Introduction
Materials and methods
Study objectives
Subjects
Study design
BTH1677 Dose Level (mg/kg) | Dosed in Phase 1a | Dosed in Phase 1b | Total Infusion Volume (mL) | BTH1677 Concentration in Infusion Volume (mg/mL)a
| Infusion Time (hr) | Rate of Infusion (mg/min)a
|
---|---|---|---|---|---|---|
0.5 | Yes | No | 250 | 0.15 | 1 | 0.63 |
1.0 | Yes | Yes | 250 | 0.3 | 1 | 1.25 |
2.0 | Yes | Yes | 250 | 0.6 | 1 | 2.50 |
4.0 | Yes | No | 500 | 0.6 | 1 | 5.00 |
Yes | Yes | 500 | 0.6 | 2 | 2.50 | |
6.0 | Yes | No | 750 | 0.6 | 3 | 2.50 |
BTH1677
Pharmacokinetic analysis
Statistical analysis
Results
Phase 1a study
Subject demographics
Phase 1a Single-Dose Study Treatment Groups | Phase 1b Multiple-Dose Study Treatment Groups | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
BTH1677 | Placebo | BTH1677 | Placebo | |||||||||||
0.5 mg/kg (1-h infusion) (n = 3) | 1 mg/kg (1-h infusion) (n = 3) | 2 mg/kg (1-h infusion) (n = 4) | 4 mg/kg (1-h infusion) (n = 2) | 4 mg/kg (2-h infusion) (n = 3) | 6 mg/kg (3-h infusion) (n = 3) | All BTH1677 (n = 18) | All BTH1677 Minus 4 mg/kg 1-h Infusion Groupa (n = 16) | All Placebob (n = 6) | 1 mg/kg (1-h infusion) (n = 3) | 2 mg/kg (1-h infusion) (n = 3) | 4 mg/kg (2-h infusion) (n = 3) | All BTH1677 (n = 9) | All Placebob (n = 3) | |
Sexc
| ||||||||||||||
Male | 2 (66.7) | 3 (100.0) | 3 (75.0) | 2 (100.0) | 2 (66.7) | 1 (33.3) | 13 (72.2) | 11 (68.8) | 6 (100.0) | 1 (33.3) | 1 (33.3) | 2 (66.7) | 4 (44.4) | 1 (33.3) |
Female | 1 (33.3) | 0 (0.0) | 1 (25.0) | 0 (0.0) | 1 (33.3) | 2 (66.7) | 5 (27.8) | 5 (31.2) | 0 (0.0) | 2 (66.7) | 2 (66.7) | 1 (33.3) | 5 (55.6) | 2 (66.7) |
Racec
| ||||||||||||||
Caucasian | 3 (100.0) | 1 (33.3) | 3 (75.0) | 2 (100.0) | 2 (67.7) | 2 (67.7) | 13 (72.2) | 11 (68.8) | 5 (83.3) | 2 (66.7) | 3 (100.0) | 3 (100.0) | 8 (88.9) | 2 (66.7) |
African-American | 0 (0.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 1 (33.3) | 1 (33.3) | 3 (16.7) | 3 (18.8) | 1 (16.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Hispanic | 0 (0.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (5.6) | 1 (6.2) | 0 (0.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 1 (11.1) | 1 (33.3) |
Asian | 0 (0.0) | 0 (0.0) | 1 (25.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (5.6) | 1 (6.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Age (years) | ||||||||||||||
Mean | 27.7 | 27.0 | 27.5 | 19.5 | 26.3 | 23.0 | 25.1 | 26.4 | 28.0 | 26.0 | 21.7 | 36.3 | 28.0 | 23.7 |
SDd
| 12.5 | 8.7 | 11.2 | 2.1 | 10.4 | 3.6 | 8.6 | 8.7 | 8.8 | 12.1 | 2.1 | 10.8 | 10.5 | 4.0 |
Median | 22.0 | 23.0 | 23.5 | 19.5 | 23.0 | 22.0 | 22.4 | 23.0 | 24.5 | 19.0 | 21.0 | 41.0 | 24.0 | 23.0 |
