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RELATIONSHIP OF TARGET CONCENTRATIONS WITH EFFICACY: RESULTS FROM THE APEX-1 STUDY OF BCX7353
Abstracts: Poster Sessions / Ann Allergy Asthma Immunol 121 (2018) S22−S62
as prophylaxis over 16 weeks each. In the open-label extension (OLE), subjects received 40 IU/kg or 60 IU/kg of C1-INH(SC) for up to 140 weeks. Exploratory analyses included the assessment of coagulation and fibrinolytic parameters (D-dimer, Prothrombin Fragments [PF] 1+2, activated Partial Thromboplastin Time [aPTT], Fibrinogen, and Prothrombin International Normalized Ratio [PT-INR]) at prescheduled visits. Results: Coagulation and fibrinolytic parameters were reported above the normal range at baseline. Treatment with C1-INH(SC) 60 IU/kg resulted in median decrease from baseline for D-dimer (COMPACT [baseline to Week 14]: 605.0 to 330.0 ng/mL; OLE [baseline to Week 140]: 510.0 to 330.0 ng/mL) and PF 1+2 (COMPACT [baseline to Week 14]: 264.0 to 185.0 pmol/L; OLE [baseline to Week 140]: 218.5 to 159.0 pmol/L). The aPTT, Fibrinogen, and PT-INR levels were stable relative to baseline over the treatment period. Results refer only to the Food and Drug Administration (FDA) approved 60 IU/kg dose. Conclusions: A reduction or stabilization in coagulation and fibrinolytic parameters was observed in HAE patients treated prophylactically with C1-INH(SC). No related thromboembolic events were reported during treatment with C1-INH (SC).
P156 EXPERIENCE WITH RECOMBINANT HUMAN C1 ESTERASE INHIBITOR FOR HEREDITARY ANGIOEDEMA ATTACKS DURING PREGNANCY J. Bernstein*,1, D. Moldovan2, R. Hakl3, L. Bellizzi4, A. Relan5, 1. Cincinnati, OH; 2. Sangeorgiu de Mures, Romania; 3. Brno, Czech Republic; 4. Leiden, Netherlands; 5. Bridgewater, NJ Introduction: Recombinant human C1 esterase inhibitor (rhC1-INH) is indicated in the United States for treating hereditary angioedema (HAE) attacks in adolescents/adults. Data are limited on rhC1-INH treatment in women with HAE who are pregnant. Methods: Pregnant women with HAE from the United States and Europe who received rhC1-INH were followed to full term and were assessed for adverse events (AEs) that occurred during pregnancy as well as for neonatal outcomes. Results: Ten pregnant women (age, 20-33 years) with HAE treated with rhC1-INH were identified. One woman received a 4200-IU dose pre-delivery as short-term prophylaxis and 9 were treated with rhC1-INH (2100 IU-4200 IU) for 1 (n=1), 2 (n=2), 4 (n=1), 6 (n=1), 8 (n=1), 9 (n=2), or 40 (n=1) HAE attacks. Ten laryngeal attacks occurred in 2 patients; all 10 attacks responded to rhC1-INH within 2 to 4 hours postdose. In addition, 4 facial attacks occurred in 1 patient and 1 in another patient that were successfully treated with 1 rhC1-INH dose and no rescue medications. There were no AEs considered related to rhC1-INH during the pregnancy period. Of 6 women with birth delivery method details available, 4 had a vaginal delivery and 2 a cesarean, all without complications. All 10 women gave birth at full term to healthy babies. No fetal distress or congenital abnormalities were reported. Conclusions: rhC1-INH treatment for HAE attacks in pregnant women was generally safe and well tolerated. All 10 women delivered healthy babies at full term without complications.
