Article Figures & Data
Figures
- FIG 1
The components of AVI-6002 are AVI-7537 and AVI-7539, each of which is a phosphorodiamidate morpholino oligomer in which the dimethylamine linkage sites have been replaced with a piperazine rings at defined locations along the backbone to confer a net positive charge.
- FIG 2
The components of AVI-6003 are AVI-7287 and AVI-7288, each of which is a phosphorodiamidate morpholino oligomer in which dimethylamine linkage sites have been replaced with a piperazine rings at defined locations along the backbone to confer a net positive charge.
- FIG 3
Time-concentration curves of the components of AVI-6002 (AVI-7537 [A] and AVI-7539 [B]) and the components of AVI-6003 (AVI-7287 [C] and AVI-7288 [D]).
- FIG 4
Mean Cmax by dose of components of AVI-6002 (AVI-7537 [○] and AVI-7539 [□]) and AVI-6003 (AVI-7287 [+] and AVI-7288 [◇]). Linear regression analysis yielded R2 values of 0.96 for AVI-7537, 0.94 for AVI-7539, 0.96 for AVI-7287, and 1.00 for AVI-7288. The Cmax (ng/ml) slopes per mg/kg dose are 5,701 ± 568 for AVI-7537, 6,069 ± 780 for AVI-7539, 5,545 ± 534 for AVI-7287, and 6,122 ± 182 for AVI-7288. An individual linear regression line is plotted for each agent.
- FIG 5
Mean AUC0–24 by dose of components of AVI-6002 (AVI-7537 [○] and AVI-7539 [□]) and AVI-6003 (AVI-7287 [+] and AVI-7288 [◇]). Linear regression analysis yielded R2 values of 0.99 for AVI-7537, 0.98 for AVI-7539, 0.99 for AVI-7287, and 1.00 for AVI-7288. The AUC0–24 (h·ng/ml) slopes per mg/kg dose are 8,095 ± 442 for AVI-7537, 8,612 ± 635 for AVI-7539, 7,961 ± 325 for AVI-7287, and 7,244 ± 154 for AVI-7288. An individual linear regression line is plotted for each agent.
Tables
- TABLE 1
Study agents
Parent compound PMOplus component Molecular mass (Da) No. of nucleobases Nucleobase composition (%) No. of piperazine rings Target A C G I T AVI-6002 AVI-7357 6,825.9 19 11 21 26 0 42 5 Ebola viral protein 24, viral matrix protein that inhibits interferon signaling AVI-7359 7,092.1 20 5 30 20 0 45 5 Ebola viral protein 35, component of the RNA-dependent RNA polymerase that antagonizes the interferon pathway AVI-6003 AVI-7287 7,491.4 21 14 24 14 10 38 6 Marburg viral protein 24, viral matrix protein that inhibits interferon signaling AVI-7288 8,179.0 23 43 17 13 4 22 5 Marburg nucleoprotein, the major nucleoprotein involved in RNA encapsulation - TABLE 2
Demographic and baseline characteristics of study subjects
Characteristic AVI-6002 study AVI-6003 study Placebo (n = 6) Dose (mg/kg) Total (n = 30) Placebo (n = 6) Dose (mg/kg) Total (n = 30) 0.01 (n = 4) 0.1 (n = 4) 1 (n = 4) 3 (n = 4) 6 (n = 4) 9 (n = 4) 0.01 (n = 4) 0.1 (n = 4) 1 (n = 4) 3 (n = 4) 6 (n = 4) 9 (n = 4) No. of subjects (%) Gender Male 2 (33) 2 (50) 2 (50) 2 (50) 2 (50) 2 (50) 3 (75) 15 (50) 5 (83) 1 (25) 2 (50) 2 (50) 2 (50) 2 (50) 2 (50) 16 (53) Female 4 (67) 2 (50) 2 (50) 2 (50) 2 (50) 2 (50) 1 (25) 15 (50) 1 (17) 3 (75) 2 (50) 