Min, Max | 19, 42 | 21, 37 | 19, 44 | 18, 21 | 18, 38 | 20, 27 | 18, 44 | 18, 44 | 21, 43 | 19, 40 | 20, 24 | 24, 44 | 19, 44 | 20, 28 |
Weight (kg) | ||||||||||||||
Mean | 92.37 | 79.43 | 79.70 | 91.30 | 67.33 | 72.23 | 79.75 | 78.31 | 84.48 | 67.50 | 65.70 | 81.27 | 71.49 | 67.30 |
SDd
| 12.208 | 23.133 | 20.112 | 8.202 | 10.748 | 21.134 | 16.585 | 17.856 | 23.531 | 6.062 | 8.072 | 9.139 | 10.037 | 16.543 |
Median | 86.50 | 83.60 | 80.50 | 91.30 | 72.30 | 66.30 | 79.48 | 79.15 | 80.45 | 64.00 | 68.10 | 83.90 | 71.10 | 58.00 |
Min | 84.2 | 54.5 | 56.6 | 85.5 | 55.0 | 54.7 | 55.5 | 54.5 | 61.7 | 64.0 | 56.7 | 71.1 | 56.7 | 57.5 |
Max | 106.4 | 100.2 | 101.2 | 97.1 | 74.7 | 95.7 | 106.4 | 106.4 | 122.7 | 74.5 | 72.3 | 88.8 | 88.8 | 86.4 |
BTH1677 drug administration
Safety
Phase 1a Single-Dose Study Treatment Groups | Phase 1b Multiple-Dose Study Treatment Groups | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
BTH1677 | Placebo | BTH1677 | Placebo | |||||||||||
0.5 mg/kg (1-h infusion) (n = 3) | 1 mg/kg (1-h infusion) (n = 3) | 2 mg/kg (1-h infusion) (n = 4) | 4 mg/kg (1-h infusion) (n = 2) | 4 mg/kg (2-h infusion) (n = 3) | 6 mg/kg (3-h infusion) (n = 3) | All BTH1677 (n = 18) | All BTH1677 Minus 4 mg/kg 1-h Infusion Groupa (n = 16) | All Placebob (n = 6) | 1 mg/kg (1-h infusion) (n = 3) | 2 mg/kg (1-h infusion) (n = 3) | 4 mg/kg (2-h infusion) (n = 3) | All BTH1677 (n = 9) | All Placebob (n = 3) | |
Subjects with AEs, n (%)c
| 3 (100.0) | 1 (33.3) | 2 (50.0) | 2 (100.0) | 1 (33.3) | 3 (100.0) | 12 (66.7) | 10 (62.5) | 3 (50.0) | 1 (33.3) | 2 (66.7) | 3 (100.0) | 6 (66.7) | 2 (66.7) |
Mild | 3 (100.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 1 (33.3) | 2 (66.7) | 7 (38.9) | 7 (43.8) | 1 (16.7) | 1 (33.3) | 0 (0.0) | 1 (33.3) | 2 (22.2) | 0 (0.0) |
Moderate | 0 (0.0) | 0 (0.0) | 2 (50.0) | 2 (100.0) | 0 (0.0) | 1 (33.3) | 5 (27.8) | 3 (18.8) | 2 (33.3) | 0 (0.0) | 2 (66.7) | 2 (66.7) | 4 (44.4) | 2 (66.7) |
Severe | 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) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
AEs, n | 4 | 1 | 3 | 10 | 2 | 8 | 28 | 18 | 10e
| 3 | 2 | 3 | 8 | 3 |
Mean AEs per subject | 1.3 | 1.0 | 1.5 | 5.0 | 2.0 | 2.7 | 2.3 | 1.1 | 3.3e
| 3.0 | 1.0 | 1.0 | 1.3 | 1.5 |
SAEs, n (%) | 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) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Deaths, n (%) | 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) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Subjects who discontinued due to AEs, n (%) | 0 (0.0) | 0 (0.0) | 1 (25.0) | 2 (100.0) | 0 (0.0) | 1 (33.3) | 4 (22.2) | 2 (12.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (33.3) | 1 (11.1) | 1 (33.3) |
Subjects with AEs assessed as treatment related, n (%)c
