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P158 Physician perspectives on long-term prophylaxis of hereditary angioedema: a pragmatic review
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Abstracts: Poster Sessions / Ann Allergy Asthma Immunol 119 (2017) S17eS96
P156 USE OF RESCUE MEDICATION IN HEREDITARY ANGIOEDEMA ATTACKS AND ITS RELATION TO ATTACK SEVERITY J. Anderson*1, G. Krishnarajah2, T. Craig3, W. Lumry4, D. Supina5, H. Feuersenger6, I. Pragst6, T. Machnig6, J. Bernstein7, 1. Birmingham, AL; 2. King of Prussia, PA; 3. Hershey, PA; 4. Dallas, TX; 5. Malvern, PA; 6. Marburg, Germany; 7. Cincinnati, OH. Introduction: Most attacks in highly symptomatic (frequent attacks) patients of hereditary angioedema (HAE) require treatment with specific HAE rescue medications (RMs). Availability of limited data on the proportion and severity of breakthrough attacks requiring RMs led to this post-hoc analysis of the COMPACT study (NEJM 2017;376:1131-40). Methods: In the COMPACT study, patients received 2 different doses of subcutaneous C1-inhibitor (C1-INH [SC]) and their corresponding placebo as prophylaxis over a 16-week treatment period each. Breakthrough attacks were possibly treated with RMs. Two of the options were C1-INH concentrate and/or icatibant. The proportion of treated attacks by treatment and severity and the number of RM doses required for each breakthrough attack were analyzed for patients on placebo and C1-INH (SC). Results: Of 1191 (both doses C1-INH [SC]: 18%; placebo: 82%) breakthrough attacks recorded across treatment arms, 913 were treated with RMs (both doses C1-INH [SC]: 62%; placebo: 80%). Of the 913 treated attacks, 820, 90% (both doses C1-INH [SC]: 127, 95%; placebo: 693, 89%) were treated with one injection of any RM, while 5% of C1-INH concentrate treated and 22% of icatibant treated attacks required treatment with 2 or more doses of a C1-INH concentrate and icatibant, respectively. Higher severity of breakthrough attacks was associated with a greater proportion of attacks requiring RMs (Mild 59%, Moderate 79%, Severe 92%). Conclusions: The use of RM for the treatment of breakthrough attacks is dependent on attack severity and most breakthrough attacks were treated with a single dose of any RM.
P157 PHARMACOKINETICS AND PHARMACODYNAMICS OF SUBCUTANEOUS VERSUS INTRAVENOUS C1-INHIBITOR FOR THE PREVENTION OF HEREDITARY ANGIOEDEMA ATTACKS B. Zuraw*1, M. Cicardi2, T. Craig3, W. Lumry4, 1. La Jolla, CA; 2. Milan, Italy; 3. Hershey, PA; 4. Dallas, TX. Introduction: The subcutaneous (SC) C1 inhibitor (C1-INH; CSL830), is effective at preventing hereditary angioedema attacks (HAEAs). The current post-hoc analysis explores pharmacokinetic (PK) and pharmacodynamics (PD) differences between SC and intravenous (IV) C1-INH dosing in relation to their preventive effects. Methods: C1-INH functional activity (C1-INH[f]) data, obtained after administration of several doses of C1-INH (SC and IV) from one study in healthy volunteers (n¼16) and two studies in subjects with HAE (n¼108), were pooled to develop a population PK model using NONMEM (v7.2). An interval-censored repeated time-to-event (TTE) model was developed that directly related C1-INH(f) to HAEAs. Results: Simulations of C1-INH(f) versus time profiles in 1000 virtual patients revealed higher trough plasma concentration (Ctrough) after twice-weekly dosing with 40 IU/kg (40%) and 60 IU/ kg (48%) SC versus 1000 IU IV (30%). Even at the highest labeled IV dose (2500 IU) Ctrough values were 20% lower than with the highest SC dose of. The median time to peak concentration (tmax)
of C1-INH (SC) was w59 hours and the median apparent plasma half-life (t1/2) w69 hours. The TTE model revealed an inverse relationship between C1-INH(f) at the time of attack and the risk of attacks. The preventive effect of C1-INH replacement seems to be maximized with SC C1-INH dosing, since Ctrough at the next dosing interval can be maintained close to the normal range (>70%). Conclusion: Prophylaxis with bodyweight-based C1-INH (SC) dosing shows consistently higher C1-INH(f) Ctrough levels than C1INH (IV) given at currently recommended fixed doses, resulting in improved HAEA prevention.