2 (50) 2 (50) 2 (50) 2 (50) 14 (47) Race White 4 (67) 2 (50) 2 (50) 3 (75) 4 (100) 3 (75) 2 (50) 20 (67) 6 (100) 2 (50) 1 (25) 1 (25) 3 (75) 3 (75) 2 (50) 18 (60) Black or African-American 1 (17) 2 (50) 1 (25) 1 (25) 0 1 (25) 2 (50) 8 (27) 0 2 (50) 2 (50) 2 (50) 0 1 (25) 2 (50) 9 (30) Asian 0 0 0 0 0 0 0 0 0 0 1 (25) 1 (25) 1 (25) 0 0 3 (10) American Indian or Alaska Native 1 (17) 0 1 (25) 0 0 0 0 2 (7) 0 0 0 0 0 0 0 0 Mean (SD) Age (yr) 28.0 (5.8) 28.3 (5.1) 30.3 (9.0) 26.5 (6.0) 23.5 (6.5) 24.0 (5.7) 23.3 (3.3) 26.4 (6.0) 33.2 (10.9) 29.0 (8.9) 35.0 (13.5) 26.5 (5.3) 32.8 (5.7) 26.3 (7.5) 33.8 (6.9) 31.1 (8.7) Wt (kg) 81.6 (10.9) 77.8 (3.3) 75.9 (14.8) 65.1 (7.1) 71.1 (10.5) 73.0 (16.2) 66.6 (7.7) 73.6 (11.3) 77.3 (14.0) 75.7 (18.4) 76.1 (12.9) 73.7 (21.7) 69.0 (4.5) 69.8 (4.6) 70.1 (5.0) 73.4 (12.3) BMIa (kg/m2) 27.0 (3.0) 27.1 (2.9) 26.4 (3.0) 22.6 (2.7) 24.2 (3.1) 26.3 (5.5) 23.7 (1.7) 25.5 (3.4) 24.5 (4.4) 26.3 (4.5) 25.3 (3.3) 24.0 (4.5) 25.2 (3.3) 23.8 (2.1) 25.2 (2.2) 24.9 (3.4) Estimated CLCR (ml/min)b 114.1 (28.4) 107.8 (6.9) 104.3 (21.0) 108.2 (20.4) 112.8 (16.2) 103.2 (12.9) 111.9 (16.8) 109.2 (18.0) 106.7 (14.5) 110.7 (14.4) 109.9 (29.4) 118.0 (4.6) 105.1 (8.3) 118.4 (17.2) 98.9 (14.5) 109.5 (17.1) - TABLE 3
Treatment-emergent adverse events occurring more than once in a given system organ class in the two AVI studies
TEAEa No. (%) of subjects AVI-6002 study AVI-6003 study Placebo (n = 6) Dose (mg/kg) AVI-6002 (n = 24) Placebo (n = 6) Dose (mg/kg) AVI-6003 (n = 24) 0.01 (n = 4) 0.1 (n = 4) 1 (n = 4) 3 (n = 4) 6 (n = 4) 9 (n = 4) 0.01 (n = 4) 0.1 (n = 4) 1 (n = 4) 3 (n = 4) 6 (n = 4) 9 (n = 4) Total 5 (83) 3 (75) 0 2 (50) 3 (75) 3 (75) 1 (25) 12 (50) 1 (17) 2 (50) 4 (100) 1 (25) 2 (50) 2 (50) 2 (50) 13 (54) Gastrointestinal disordersb 1 (17) 2 (50) 0 0 2 (50) 1 (25) 0 5 (21) 0 0 2 (50) 0 1 (25) 1 (25) 1 (25) 5 (21) Nervous system disordersc 0 3 (75) 0 0 0 1 (25) 0 4 (17) 0 1 (25) 2 (50) 0 1 (25) 1 (25) 1 (25) 6 (25) Respiratory, thoracic, and mediastinal disordersd 1 (17) 1 (25) 0 0 0 1 (25) 0 2 (8) 0 0 1 (25) 0 0 0 1 (25) 2 (8) General disorders and administrative site conditionse 3 (50) 2 (50) 0 0 0 0 0 2 (8) 0 0 0 0 1 (25) 0 0 1 (4) Musculoskeletal and connective tissue disordersf 0 0 0 0 0 0 0 0 1 (17) 0 0 0 0 0 1 (25) 1 (4) ↵a TEAE, treatment-emergent adverse event.
↵b Gastrointestinal disorders included nausea in three subjects and abdominal discomfort, upper abdominal pain, diarrhea, and vomiting in one subject each in the AVI-6002 study and abdominal distension, abdominal pain, gastroesophageal reflux disease, anorectal discomfort, aphthous stomatitis, nausea, and vomiting in one subject each in the AVI-6003 study.
↵c Nervous system disorders included headache in four subjects and somnolence in one subject in the AVI-6002 study and headache in three subjects, dizziness in two subjects, and cataplexy, dysgeusia, and tremor in one subject each in the AVI-6003 study.
