icatibant, a selective bradykinin b2 receptor antagonist used in hereditary angioedema due to c1...

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646 C1 Esterase Inhibitor: Retrospective Validation of a Commonly Used Endpoint in Hereditary Angioedema Studies, Time to Onset of Relief, in a Global, Multicenter, Randomized, Placebo-Controlled Study (I.M.P.A.C.T.1) A. Bewtra 1 , J. Bernstein 2 , B. Ritchie 3 , R. Levy 4 , R. Wasserman 5 , D. Hur- ewitz 6 , K. Obtulowicz 7 , A. Reshef 8 , D. Moldovan 9 , T. Shirov 10 , V. Griv- cheva-Panovska 11 , P. Kiessling 12 , H. Keinecke 13 , T. Craig 14 ; 1 Creighton University School of Medicine, Omaha, NE, 2 University of Cincinnati Medical Center and Bernstein Clinical Research Center, Cincinnati, OH, 3 University of Alberta, Departments of Medicine and Medical Oncol- ogy, Edmonton, AB, CANADA, 4 Family Allergy and Asthma Center, At- lanta, GA, 5 Pediatric Allergy Immunology Associates, Dallas, TX, 6 Allergy Clinic of Tulsa, Inc., Tulsa, OK, 7 Jagiellonian University Hospi- tal, Krakow, POLAND, 8 The Chaim Sheba Medical Center, Tel Hashomer, ISRAEL, 9 University of Medicine and Pharmacy, 4th Medical Clinic, Tirgu Mures, ROMANIA, 10 University Hospital, Sofia, BULGA- RIA, 11 PHI-University Clinical Center, Department of Dermatology, Al- lergology and Clinical Immunology, Skopje, MACEDONIA, THE FORMER YUGOSLAV REPUBLIC OF, 12 CSL Behring, Marburg, GER- MANY, 13 Accovion GmbH, Marburg, GERMANY, 14 Penn State Univer- sity College of Medicine, Hershey, PA. RATIONALE: C1 esterase inhibitor (C1-INH) replacement therapy is the recommended treatment for acute attacks in hereditary angioedema (HAE). Time to onset of symptom relief is a common primary endpoint for efficacy but has never been validated by correlation analysis with the course of HAE symptoms. We retrospectively validated the primary end- point for the I.M.P.A.C.T.1 study. METHODS: Ninety-eight abdominal attacks were treated with 10 or 20 U/kg body weight of a highly purified C1-INH concentrate (Berinert Ò ), or placebo. The primary endpoint was the time to onset of symptom relief, as determined by patient responses to a standard question posed at appro- priate intervals for up to 24 h after treatment. In addition patients assessed the intensity of the HAE symptoms pain, nausea, vomiting, cramps, and di- arrhea individually over time. By Spearman rank correlation, the primary endpoint was compared with the time to first reduction a) of the intensity of any symptom present at baseline, b) of the sum of symptom intensity scores, and c) of the intensity of the last symptom present at baseline. RESULTS: The time to first reduction of the last symptom present at base- line had the highest correlation with the primary endpoint (0.77). The cor- relation was considerably lower for the time to first reduction of symptom intensity (0.60), and the time to first reduction of the sum of symptom in- tensity scores (0.63). CONCLUSIONS: A retrospective validation confirmed that the time to onset of symptom relief, as determined by patients, is an appropriate end- point for assessing the efficacy of C1-INH therapy. 647 Frequency and Types of Hereditary Angioedema Prodromes as Reported by Patients M. J. Prematta 1 , C. Laudadio 2 , T. Craig 1 ; 1 Penn State University, Milton S. Hershey Medical Center, Hershey, PA, 2 CSL Behring, King of Prussia, PA. RATIONALE: Only limited amounts of data have been published about prodromal symptoms associated with hereditary angioedema (HAE). The goal of this study is to report data regarding prodromal symptoms pa- tients experienced before an HAE exacerbation from two different surveys. METHODS: Data were obtained from a retrospective and prospective survey. IRB approval and written consent was obtained from all research subjects. A prospective survey was administered to subjects with HAE en- rolled in an open-label study of human pasteurized C1 esterase inhibitor concentrate. Subjects were queried on the presence of prodromal symptoms at the time they were seeking treatment. The retrospective survey was a four page survey sent by mail to 158 HAE patients. The survey focused on questions related to prodromal symptoms prior to the last HAE attack. RESULTS: The prospective study included 253 attacks, and the retrospec- tive study included 52 attacks. After combining datasets, data regarding prodromes was obtained for 305 HAE exacerbations, and patients reported the presence of a prodrome before 70.5% of exacerbations. The most frequent prodromes experienced before an HAE exacerbation included fa- tigue (45.2%); GI complaints (40.7%); muscle aches or flu-like symptoms (25.9%); rash (21.0%); and numbness or tingling (10.5%). CONCLUSIONS: Seventy and one half percent of patients reported pro- dromal symptoms before HAE attacks. This high frequency suggests that prodromal symptoms could be a reliable indication to begin treatment in order to prevent an acute HAE attack. 