P158 PHYSICIAN PERSPECTIVES ON LONG-TERM PROPHYLAXIS OF HEREDITARY ANGIOEDEMA: A PRAGMATIC REVIEW R. Beckerman*1, D. Barnes2, D. Supina3, G. Krishnarajah4, 1. New York, NY; 2. Ottawa, ON, Canada; 3. Malvern, PA; 4. King of Prussia, PA. Introduction: Hereditary angioedema (HAE), a rare genetic disorder, results from an inherited deficiency or dysfunction of C1-inhibitor (C1-INH). Recurrent episodes of angioedema are associated with considerable morbidity and quality-of-life (QoL) impact. Long-term prophylaxis (LTP) to reduce breakthrough attack frequency and severity can ameliorate this burden. There are differences in opinion about the appropriate LTP initiation criteria and regimen. This study describes international physician perspectives on these issues via a literature review. Methods: A targeted search of peer-reviewed studies published from 2002-2017 was conducted. Inclusion criteria were publications discussing the physician perspective on the appropriate LTP criteria and/or regimen. Exclusion criteria were documents other than comments, consensuses, guidelines, letters, reviews, and editorials; and, articles including only pediatric patients. References were reviewed and evaluated for inclusion. Results: 367 articles were identified; 327 were excluded and 6 additional were included based on the references review. 28% of inclusions were guidelines; 26% were expert consensuses. 47% provided an international perspective; the remainder were country-specific. 68% were published post-2011: these were more likely to define a broader set of criteria, including QoL as LTP initiation criteria; less likely to cite number attacks as a primary LTP criterion; less likely to promote androgens as LTP regimens, and more likely to recommend C1-INH for LTP without restriction. Conclusion: Physicians’ perspectives on LTP have changed over time, and increasingly include the consideration of LTP treatment with C1-INH regardless of past androgen use, and the impact of HAE on patients’ QoL as a criterion for LTP initiation.
P159 ATTACKS AVOIDED AND COST OFFSETS ASSOCIATED WITH SUBCUTANEOUS C1-INHIBITOR (HUMAN) LONGTERM PROPHYLAXIS OF HEREDITARY ANGIOEDEMA C. Graham*1, T. Machnig2, H. Knox1, D. Supina3, G. Krishnarajah4, 1. Research Triangle Park, NC; 2. Marburg, Germany; 3. Malvern, PA; 4. King of Prussia, PA. Introduction: C1-esterase inhibitor (human) subcutaneous (C1INH(SC)) is a new treatment for long-term prophylaxis (LTP) of hereditary angioedema (HAE). HAE disease burden is high, and includes unpredictable, painful and temporarily disfiguring attacks of swelling that can lead to hospitalization and death. An economic model was constructed to estimate breakthrough attacks avoided and acute medication cost savings associated with LTP with C1-
Abstracts: Poster Sessions / Ann Allergy Asthma Immunol 119 (2017) S17eS96
P156 USE OF RESCUE MEDICATION IN HEREDITARY ANGIOEDEMA ATTACKS AND ITS RELATION TO ATTACK SEVERITY J. Anderson*1, G. Krishnarajah2, T. Craig3, W. Lumry4, D. Supina5, H. Feuersenger6, I. Pragst6, T. Machnig6, J. Bernstein7, 1. Birmingham, AL; 2. King of Prussia, PA; 3. Hershey, PA; 4. Dallas, TX; 5. Malvern, PA; 6. Marburg, Germany; 7. Cincinnati, OH. Introduction: Most attacks in highly symptomatic (frequent attacks) patients of hereditary angioedema (HAE) require treatment with specific HAE rescue medications (RMs). Availability of limited data on the proportion and severity of breakthrough attacks requiring RMs led to this post-hoc analysis of the COMPACT study (NEJM 2017;376:1131-40). Methods: In the COMPACT study, patients received 2 different doses of subcutaneous C1-inhibitor (C1-INH [SC]) and their corresponding placebo as prophylaxis over a 16-week treatment period each. Breakthrough attacks were possibly treated with RMs. Two of the options were C1-INH concentrate and/or icatibant. The proportion of treated attacks by treatment and severity and the number of RM doses required for each breakthrough attack were analyzed for patients on placebo and C1-INH (SC). Results: Of 1191 (both doses C1-INH [SC]: 18%; placebo: 82%) breakthrough attacks recorded across treatment arms, 913 were treated with RMs (both doses C1-INH [SC]: 62%; placebo: 80%). Of the 913 treated attacks, 820, 90% (both doses C1-INH [SC]: 127, 95%; placebo: 693, 89%) were treated with one injection of any RM, while 5% of C1-INH concentrate treated and 22% of icatibant treated attacks required treatment with 2 or more doses of a C1-INH concentrate and icatibant, respectively. Higher severity of breakthrough attacks was associated with a greater proportion of attacks requiring RMs (Mild 59%, Moderate 79%, Severe 92%). Conclusions: The use of RM for the treatment of breakthrough attacks is dependent on attack severity and most breakthrough attacks were treated with a single dose of any RM.