P157 RELATIONSHIP OF TARGET CONCENTRATIONS WITH EFFICACY: RESULTS FROM THE APEX-1 STUDY OF BCX7353 H. Farkas1, E. Aygoren-Pursun*,2, V. Grivcheva Panovska3, A. Huissoon4, T. Kinaciyan5, S. Murray6, M. Cornpropst6, W. Sheridan6, M. Maurer7, M. Cicardi8, 1. Budapest, Hungary; 2. Frankfurt, Germany; 3. Skopje, Macedonia, The Former Yugoslav Republic of; 4. Birmingham, United Kingdom; 5. Vienna, Austria; 6. Durham, NC; 7. Berlin, Germany; 8. Milano, Italy
S33
Introduction: Hereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating swelling. APeX-1 was a Phase 2, double-blind, placebo-controlled study to evaluate the prevention of attacks with BCX7353, a once daily oral kallikrein inhibitor, in patients with HAE. Methods: Patients with Type I or II HAE with a history of at least 0.5 HAE attacks/week were randomized to four different BCX7353 doses (62.5mg, 125mg, 250mg, 350mg once daily) or placebo for 4 weeks. Subjects completed diaries to record angioedema attack details. A trough sample for BCX7353 analysis was drawn on Day 15. Results: There was a dose-dependent reduction in mean HAE attack rate relative to the mean historical attack rate through 125mg (0.66 attacks/week reduction at this dose); efficacy at doses ≥ 250mg was likely confounded by drug-related adverse events misattributed as attacks. Mean plasma trough BCX7353 levels also increased by dose level with 57% of subjects in the 125mg group achieving the target trough concentration ( ≥ 4xEC50 at 24h post-dose). Subjects were individually classified by achieving or not achieving the target trough. The odds for subjects achieving ≥ 50%, ≥ 70%, or ≥ 90% reduction in attacks if the target trough was met or exceeded were 5.6-, 12.9- and 26.4-times higher, respectively, than for subjects who did not meet or exceed target trough level. Conclusions: Maintenance of BCX7353 plasma concentrations above the target trough concentration increased the odds of reducing HAE attacks. A BCX7353 dose >125mg and <250 mg may result in more subjects with drug concentrations in the target range for efficacy, with acceptable tolerability.
P158 PHARMACOKINETICS AND PHARMACODYNAMICS OF BCX7353, AN ORAL PLASMA KALLIKREIN INHIBITOR, IN HEALTHY JAPANESE SUBJECTS M. Cornpropst*,1, S. Dobo1, P. Collis1, J. Collier2, W. Sheridan1, 1. Durham, NC; 2. Nottingham, United Kingdom Introduction: BCX7353 is an oral kallikrein inhibitor being studied for prevention and treatment of hereditary angioedema (HAE) attacks in Western patients. HAE afflicts all ethnic groups. An ethnobridging study was conducted in healthy Japanese subjects to support development of BCX7353 in Japanese HAE patients. Methods: BCX7353 was administered as a single dose (100mg or 500mg) or as 7 daily doses (250mg) to healthy subjects born in Japan living abroad The pharmacokinetic and kallikrein inhibition profiles were determined up to 96-hours post-last dose. BCX7353 concentrations were determined using a validated mass spectrometry assay and kallikrein inhibition was assessed with an ellagic acid-initiated contact activation assay. Results: Median BCX7353 Cmax was 5-6h post-dose; concentrations declined with a half-life of 46-73h (geometric mean across groups). Compared with Western subjects, geometric mean BCX7353 AUC and Cmax for Japanese subjects were higher by 84% and 66% at 100mg x1, 19% and 27% at 500mg x1, and 13% and 20% for 250mg QD, respectively. At 500mg single doses, mean kallikrein activity was fully suppressed (>80%) from 2-16 and 2-12h post-500mg dose for Western and Japanese subjects, respectively; post-Day 7 250mg dose, kallikrein activity was suppressed from 2-16h and for 24h in Western and Japanese subjects, respectively. Conclusions: Ethnic, healthy Japanese subjects have profiles for BCX7353 pharmacokinetics and kallikrein inhibition comparable to Western subjects at doses similar to those under evaluation in Western HAE patients enrolled in attack prevention and treatment trials. These data support administration of similar doses to Japanese HAE patients.