,
d
| 2 (66.7) | 1 (33.3) | 1 (25.0) | 2 (100.0) | 0 (0.0) | 3 (100.0) | 9 (50.0) | 7 (43.8) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (66.7) | 2 (22.2) | 1 (33.3) |
Mild | 2 (66.7) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (66.7) | 5 (27.8) | 5 (31.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (33.3) | 1 (11.1) | 0 (0.0) |
Moderate | 0 (0.0) | 0 (0.0) | 1 (25.0) | 2 (100.0) | 0 (0.0) | 1 (33.3) | 4 (22.2) | 2 (12.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (33.3) | 1 (11.1) | 1 (33.3) |
Severe | 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) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
AEs assessed as treatment related, n | 2 | 1 | 1 | 9 | 0 | 8 | 21 | 12 | 0 | 0 | 0 | 2 | 2 | 1 |
Mean treatment-related AEs per subject | 1.0 | 1.0 | 1.0 | 4.5 | 0.0 | 2.7 | 2.3 | 1.7 | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 1.0 |
System Organ Class and Preferred Term a,b
| Treatment Group | |||||||
---|---|---|---|---|---|---|---|---|
BTH1677 | Placebo | |||||||
0.5 mg/kg (1-h infusion) (n = 3) | 1 mg/kg (1-h infusion) (n = 3) | 2 mg/kg (1-h infusion) (n = 4) | 4 mg/kg (1-h infusion) (n = 2) | 4 mg/kg (2-h infusion) (n = 3) | 6 mg/kg (3-h infusion) (n = 3) | All BTH1677 (n = 18) | All Placeboc (n = 6) | |
Subjects with any AE/Treatment-related AE
|
3/2
|
1/1
|
2/1
|
2/2
|
1/0
|
3/3
|
12/9
|
3/0
|
Cardiac disorders
|
0/0
|
0/0
|
0/0
|
1/1
|
0/0
|
0/0
|
1/1
|
0/0
|
Tachycardia | 0/0 | 0/0 | 0/0 | 1/1d
| 0/0 | 0/0 | 1/0 | 0/0 |
Eye disorders
|
0/0
|
0/0
|
0/0
|
0/0
|
0/0
|
0/0
|
0/0
|
1/0
|
Photophobia | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 1/0 |
Gastrointestinal disorders
|
0/0
|
0/0
|
0/0
|
1/1
|
0/0
|
1/1
|
2/2
|
1/0
|
Nausea | 0/0 | 0/0 | 0/0 | 1/1d
| 0/0 | 1/1 | 2/2 | 0/0 |
Diarrhea | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 1/0 |
Flatulence | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 1/0 |
Gingival pain | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 1/0 |
Toothache | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 1/0 |
General disorders and administration site conditions
|
0/0
|
1/1
|
0/0
|
0/0
|
0/0
|
2/2
|
3/3
|
0/0
|
Chest discomfort | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 1/1 | 1/1 | 0/0 |
Chills | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 1/1 | 1/1 | 0/0 |
Infusion site pain | 0/0 | 1/1 | 0/0 | 0/0 | 0/0 | 0/0 | 1/1 | 0/0 |
Infections and infestations
|
1/0
|
0/0
|
0/0
|
0/0
|
0/0
|
0/0
|
1/0
|
0/0
|
Upper respiratory tract infection | 1/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 1/0 | 0/0 |
Injury, poisoning and procedural complications
|
0/0
|
0/0
|
1/0
|
0/0
|
1/0
|
0/0
|
2/0
|
0/0