P157 PHARMACOKINETICS AND PHARMACODYNAMICS OF SUBCUTANEOUS VERSUS INTRAVENOUS C1-INHIBITOR FOR THE PREVENTION OF HEREDITARY ANGIOEDEMA ATTACKS B. Zuraw*1, M. Cicardi2, T. Craig3, W. Lumry4, 1. La Jolla, CA; 2. Milan, Italy; 3. Hershey, PA; 4. Dallas, TX. Introduction: The subcutaneous (SC) C1 inhibitor (C1-INH; CSL830), is effective at preventing hereditary angioedema attacks (HAEAs). The current post-hoc analysis explores pharmacokinetic (PK) and pharmacodynamics (PD) differences between SC and intravenous (IV) C1-INH dosing in relation to their preventive effects. Methods: C1-INH functional activity (C1-INH[f]) data, obtained after administration of several doses of C1-INH (SC and IV) from one study in healthy volunteers (n¼16) and two studies in subjects with HAE (n¼108), were pooled to develop a population PK model using NONMEM (v7.2). An interval-censored repeated time-to-event (TTE) model was developed that directly related C1-INH(f) to HAEAs. Results: Simulations of C1-INH(f) versus time profiles in 1000 virtual patients revealed higher trough plasma concentration (Ctrough) after twice-weekly dosing with 40 IU/kg (40%) and 60 IU/ kg (48%) SC versus 1000 IU IV (30%). Even at the highest labeled IV dose (2500 IU) Ctrough values were 20% lower than with the highest SC dose of. The median time to peak concentration (tmax)
of C1-INH (SC) was w59 hours and the median apparent plasma half-life (t1/2) w69 hours. The TTE model revealed an inverse relationship between C1-INH(f) at the time of attack and the risk of attacks. The preventive effect of C1-INH replacement seems to be maximized with SC C1-INH dosing, since Ctrough at the next dosing interval can be maintained close to the normal range (>70%). Conclusion: Prophylaxis with bodyweight-based C1-INH (SC) dosing shows consistently higher C1-INH(f) Ctrough levels than C1INH (IV) given at currently recommended fixed doses, resulting in improved HAEA prevention.
P158 PHYSICIAN PERSPECTIVES ON LONG-TERM PROPHYLAXIS OF HEREDITARY ANGIOEDEMA: A PRAGMATIC REVIEW R. Beckerman*1, D. Barnes2, D. Supina3, G. Krishnarajah4, 1. New York, NY; 2. Ottawa, ON, Canada; 3. Malvern, PA; 4. King of Prussia, PA. Introduction: Hereditary angioedema (HAE), a rare genetic disorder, results from an inherited deficiency or dysfunction of C1-inhibitor (C1-INH). Recurrent episodes of angioedema are associated with considerable morbidity and quality-of-life (QoL) impact. Long-term prophylaxis (LTP) to reduce breakthrough attack frequency and severity can ameliorate this burden. There are differences in opinion about the appropriate LTP initiation criteria and regimen. This study describes international physician perspectives on these issues via a literature review. Methods: A targeted search of peer-reviewed studies published from 2002-2017 was conducted. Inclusion criteria were publications discussing the physician perspective on the appropriate LTP criteria and/or regimen. Exclusion criteria were documents other than comments, consensuses, guidelines, letters, reviews, and editorials; and, articles including only pediatric patients. References were reviewed and evaluated for inclusion. Results: 367 articles were identified; 327 were excluded and 6 additional were included based on the references review. 28% of inclusions were guidelines; 26% were expert consensuses. 47% provided an international perspective; the remainder were country-specific. 68% were published post-2011: these were more likely to define a broader set of criteria, including QoL as LTP initiation criteria; less likely to cite number attacks as a primary LTP criterion; less likely to promote androgens as LTP regimens, and more likely to recommend C1-INH for LTP without restriction. Conclusion: Physicians’ perspectives on LTP have changed over time, and increasingly include the consideration of LTP treatment with C1-INH regardless of past androgen use, and the impact of HAE on patients’ QoL as a criterion for LTP initiation.
P159 ATTACKS AVOIDED AND COST OFFSETS ASSOCIATED WITH SUBCUTANEOUS C1-INHIBITOR (HUMAN) LONGTERM PROPHYLAXIS OF HEREDITARY ANGIOEDEMA C. Graham*1, T. Machnig2, H. Knox1, D. Supina3, G. Krishnarajah4, 1. Research Triangle Park, NC; 2. Marburg, Germany; 3. Malvern, PA; 4. King of Prussia, PA. Introduction: C1-esterase inhibitor (human) subcutaneous (C1INH(SC)) is a new treatment for long-term prophylaxis (LTP) of hereditary angioedema (HAE). HAE disease burden is high, and includes unpredictable, painful and temporarily disfiguring attacks of swelling that can lead to hospitalization and death. An economic model was constructed to estimate breakthrough attacks avoided and acute medication cost savings associated with LTP with C1-