as prophylaxis over 16 weeks each. In the open-label extension (OLE), subjects received 40 IU/kg or 60 IU/kg of C1-INH(SC) for up to 140 weeks. Exploratory analyses included the assessment of coagulation and fibrinolytic parameters (D-dimer, Prothrombin Fragments [PF] 1+2, activated Partial Thromboplastin Time [aPTT], Fibrinogen, and Prothrombin International Normalized Ratio [PT-INR]) at prescheduled visits. Results: Coagulation and fibrinolytic parameters were reported above the normal range at baseline. Treatment with C1-INH(SC) 60 IU/kg resulted in median decrease from baseline for D-dimer (COMPACT [baseline to Week 14]: 605.0 to 330.0 ng/mL; OLE [baseline to Week 140]: 510.0 to 330.0 ng/mL) and PF 1+2 (COMPACT [baseline to Week 14]: 264.0 to 185.0 pmol/L; OLE [baseline to Week 140]: 218.5 to 159.0 pmol/L). The aPTT, Fibrinogen, and PT-INR levels were stable relative to baseline over the treatment period. Results refer only to the Food and Drug Administration (FDA) approved 60 IU/kg dose. Conclusions: A reduction or stabilization in coagulation and fibrinolytic parameters was observed in HAE patients treated prophylactically with C1-INH(SC). No related thromboembolic events were reported during treatment with C1-INH (SC).
P156 EXPERIENCE WITH RECOMBINANT HUMAN C1 ESTERASE INHIBITOR FOR HEREDITARY ANGIOEDEMA ATTACKS DURING PREGNANCY J. Bernstein*,1, D. Moldovan2, R. Hakl3, L. Bellizzi4, A. Relan5, 1. Cincinnati, OH; 2. Sangeorgiu de Mures, Romania; 3. Brno, Czech Republic; 4. Leiden, Netherlands; 5. Bridgewater, NJ Introduction: Recombinant human C1 esterase inhibitor (rhC1-INH) is indicated in the United States for treating hereditary angioedema (HAE) attacks in adolescents/adults. Data are limited on rhC1-INH treatment in women with HAE who are pregnant. Methods: Pregnant women with HAE from the United States and Europe who received rhC1-INH were followed to full term and were assessed for adverse events (AEs) that occurred during pregnancy as well as for neonatal outcomes. Results: Ten pregnant women (age, 20-33 years) with HAE treated with rhC1-INH were identified. One woman received a 4200-IU dose pre-delivery as short-term prophylaxis and 9 were treated with rhC1-INH (2100 IU-4200 IU) for 1 (n=1), 2 (n=2), 4 (n=1), 6 (n=1), 8 (n=1), 9 (n=2), or 40 (n=1) HAE attacks. Ten laryngeal attacks occurred in 2 patients; all 10 attacks responded to rhC1-INH within 2 to 4 hours postdose. In addition, 4 facial attacks occurred in 1 patient and 1 in another patient that were successfully treated with 1 rhC1-INH dose and no rescue medications. There were no AEs considered related to rhC1-INH during the pregnancy period. Of 6 women with birth delivery method details available, 4 had a vaginal delivery and 2 a cesarean, all without complications. All 10 women gave birth at full term to healthy babies. No fetal distress or congenital abnormalities were reported. Conclusions: rhC1-INH treatment for HAE attacks in pregnant women was generally safe and well tolerated. All 10 women delivered healthy babies at full term without complications.
