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ORAL ADMINISTRATION OF A LIQUID FORMULATION OF BCX7353 RAPIDLY PROVIDES SUSTAINED CONCENTRATIONS AND KALLIKREIN INHIBITION
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Abstracts: Poster Sessions / Ann Allergy Asthma Immunol 121 (2018) S22−S62
No pediatric patients discontinued treatment due to a related adverse event. Conclusions: Data from pediatric patients treated with C1-INH (SC) for ≥ 1 year did not reveal any efficacy differences relative to adult patients. C1-INH (SC) is effective and well tolerated in children and adolescents with HAE.
P152 LONG-TERM EFFICACY AND SAFETY OF SUBCUTANEOUS C1-INHIBITOR IN ELDERLY PATIENTS WITH HEREDITARY ANGIOEDEMA TYPE I/II J. Bernstein*,1, L. Schwartz2, H. Feuersenger3, I. Pragst4, J. Chiao5, I. Jacobs5, 1. Cincinnati, OH; 2. Richmond, VA; 3. Marburg, Hessen, Germany; 4. Marburg, Germany; 5. King of Prussia, PA Introduction: Elderly patients ≥ 65 years old with hereditary angioedema (HAE) type I/II due to C1-inhibitor (C1-INH) deficiency may have an altered response to treatment and be at higher risk for treatment-related adverse events (AEs) due to comorbidities and polypharmacy. Subcutaneous (SC) C1-INH is indicated for routine prophylaxis to prevent HAE attacks in adolescents and adults. This post-hoc analysis examined the efficacy and safety of C1-INH (SC) in patients ≥ 65 years old treated in an open-label extension study. Methods: Eligible patients (entry criteria: ≥ 6 years old, ≥ 4 attacks/ 8-week interval) were treated with C1-INH (SC) 40 or 60 IU/kg twice weekly and studied for ≤ 140 weeks. For this analysis, patients were stratified by age (<65 years). Efficacy outcomes such as attack rates and responder analysis, as well as safety endpoints and patient profiles, were evaluated for these 2 subgroups. Results: Of 126 patients, 10 were ≥ 65 years old (mean age [range], 68 years [65-72]; mean duration of treatment, 80 weeks). Elderly patients had a >70% median reduction in attacks relative to their attack rate prior to randomization, with 3 patients being completely attack free for up to 2.4 years. Overall, the most frequently reported AEs were nasopharyngitis, injection-site reactions, headache, and upper respiratory tract infection. No thromboembolic event was reported in these elderly patients. Conclusions: C1-INH (SC) is safe and effective for long-term prophylaxis of HAE attacks in elderly patients aged ≥ 65. These findings are consistent with those from the COMPACT phase III study.
P153 ORAL ADMINISTRATION OF A LIQUID FORMULATION OF BCX7353 RAPIDLY PROVIDES SUSTAINED CONCENTRATIONS AND KALLIKREIN INHIBITION € renA. Mathis1, M. DeSpirito2, M. Cornpropst*,1, W. Sheridan1, E. Aygo € rsu € n3, 1. Durham, NC; 2. Raleigh, NC; 3. Frankfurt, Germany Pu Introduction: BCX7353 is an investigational oral kallikrein inhibitor in Phase 3 studies for prevention of HAE attacks. A capsule formulation of BCX7353 is rapidly absorbed and exhibits a long half-life, which also may permit effective treatment of acute attacks in HAE patients. A Phase I study in HAE patients was conducted to determine whether a liquid formulation of BCX7353 may optimize on these attributes as an attack treatment. Methods: Six subjects with HAE Type I or II were given a single 750 mg BCX7353 dose orally as a reconstituted solution in an intercritical period between attacks. The pharmacokinetic and kallikrein inhibition profiles were determined through 24h post-dose. BCX7353 plasma concentrations were determined using a validated mass spectrometry assay and kallikrein inhibition was assessed with an ellagic acid-initiated contact activation assay. Results: Maximal concentrations were reached at approximately 2h postdose across subjects (median). Mean concentrations exceeded the target
concentration for plasma kallikrein suppression (i.e., 4x EC50) at 15 minutes post-dose; all subjects exceeded this target by at least 2.4-fold at 30 minutes post-dose and maintained concentrations over the target through 24h post-dose. A mean of 49% kallikrein inhibition relative to baseline activity was demonstrated at 15 minutes post-dose; >80% inhibition was measured between 1-8h, with 71% inhibition at 24h post-dose. Conclusions: BCX7353 750 mg administered orally as a liquid formulation produced sustained plasma concentrations that potently inhibited kallikrein through at least 24 hours post-dose. These results support proof-of-concept studies to assess the efficacy of a liquid formulation of BCX7353 in the treatment of HAE attacks.