↵d Respiratory, thoracic, and mediastinal disorders included sinus congestion in three subjects in the AVI-6002 study and nasal congestion and rhinorrhea in one subject each in the AVI-6003 study.
↵e General disorders and administrative site conditions included chest discomfort, fatigue, feeling cold, and infusion site erythema in one one subject each in the AVI-6002 study and fatigue in one subject in the AVI-6003 study.
↵f Musculoskeletal and connective tissue disorders included arthralgia and muscle tightness in one subject each in the AVI-6003 study.
- TABLE 4
PK parameters of components of AVI-6002 (AVI-7537 and AVI-7539) and AVI-6003 (AVI-7287 and AVI-7288)
Component and dose (mg/kg) Mean (SD) Cmax (ng/ml) AUC0–24 (h·ng/ml) Tmax (h) Plasma half-life (h) CLP (ml/h/kg) Vss (ml/kg) AVI-7537 0.005 185 (108) 285 (173) 0.5 (0.08) 2.0 (0.30) 31 (32.6) 65 (68.2) 0.05 425 (99) 617 (237) 0.5 (0.00) 2.0 (0.57) 89 (29.1) 183 (23.8) 0.5 3,360 (974) 4,060 (462) 0.5 (0.00) 3.6 (0.25) 122 (11.5) 382 (139.0) 1.5 6,460 (2,370) 10,100 (2,140) 0.5 (0.00) 2.8 (0.81) 152 (32.3) 406 (124.0) 3.0 20,900 (5,220) 27,000 (6,520) 0.5 (0.07) 4.6 (1.17) 114 (22.9) 334 (42.6) 4.5 24,100 (3,440) 35,300 (3,700) 0.5 (0.08) 4.0 (0.71) 126 (12.6) 453 (70.8) AVI-7539 0.005 242 (67) 338 (72) 0.5 (0.07) 2.1 (0.09) 15 (2.7) 48 (40.3) 0.05 399 (107) 519 (150) 0.5 (0.09) 1.9 (0.63) 103 (28.5) 201 (13.8) 0.5 3,480 (1,130) 3,950 (658) 0.5 (0.06) 2.9 (0.80) 127 (18.9) 387 (125.0) 1.5 7,910 (1,440) 10,900 (1,950) 0.5 (0.07) 2.5 (0.92) 140 (24.4) 329 (91.2) 3.0 24,000 (4,330) 30,100 (6,250) 0.5 (0.00) 4.6 (1.21) 101 (19.4) 273 (38.6) 4.5 24,800 (2,090) 36,700 (2,420) 0.6 (0.00) 3.9 (1.01) 121 (7.9) 401 (35.1) AVI-7287 0.005 34 (8) 48 (11) 0.6 (0.14) 1.6 (0.92) 94 (15.8) 189 (99.8) 0.05 313 (89) 338 (65) 0.5 (0.08) 1.8 (0.26) 151 (31.0) 299 (65.3) 0.5 2,550 (486) 4,000 (729) 0.5 (0.14) 1.9 (0.46) 129 (27.0) 278 (33.9) 1.5 11,000 (1,530) 14,700 (3,470) 0.5 (0.0) 2.2 (0.33) 105 (24.7) 267 (50.4) 3.0 20,100 (4,290) 24,900 (3,200) 0.5 (0.0) 5.0 (2.04) 120 (17.0) 354 (88.9) 4.5 23,300 (2,770) 35,400 (3,720) 0.4 (0.11) 3.7 (1.46) 123 (12.3) 537 (169.0) AVI-7288 0.005 36 (7) 45 (7) 0.4 (0.12) 1.2 (0.48) 104 (17.6) 158 (21.0) 0.05 272 (97) 322 (105) 0.5 (0.06) 1.6 (0.19) 171 (67.9) 303 (142.0) 0.5 2,660 (271) 4,060 (638) 0.5 (0.01) 1.7 (0.46) 126 (23.4) 241 (30.5) 1.5 8,210 (460) 11,500 (1,680) 0.5 (0.01) 2.4 (0.53) 133 (19.2) 277 (38.4) 3.0 19,300 (290) 22,900 (1,170) 0.5 (0.01) 4.1 (1.95) 130 (7.2) 315 (131.0) 4.5 26,900 (5,040) 32,200 (3,480) 0.5 (0.06) 5.5 (2.51) 136 (11.6) 569 (298.0)