P157 RELATIONSHIP OF TARGET CONCENTRATIONS WITH EFFICACY: RESULTS FROM THE APEX-1 STUDY OF BCX7353 H. Farkas1, E. Aygoren-Pursun*,2, V. Grivcheva Panovska3, A. Huissoon4, T. Kinaciyan5, S. Murray6, M. Cornpropst6, W. Sheridan6, M. Maurer7, M. Cicardi8, 1. Budapest, Hungary; 2. Frankfurt, Germany; 3. Skopje, Macedonia, The Former Yugoslav Republic of; 4. Birmingham, United Kingdom; 5. Vienna, Austria; 6. Durham, NC; 7. Berlin, Germany; 8. Milano, Italy
S33
Introduction: Hereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating swelling. APeX-1 was a Phase 2, double-blind, placebo-controlled study to evaluate the prevention of attacks with BCX7353, a once daily oral kallikrein inhibitor, in patients with HAE. Methods: Patients with Type I or II HAE with a history of at least 0.5 HAE attacks/week were randomized to four different BCX7353 doses (62.5mg, 125mg, 250mg, 350mg once daily) or placebo for 4 weeks. Subjects completed diaries to record angioedema attack details. A trough sample for BCX7353 analysis was drawn on Day 15. Results: There was a dose-dependent reduction in mean HAE attack rate relative to the mean historical attack rate through 125mg (0.66 attacks/week reduction at this dose); efficacy at doses ≥ 250mg was likely confounded by drug-related adverse events misattributed as attacks. Mean plasma trough BCX7353 levels also increased by dose level with 57% of subjects in the 125mg group achieving the target trough concentration ( ≥ 4xEC50 at 24h post-dose). Subjects were individually classified by achieving or not achieving the target trough. The odds for subjects achieving ≥ 50%, ≥ 70%, or ≥ 90% reduction in attacks if the target trough was met or exceeded were 5.6-, 12.9- and 26.4-times higher, respectively, than for subjects who did not meet or exceed target trough level. Conclusions: Maintenance of BCX7353 plasma concentrations above the target trough concentration increased the odds of reducing HAE attacks. A BCX7353 dose >125mg and <250 mg may result in more subjects with drug concentrations in the target range for efficacy, with acceptable tolerability.
P158 PHARMACOKINETICS AND PHARMACODYNAMICS OF BCX7353, AN ORAL PLASMA KALLIKREIN INHIBITOR, IN HEALTHY JAPANESE SUBJECTS M. Cornpropst*,1, S. Dobo1, P. Collis1, J. Collier2, W. Sheridan1, 1. Durham, NC; 2. Nottingham, United Kingdom Introduction: BCX7353 is an oral kallikrein inhibitor being studied for prevention and treatment of hereditary angioedema (HAE) attacks in Western patients. HAE afflicts all ethnic groups. An ethnobridging study was conducted in healthy Japanese subjects to support development of BCX7353 in Japanese HAE patients. Methods: BCX7353 was administered as a single dose (100mg or 500mg) or as 7 daily doses (250mg) to healthy subjects born in Japan living abroad The pharmacokinetic and kallikrein inhibition profiles were determined up to 96-hours post-last dose. BCX7353 concentrations were determined using a validated mass spectrometry assay and kallikrein inhibition was assessed with an ellagic acid-initiated contact activation assay. Results: Median BCX7353 Cmax was 5-6h post-dose; concentrations declined with a half-life of 46-73h (geometric mean across groups). Compared with Western subjects, geometric mean BCX7353 AUC and Cmax for Japanese subjects were higher by 84% and 66% at 100mg x1, 19% and 27% at 500mg x1, and 13% and 20% for 250mg QD, respectively. At 500mg single doses, mean kallikrein activity was fully suppressed (>80%) from 2-16 and 2-12h post-500mg dose for Western and Japanese subjects, respectively; post-Day 7 250mg dose, kallikrein activity was suppressed from 2-16h and for 24h in Western and Japanese subjects, respectively. Conclusions: Ethnic, healthy Japanese subjects have profiles for BCX7353 pharmacokinetics and kallikrein inhibition comparable to Western subjects at doses similar to those under evaluation in Western HAE patients enrolled in attack prevention and treatment trials. These data support administration of similar doses to Japanese HAE patients.