|
(0.0)
|
0
|
(0.0)
|
0
|
(0.0)
|
Serious Adverse Event
|
1
|
(1.9)
|
0
|
(0.0)
|
0
|
(0.0)
|
0
|
(0.0)
|
AE leading to discontinuation
|
1
|
(1.9)
|
0
|
(0.0)
|
0
|
(0.0)
|
0
|
(0.0)
|
Adverse drug reactions
|
2
|
(3.8)
|
3
|
(5.6)
|
9
|
(17.3)
|
2
|
(3.8)
|
Constipation
|
|
|
|
|
1
|
(1.9)
|
|
|
Nausea
|
|
|
|
|
|
|
1
|
(1.9)
|
Decreased appetite
|
|
|
|
|
1
|
(1.9)
|
|
|
Headache
|
|
|
1
|
(1.9)
|
|
|
|
|
Somnolence
|
2
|
(3.8)
|
2
|
(3.7)
|
5
|
(9.6)
|
|
|
Inappropriate affect
|
|
|
|
|
2
|
(3.8)
|
|
|
Insomnia
|
|
|
|
|
1
|
(1.9)
|
|
|
Eczema
|
|
|
|
|
|
|
1
|
(1.9)
|