P154 HEREDITARY ANGIOEDEMA C1-INH REPLACEMENT THERAPY AND COEXISTING AUTOIMMUNE DISORDERS: FINDINGS FROM A CLAIMS DATABASE H. Farkas*,1, M. Fridman2, S. Krishnarajah3, J. Chiao3, T. Machnig4, S. Prusty4, M. Berger3, 1. Budapest, Hungary; 2. Los Angeles, CA; 3. King of Prussia, PA; 4. Marburg, Germany Introduction: Hereditary angioedema (HAE) has been linked with an increase in autoimmune diseases. Plasma-derived C1 esterase inhibitor (C1-INH) is safe and effective for treatment and prevention of HAE attacks. It is plausible that C1-INH replacement decreases autoimmunity by normalizing complement. Methods: HAE patients were identified in the IMS Health PharMetrics Plus claims database between Jan 2012 and Dec 2015 by diagnosis code, and classified by their HAE treatment into “Plasma-derived C1INH FDA-approved treatments”, or “Other (non-C1-INH) treatments” groups. Continuous enrollment in the health plan with at least 12 months of follow-up was required. The frequency of visit claims for autoimmune conditions during follow-up was identified by primary or secondary diagnosis codes, including lupus, rheumatoid arthritis (RA), alopecia, sicca, connective tissue disorders and immuno-deficiency disorders. Mean visits per patient per year (PPPY) by treatment group, gender and age ( Results: 589 HAE patients were identified: 69% female and 27% age ≥ 50 years. 276 (729) patients (patient years) received C1-INH and 313 (860) other treatments. The mean (95% CI) number of visits for autoimmune diagnoses PPPY were 1.75 (0.82, 2.67) vs 3.67 (1.56, 5.78) respectively for C1-INH vs other treatments. Fewer visits with C1-INH treatment were predominantly observed in females Conclusions: This exploratory analysis suggested a possible benefit of HAE treatment with plasma-derived C1-INH, particularly in younger women with coexisting autoimmune disorders. Confirmation with larger independent samples and further research are needed/warranted.
P155 EFFECTS OF SUBCUTANEOUS C1ESTERASE INHIBITOR ON COAGULATION AND FIBRINOLYTIC PARAMETERS A. Reshef*,1, D. Levy2, B. Zuraw2, H. Longhurst3, M. Cicardi4, T. Craig5, P. Keith6, H. Feuersenger7, I. Pragst8, J. Chiao9, S. Prusty7, T. Machnig8, I. Jacobs9, 1. Ashkelon, Israel; 2. Berkeley, CA; 3. London, London, United Kingdom; 4. Milano, Italy; 5. Hershey, PA; 6. Hamilton, Canada; 7. Marburg, Hessen, Germany; 8. Marburg, Germany; 9. King of Prussia, PA Introduction: Replacement therapy with subcutaneous C1-esterase inhibitor (C1-INH[SC]) 60 IU/kg twice weekly is approved for routine prophylaxis to prevent hereditary angioedema (HAE) attacks. Coagulation and fibrinolytic parameters levels tend to be elevated in HAE patients. We evaluated the effects of C1-INH(SC) on these parameters. Methods: In the COMPACT study, subjects received 40 IU/kg or 60 IU/kg of plasma-derived C1-INH(SC) and a corresponding placebo,
Abstracts: Poster Sessions / Ann Allergy Asthma Immunol 121 (2018) S22−S62
No pediatric patients discontinued treatment due to a related adverse event. Conclusions: Data from pediatric patients treated with C1-INH (SC) for ≥ 1 year did not reveal any efficacy differences relative to adult patients. C1-INH (SC) is effective and well tolerated in children and adolescents with HAE.