648 Icatibant, a Selective Bradykinin B2 Receptor Antagonist Used in Hereditary Angioedema Due to C1 Inhibitor Deficiency K. Bork; University of Mainz, Mainz, GERMANY RATIONALE: Icatibant is a novel bradykinin B2 receptor antagonist used in hereditary angioedema. To present efficacy and safety data in daily prac- tice outside of clinical trials. METHODS: 10 patients (5 women, 5 men) with hereditary angioedema received 30 mg icatibant subcutaneously for 10 acute attacks (6 abdominal pain attacks, 3 arm swellings, and 1 facial swelling). Times between the be- ginning of the attack, the injection, the first relief of symptoms and the end of symptoms were determined and compared with 10 earlier attacks in the same location per patient. RESULTS: Time between attack onset and icatibant injection was 3.161.2 hours in the mean. The mean time between the injection and the first symp- tom relief was 30616.4 minutes for abdominal attacks and 41.3614.4 min- utes for skin swellings. In untreated attacks, the mean time to first symptom relief was 26.26 9.2 hours in abdominal attacks and 46.6614.7 hours in skin swellings. The total duration of the treated attacks was 18.8621.4 hours in abdominal attacks and 16.1614.2 hours in skin swellings. The du- ration of untreated attacks was 796 44.3 hours in abdominal attacks and 81616.9 hours in skin swellings. One patient had a return of abdominal symptoms 6 hours after the icatibant injection. Side effects included reac- tions at the injection sites which resolved without medical intervention. CONCLUSIONS: Treatment of acute attacks of hereditary angioedema in daily practice confirms efficacy data of icatibant as shown in clinical trials. 649 Interim Results from Continuation-the Ongoing, Open-Label, Extension Study of Ecallantide for the Treatment of Acute Attacks of Hereditary Angioedema A. J. MacGinnitie 1 , W. E. Pullman 2 , P. T. Horn 2 ; 1 Childrens Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 2 Dyax Corp, Cambridge, MA. RATIONALE: Hereditary angioedema (HAE) is a rare and potentially fatal disease characterized by unpredictable, acute swelling attacks. Interim re- sults from the Continuation study (DX-88/19) of ecallantide, a novel plasma kallikrein inhibitor, for the treatment of acute HAE attacks are reported. METHODS: This is an ongoing, non-randomized, open-label study in pa- tients with mild, moderate, or severe acute HAE attacks affecting any an- atomic location. Patients can receive treatment for multiple attacks. Efficacy endpoints include 2 validated, HAE-specific, patient-reported out- come measures: Mean Symptom Complex Severity (MSCS) score and Treatment Outcome Score (TOS). Interim efficacy data were analyzed across treatment episodes 1 through 6. RESULTS: Through 12 March 2009, 138 patients enrolled in DX-88/19; 95 received ecallantide for 278 total treatment episodes. Across treatment episodes, mean change from baseline in MSCS score at 4 hours ranged from -0.93 to -1.15, indicating significant symptom improvement. Improvement was also demonstrated by mean 4-hour TOS scores of 54.3 to 68.3. The proportion of patients demonstrating significant improvement at 4 hours ranged from 46.0% to 58.3%. Treatment-emergent adverse events were generally mild or moderate and unrelated to ecallantide. One anaphylaxis case and 2 cases of moderate/severe hypersensitivity (ur- ticaria and chest discomfort/flushing) were reported; the patients recovered without sequelae. All 3 patients were anti-ecallantide-antibody positive. Eight additional cases of possible mild or moderate hypersensitivity (in- volving urticaria, pruritus, flushing, or rash) were also reported. CONCLUSIONS: This study provides further evidence that ecallantide is efficacious for the treatment of acute HAE attacks, and the observed safety profile remains unchanged. J ALLERGY CLIN IMMUNOL VOLUME 125, NUMBER 2 Abstracts AB165 MONDAY