|
Back injury | 0/0 | 0/0 | 1/0 | 0/0 | 0/0 | 0/0 | 1/0 | 0/0 |
Laceration | 0/0 | 0/0 | 0/0 | 0/0 | 1/0 | 0/0 | 1/0 | 0/0 |
Investigations
|
0/0
|
0/0
|
0 /0
|
1/0
|
0/0
|
0/0
|
1/0
|
0/0
|
White blood cell count decreased | 0/0 | 0/0 | 0/0 | 1/0 | 0/0 | 0/0 | 1/0 | 0/0 |
Musculoskeletal and connective tissue disorders
|
0/0
|
0/0
|
1/0
|
0/0
|
0/0
|
0/0
|
1/0
|
0/0
|
Arthralgia | 0/0 | 0/0 | 1/0 | 0/0 | 0/0 | 0/0 | 1/0 | 0/0 |
Nervous system disorders
|
2/2
|
0/0
|
0/0
|
1/1
|
0/0
|
2/2
|
5/5
|
2/0
|
Headache | 2/2 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 2/2 | 2/0 |
Dizziness | 0/0 | 0/0 | 0/0 | 1/1d
| 0/0 | 0/0 | 1/1 | 1/0 |
Paraesthesia | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 2/2d
| 2/2 | 0/0 |
Hypoaesthesia | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 1/1d
| 1/1 | 0/0 |
Migraine | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 1/0 |
Respiratory, thoracic and mediastinal disorders
|
1/0
|
0/0
|
0/0
|
2/2
|
0/0
|
1/1
|
4/3
|
0/0
|
Dyspnea | 0/0 | 0/0 | 0/0 | 2/2d
| 0/0 | 1/1d
| 3/3 | 0/0 |
Throat irritation | 1/0 | 0/0 | 0/0 | 0/0 | 0/0 | 0/0 | 1/0 | 0/0 |
Skin and subcutaneous tissue disorders
|
0/0
|
0/0
|
1/1
|
2/2
|
1/0
|
1/1
|
5/4
|
0/0
|
Rash | 0/0 | 0/0 | 1/1d
| 0/0 | 0/0 | 1/1d
| 2/2 | 0/0 |
Ecchymosis | 0/0 | 0/0 | 0/0 | 0/0 | 1/0 | 0/0 | 1/0 | 0/0 |
Hyperhidrosis | 0/0 | 0/0 | 0/0 | 1/1d
| 0/0 | 0/0 | 1/1 | 0/0 |
Pruritus | 0/0 | 0/0 | 0/0 | 1/1d
| 0/0 | 0/0 | 1/1 | 0/0 |
Vascular disorders
|
0/0
|
0/0
|
0/0
|
2/2
|
0/0
|
0/0
|
2/2
|
0/0
|
Flushing | 0/0 | 0/0 | 0/0 | 2/2d
| 0/0 | 0/0 | 2/2 | 0/0 |
Phase 1b study
Subject demographics
BTH1677 drug administration
Safety
System Organ Class and Preferred Terma
,
b
| Treatment Group | ||||
---|---|---|---|---|---|
BTH1677 | Placebo | ||||
1 mg/kg (1-h infusion) (n = 3) | 2 mg/kg (1-h infusion) (n = 3) | 4 mg/kg (2-h infusion) (n = 3) | All BTH1677 (n = 9) | All Placeboc (n = 3) | |
Subjects with any AE/Treatment-related AE
|
1/0
|
2/0
|
3/2
|
6/2
|
2/1
|
Blood and lymphatic system disorders
|
0/0
|
1/0
|
0/0
|
1/0
|
0/0
|
Anemia | 0/0 | 1/0 | 0/0 | 1/0 | 0/0 |
Eye disorders
|
1/0
|
0/0
|
1/1
|
2/1
|
0/0
|
Conjunctivitis | 0/0 | 0/0 | 1/1d
| 1/1 | 0/0 |
Vision blurred | 1/0 | 0/0 | 0/0 | 1/0 | 0/0 |
General disorders and administration site conditions
|
1/0
|
0/0
|
0/0
|
1/0
|
1/0
|
Fatigue | 1/0 | 0/0 | 0/0 | 1/0 | 0/0 |
Pain | 0/0 | 0/0 | 0/0 | 0/0 | 1/0 |
Injury, poisoning, and procedural complications
|
0/0
|
1/0
|
0/0
|
1/0
|
0/0
|
Excoriation | 0/0 | 1/0 | 0/0 | 1/0 | 0/0 |
Investigations
|
0/0
|
0/0
|
0/0
|
0/0
|
1/1
|
Blood creatinine kinase increased | 0/0 | 0/0 | 0/0 | 0/0 | 1/1d
|
Musculoskeletal and connective tissue disorders
|
0/0
|
0/0
|
1/0