P152 LONG-TERM EFFICACY AND SAFETY OF SUBCUTANEOUS C1-INHIBITOR IN ELDERLY PATIENTS WITH HEREDITARY ANGIOEDEMA TYPE I/II J. Bernstein*,1, L. Schwartz2, H. Feuersenger3, I. Pragst4, J. Chiao5, I. Jacobs5, 1. Cincinnati, OH; 2. Richmond, VA; 3. Marburg, Hessen, Germany; 4. Marburg, Germany; 5. King of Prussia, PA Introduction: Elderly patients ≥ 65 years old with hereditary angioedema (HAE) type I/II due to C1-inhibitor (C1-INH) deficiency may have an altered response to treatment and be at higher risk for treatment-related adverse events (AEs) due to comorbidities and polypharmacy. Subcutaneous (SC) C1-INH is indicated for routine prophylaxis to prevent HAE attacks in adolescents and adults. This post-hoc analysis examined the efficacy and safety of C1-INH (SC) in patients ≥ 65 years old treated in an open-label extension study. Methods: Eligible patients (entry criteria: ≥ 6 years old, ≥ 4 attacks/ 8-week interval) were treated with C1-INH (SC) 40 or 60 IU/kg twice weekly and studied for ≤ 140 weeks. For this analysis, patients were stratified by age (<65 years). Efficacy outcomes such as attack rates and responder analysis, as well as safety endpoints and patient profiles, were evaluated for these 2 subgroups. Results: Of 126 patients, 10 were ≥ 65 years old (mean age [range], 68 years [65-72]; mean duration of treatment, 80 weeks). Elderly patients had a >70% median reduction in attacks relative to their attack rate prior to randomization, with 3 patients being completely attack free for up to 2.4 years. Overall, the most frequently reported AEs were nasopharyngitis, injection-site reactions, headache, and upper respiratory tract infection. No thromboembolic event was reported in these elderly patients. Conclusions: C1-INH (SC) is safe and effective for long-term prophylaxis of HAE attacks in elderly patients aged ≥ 65. These findings are consistent with those from the COMPACT phase III study.
P153 ORAL ADMINISTRATION OF A LIQUID FORMULATION OF BCX7353 RAPIDLY PROVIDES SUSTAINED CONCENTRATIONS AND KALLIKREIN INHIBITION € renA. Mathis1, M. DeSpirito2, M. Cornpropst*,1, W. Sheridan1, E. Aygo € rsu € n3, 1. Durham, NC; 2. Raleigh, NC; 3. Frankfurt, Germany Pu Introduction: BCX7353 is an investigational oral kallikrein inhibitor in Phase 3 studies for prevention of HAE attacks. A capsule formulation of BCX7353 is rapidly absorbed and exhibits a long half-life, which also may permit effective treatment of acute attacks in HAE patients. A Phase I study in HAE patients was conducted to determine whether a liquid formulation of BCX7353 may optimize on these attributes as an attack treatment. Methods: Six subjects with HAE Type I or II were given a single 750 mg BCX7353 dose orally as a reconstituted solution in an intercritical period between attacks. The pharmacokinetic and kallikrein inhibition profiles were determined through 24h post-dose. BCX7353 plasma concentrations were determined using a validated mass spectrometry assay and kallikrein inhibition was assessed with an ellagic acid-initiated contact activation assay. Results: Maximal concentrations were reached at approximately 2h postdose across subjects (median). Mean concentrations exceeded the target
concentration for plasma kallikrein suppression (i.e., 4x EC50) at 15 minutes post-dose; all subjects exceeded this target by at least 2.4-fold at 30 minutes post-dose and maintained concentrations over the target through 24h post-dose. A mean of 49% kallikrein inhibition relative to baseline activity was demonstrated at 15 minutes post-dose; >80% inhibition was measured between 1-8h, with 71% inhibition at 24h post-dose. Conclusions: BCX7353 750 mg administered orally as a liquid formulation produced sustained plasma concentrations that potently inhibited kallikrein through at least 24 hours post-dose. These results support proof-of-concept studies to assess the efficacy of a liquid formulation of BCX7353 in the treatment of HAE attacks.