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J ALLERGY CLIN IMMUNOL

VOLUME 125, NUMBER 2

Abstracts AB165

MO

ND

AY

646 C1 Esterase Inhibitor: Retrospective Validation of a CommonlyUsed Endpoint in Hereditary Angioedema Studies, Time toOnset of Relief, in a Global, Multicenter, Randomized,Placebo-Controlled Study (I.M.P.A.C.T.1)

A. Bewtra1, J. Bernstein2, B. Ritchie3, R. Levy4, R. Wasserman5, D. Hur-

ewitz6, K. Obtulowicz7, A. Reshef8, D. Moldovan9, T. Shirov10, V. Griv-

cheva-Panovska11, P. Kiessling12, H. Keinecke13, T. Craig14; 1Creighton

University School of Medicine, Omaha, NE, 2University of Cincinnati

Medical Center and Bernstein Clinical Research Center, Cincinnati,

OH, 3University of Alberta, Departments of Medicine and Medical Oncol-

ogy, Edmonton, AB, CANADA, 4Family Allergy and Asthma Center, At-

lanta, GA, 5Pediatric Allergy Immunology Associates, Dallas, TX,6Allergy Clinic of Tulsa, Inc., Tulsa, OK, 7Jagiellonian University Hospi-

tal, Krakow, POLAND, 8The Chaim Sheba Medical Center, Tel

Hashomer, ISRAEL, 9University of Medicine and Pharmacy, 4th Medical

Clinic, Tirgu Mures, ROMANIA, 10University Hospital, Sofia, BULGA-

RIA, 11PHI-University Clinical Center, Department of Dermatology, Al-

lergology and Clinical Immunology, Skopje, MACEDONIA, THE

FORMER YUGOSLAV REPUBLIC OF, 12CSL Behring, Marburg, GER-

MANY, 13Accovion GmbH, Marburg, GERMANY, 14Penn State Univer-

sity College of Medicine, Hershey, PA.

RATIONALE: C1 esterase inhibitor (C1-INH) replacement therapy is the

recommended treatment for acute attacks in hereditary angioedema

(HAE). Time to onset of symptom relief is a common primary endpoint

for efficacy but has never been validated by correlation analysis with the

course of HAE symptoms. We retrospectively validated the primary end-

point for the I.M.P.A.C.T.1 study.

METHODS: Ninety-eight abdominal attacks were treated with 10 or 20

U/kg body weight of a highly purified C1-INH concentrate (Berinert�),

or placebo. The primary endpoint was the time to onset of symptom relief,

as determined by patient responses to a standard question posed at appro-

priate intervals for up to 24 h after treatment. In addition patients assessed

the intensity of the HAE symptoms pain, nausea, vomiting, cramps, and di-

arrhea individually over time. By Spearman rank correlation, the primary

endpoint was compared with the time to first reduction a) of the intensity of

any symptom present at baseline, b) of the sum of symptom intensity

scores, and c) of the intensity of the last symptom present at baseline.

RESULTS: The time to first reduction of the last symptom present at base-

line had the highest correlation with the primary endpoint (0.77). The cor-

relation was considerably lower for the time to first reduction of symptom

intensity (0.60), and the time to first reduction of the sum of symptom in-

tensity scores (0.63).

CONCLUSIONS: A retrospective validation confirmed that the time to

onset of symptom relief, as determined by patients, is an appropriate end-

point for assessing the efficacy of C1-INH therapy.

647 Frequency and Types of Hereditary Angioedema Prodromes asReported by Patients

M. J. Prematta1, C. Laudadio2, T. Craig1; 1Penn State University, Milton

S. Hershey Medical Center, Hershey, PA, 2CSL Behring, King of Prussia, PA.

RATIONALE: Only limited amounts of data have been published about

prodromal symptoms associated with hereditary angioedema (HAE).

The goal of this study is to report data regarding prodromal symptoms pa-

tients experienced before an HAE exacerbation from two different surveys.

METHODS: Data were obtained from a retrospective and prospective

survey. IRB approval and written consent was obtained from all research

subjects. A prospective survey was administered to subjects with HAE en-

rolled in an open-label study of human pasteurized C1 esterase inhibitor

concentrate. Subjects were queried on the presence of prodromal symptoms

at the time they were seeking treatment. The retrospective survey was a four

page survey sent by mail to 158 HAE patients. The survey focused on

questions related to prodromal symptoms prior to the last HAE attack.