|
1/0
|
1/0
|
Musculoskeletal stiffness | 0/0 | 0/0 | 1/0 | 1/0 | 0/0 |
Myalgia | 0/0 | 0/0 | 0/0 | 0/0 | 1/0 |
Nervous system disorders
|
1/0
|
0/0
|
1/1
|
2/1
|
0/0
|
Headache | 1/0 | 0/0 | 1/1 | 2/1 | 0/0 |
Pharmacokinetic analysis
Pharmacokinetic Parametersa
| ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
BTH1677 Dose (mg/kg) | Infusion Time (hr) | N | AUC(0–24) (hr*mcg/mL) | AUC(0-last) (hr*mcg/mL) | AUC(0-∞) (hr*mcg/mL) | CL (mL/h) | Cmax (mcg/mL) | t1/2 (hr) | Tmax (hr) | Vss (mL) |
0.5 | 1.0 | 3 | 56.55 ± 9.72 | 74.18 ± 8.11 | 74.96 ± 8.12 | 619.25 ± 84.21 | 14.76 ± 4.09 | 28.55 ± 18.96 | 1.00 ± 0.00 | 10,330.31 ± 1717.26 |
1 | 1.0 | 3 | 119.69 ± 43.99 | 166.76 ± 57.12 | 169.53 ± 59.58 | 475.73 ± 31.88 | 29.72 ± 16.60 | 31.10 ± 10.00 | 1.08 ± 0.14 | 10,903.43 ± 416.17 |
2 | 1.0 | 3 | 233.04 ± 60.25 | 290.89 ± 76.53 | 292.33 ± 75.65 | 530.38 ± 144.79 | 32.83 ± 9.08 | 23.36 ± 8.69 | 1.00 ± 0.00 | 7794.36 ± 4131.94 |
4b
| 1.0 | 2 | 83.01 ± 41.98 | 315.73 ± 159.99 | NCc
| NC | 5.94 ± 3.05 | NC | 1.12 ± 0.18 | NC |
4 | 2.0 | 3 | 325.43 ± 58.16 | 429.69 ± 65.77 | 442.66 ± 60.63 | 617.91 ± 143.58 | 51.24 ± 15.45 | 32.75 ± 12.22 | 2.00 ± 0.00 | 14,400.69 ± 7379.93 |
6d
| 3.0 | 3 | 459.60 ± 174.05 | 868.01 ± 107.06 | 837.59 ± 116.59 | 441.76 ± 120.25 | 53.60 ± 28.24 | 29.52 ± 1.55 | 2.67 ± 1.53 | 10,386.67 ± 1728.99 |
Pharmacokinetic Parametersa
| ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Day 0
| ||||||||||
BTH1677 Dose (mg/kg) | Infusion Time (hr) | N | AUC(0–24) (hr*mcg/mL) | AUC(0-∞)
b (hr*mcg/mL) | CL b (mL/h) | Cmax (mcg/mL) | t1/2β
b (hr) | Tmax
c (hr) | Vss
b (mL) | |
1 | 1.0 | 3 | 100.64 ± 8.92 | 132.97 ± 26.84 | 522.90 ± 121.60 | 12.65 ± 2.89 | 13.83 ± 3.97 | 2.00 ± 1.73 | 7890.09 ± 575.59 | |
2 | 1.0 | 3 | 181.17 ± 24.35 | 214.98 ± 31.19 | 619.83 ± 123.40 | 36.82 ± 4.73 | 12.33 ± 1.88 | 1.08 ± 0.14 | 6895.74 ± 1228.75 | |
4 | 2.0 | 3 | 369.70 ± 36.14 | 448.25 ± 60.18 | 734.56 ± 139.45 | 63.32 ± 16.48 | 11.66 ± 4.06 | 2.50 ± 0.00 | 8966.61 ± 2812.58 | |
Day 6–30 (Steady State Days)
| ||||||||||
BTH1677 Dose (mg/kg) | Infusion Time (hr) | N | AUC(0-λ) (hr*mcg/mL) | AUC(0-last) (hr*mcg/mL) | AUC(0-∞) (hr*mcg/mL) | CLss (mL/h) | Cmax (mcg/mL) | t½β (hr) | Tmax
c (hr) | Vss (mL) |
1 | 1.0 | 3 | 134.17 ± 36.10 | 332.57 ± 145.99 | 335.20 ± 146.61 | 528.95 ± 146.83 | 17.06 ± 2.92 | 80.97 ± 48.04 | 1.42 ± 0.52 | 20,385.20 ± 3273.42 |
2 | 1.0 | 3 | 230.85 ± 25.20 | 615.85 ± 120.44 | 624.57 ± 117.06 | 572.11 ± 79.72 | 31.93 ± 3.96 | 109.51 ± 21.80 | 1.50 ± 0.50 | 27,223.33 ± 4208.05 |
4 | 2.0 | 2d
| 639.20 ± 99.43 | 1483.88 ± 210.62 | 1494.10 ± 213.00 | 512.61 ± 158.06 | 78.07 ± 21.57 | 95.16 ± 4.93 | 2.62 ± 0.53 | 21,986.52 ± 15,281.20 |