P154 HEREDITARY ANGIOEDEMA C1-INH REPLACEMENT THERAPY AND COEXISTING AUTOIMMUNE DISORDERS: FINDINGS FROM A CLAIMS DATABASE H. Farkas*,1, M. Fridman2, S. Krishnarajah3, J. Chiao3, T. Machnig4, S. Prusty4, M. Berger3, 1. Budapest, Hungary; 2. Los Angeles, CA; 3. King of Prussia, PA; 4. Marburg, Germany Introduction: Hereditary angioedema (HAE) has been linked with an increase in autoimmune diseases. Plasma-derived C1 esterase inhibitor (C1-INH) is safe and effective for treatment and prevention of HAE attacks. It is plausible that C1-INH replacement decreases autoimmunity by normalizing complement. Methods: HAE patients were identified in the IMS Health PharMetrics Plus claims database between Jan 2012 and Dec 2015 by diagnosis code, and classified by their HAE treatment into “Plasma-derived C1INH FDA-approved treatments”, or “Other (non-C1-INH) treatments” groups. Continuous enrollment in the health plan with at least 12 months of follow-up was required. The frequency of visit claims for autoimmune conditions during follow-up was identified by primary or secondary diagnosis codes, including lupus, rheumatoid arthritis (RA), alopecia, sicca, connective tissue disorders and immuno-deficiency disorders. Mean visits per patient per year (PPPY) by treatment group, gender and age ( Results: 589 HAE patients were identified: 69% female and 27% age ≥ 50 years. 276 (729) patients (patient years) received C1-INH and 313 (860) other treatments. The mean (95% CI) number of visits for autoimmune diagnoses PPPY were 1.75 (0.82, 2.67) vs 3.67 (1.56, 5.78) respectively for C1-INH vs other treatments. Fewer visits with C1-INH treatment were predominantly observed in females Conclusions: This exploratory analysis suggested a possible benefit of HAE treatment with plasma-derived C1-INH, particularly in younger women with coexisting autoimmune disorders. Confirmation with larger independent samples and further research are needed/warranted.
P155 EFFECTS OF SUBCUTANEOUS C1ESTERASE INHIBITOR ON COAGULATION AND FIBRINOLYTIC PARAMETERS A. Reshef*,1, D. Levy2, B. Zuraw2, H. Longhurst3, M. Cicardi4, T. Craig5, P. Keith6, H. Feuersenger7, I. Pragst8, J. Chiao9, S. Prusty7, T. Machnig8, I. Jacobs9, 1. Ashkelon, Israel; 2. Berkeley, CA; 3. London, London, United Kingdom; 4. Milano, Italy; 5. Hershey, PA; 6. Hamilton, Canada; 7. Marburg, Hessen, Germany; 8. Marburg, Germany; 9. King of Prussia, PA Introduction: Replacement therapy with subcutaneous C1-esterase inhibitor (C1-INH[SC]) 60 IU/kg twice weekly is approved for routine prophylaxis to prevent hereditary angioedema (HAE) attacks. Coagulation and fibrinolytic parameters levels tend to be elevated in HAE patients. We evaluated the effects of C1-INH(SC) on these parameters. Methods: In the COMPACT study, subjects received 40 IU/kg or 60 IU/kg of plasma-derived C1-INH(SC) and a corresponding placebo,