RESULTS: The prospective study included 253 attacks, and the retrospec-

tive study included 52 attacks. After combining datasets, data regarding

prodromes was obtained for 305 HAE exacerbations, and patients reported

the presence of a prodrome before 70.5% of exacerbations. The most

frequent prodromes experienced before an HAE exacerbation included fa-

tigue (45.2%); GI complaints (40.7%); muscle aches or flu-like symptoms

(25.9%); rash (21.0%); and numbness or tingling (10.5%).

CONCLUSIONS: Seventy and one half percent of patients reported pro-

dromal symptoms before HAE attacks. This high frequency suggests that

prodromal symptoms could be a reliable indication to begin treatment in

order to prevent an acute HAE attack.

648 Icatibant, a Selective Bradykinin B2 Receptor AntagonistUsed in Hereditary Angioedema Due to C1 Inhibitor Deficiency

K. Bork; University of Mainz, Mainz, GERMANY

RATIONALE: Icatibant is a novel bradykinin B2 receptor antagonist used

in hereditary angioedema. To present efficacy and safety data in daily prac-

tice outside of clinical trials.

METHODS: 10 patients (5 women, 5 men) with hereditary angioedema

received 30 mg icatibant subcutaneously for 10 acute attacks (6 abdominal

pain attacks, 3 arm swellings, and 1 facial swelling). Times between the be-

ginning of the attack, the injection, the first relief of symptoms and the end

of symptoms were determined and compared with 10 earlier attacks in the

same location per patient.

RESULTS: Time between attack onset and icatibant injection was 3.161.2

hours in the mean. The mean time between the injection and the first symp-

tom relief was 30616.4 minutes for abdominal attacks and 41.3614.4 min-

utes for skin swellings. In untreated attacks, the mean time to first symptom

relief was 26.26 9.2 hours in abdominal attacks and 46.6614.7 hours in

skin swellings. The total duration of the treated attacks was 18.8621.4

hours in abdominal attacks and 16.1614.2 hours in skin swellings. The du-

ration of untreated attacks was 796 44.3 hours in abdominal attacks and

81616.9 hours in skin swellings. One patient had a return of abdominal

symptoms 6 hours after the icatibant injection. Side effects included reac-

tions at the injection sites which resolved without medical intervention.

CONCLUSIONS: Treatment of acute attacks of hereditary angioedema in

daily practice confirms efficacy data of icatibant as shown in clinical trials.

649 Interim Results from Continuation-the Ongoing, Open-Label,Extension Study of Ecallantide for the Treatment of AcuteAttacks of Hereditary Angioedema

A. J. MacGinnitie1, W. E. Pullman2, P. T. Horn2; 1Childrens Hospital of

Pittsburgh of UPMC, Pittsburgh, PA, 2Dyax Corp, Cambridge, MA.

RATIONALE: Hereditary angioedema (HAE) is a rare and potentially fatal

disease characterized by unpredictable, acute swelling attacks. Interim re-

sults from the Continuation study (DX-88/19) of ecallantide, a novel plasma

kallikrein inhibitor, for the treatment of acute HAE attacks are reported.

METHODS: This is an ongoing, non-randomized, open-label study in pa-

tients with mild, moderate, or severe acute HAE attacks affecting any an-

atomic location. Patients can receive treatment for multiple attacks.

Efficacy endpoints include 2 validated, HAE-specific, patient-reported out-

come measures: Mean Symptom Complex Severity (MSCS) score and

Treatment Outcome Score (TOS). Interim efficacy data were analyzed

across treatment episodes 1 through 6.

RESULTS: Through 12 March 2009, 138 patients enrolled in DX-88/19;

95 received ecallantide for 278 total treatment episodes. Across treatment

episodes, mean change from baseline in MSCS score at 4 hours ranged

from -0.93 to -1.15, indicating significant symptom improvement.

Improvement was also demonstrated by mean 4-hour TOS scores of 54.3

to 68.3. The proportion of patients demonstrating significant improvement

at 4 hours ranged from 46.0% to 58.3%. Treatment-emergent adverse

events were generally mild or moderate and unrelated to ecallantide.

One anaphylaxis case and 2 cases of moderate/severe hypersensitivity (ur-

ticaria and chest discomfort/flushing) were reported; the patients recovered

without sequelae. All 3 patients were anti-ecallantide-antibody positive.

Eight additional cases of possible mild or moderate hypersensitivity (in-

volving urticaria, pruritus, flushing, or rash) were also reported.

CONCLUSIONS: This study provides further evidence that ecallantide is

efficacious for the treatment of acute HAE attacks, and the observed safety

profile remains unchanged.