hereditary angioedema ii

HEREDITARY HEREDITARY HEREDITARY HEREDITARY HEREDITARY HEREDITARY HEREDITARY HEREDITARY ANGIOEDEMAANGIOEDEMAANGIOEDEMAANGIOEDEMAANGIOEDEMAANGIOEDEMAANGIOEDEMAANGIOEDEMA

CHULEEPORN KONGMEESOOK , M.D.CHULEEPORN KONGMEESOOK , M.D.

OutlineOutline

•• TreatmentTreatment

�� PastPast

�� PresentPresent

�� FutureFuture

HAE with normal C1INHHAE with normal C1INH

•• No controlled treatment studies No controlled treatment studies

•• Corticosteroids and antihistamines Corticosteroids and antihistamines ineffective ineffective

TreatmentTreatment

•• May respond to the same drugs as useful May respond to the same drugs as useful in patients with HAE due to reduced in patients with HAE due to reduced C1INH C1INH

Middleton's Middleton's allergy:principlesallergy:principles and practice 8th editionand practice 8th edition

NonhistaminergicNonhistaminergic idiopathic idiopathic angioedemaangioedema

•• Little is known Little is known

TreatmentTreatment


Treatment : The pastTreatment : The past

Acute attacksAcute attacks

•• Until late 2008, no drug approved in USUntil late 2008, no drug approved in US

•• Symptomatic control of swellingSymptomatic control of swelling

Bruce L Bruce L ZurawZuraw AllergyAllergy, , AsthmaAsthma & & ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88


Acute attacksAcute attacks

•• Abdominal attack : Aggressive IV Abdominal attack : Aggressive IV replacement, control of pain and nausea replacement, control of pain and nausea with with parenteralparenteral narcotic and antiemetic narcotic and antiemetic drugs drugs

•• Airway attack : Airway attack : IntubateIntubate or emergency or emergency tracheotomytracheotomy

•• AngioedemaAngioedema of extremities : Not require of extremities : Not require treatment treatment



LongLong--term prophylaxisterm prophylaxis

•• Goal : Decrease frequency and/or Goal : Decrease frequency and/or

severity of swelling attacksseverity of swelling attacks




•• Anabolic androgens Anabolic androgens

•• DanazolDanazol and and StanozololStanozolol (synthetic 17(synthetic 17--aa--alkylated androgens )alkylated androgens )

�� 2 mg 2 mg StanozololStanozolol daily or AD daily or AD

or 200 mg or 200 mg DanazolDanazol daily or ADdaily or AD

•• Precise mechanism be elucidatedPrecise mechanism be elucidated




•• AntiAnti--fibrinolyticsfibrinolytics

•• Epsilon Epsilon aminocaproicaminocaproic acid (EACA or acid (EACA or

AmicarAmicar) and ) and TranexamicTranexamic acidacidAmicarAmicar) and ) and TranexamicTranexamic acidacid

•• Reserved for not tolerate anabolic Reserved for not tolerate anabolic androgens androgens (children and pregnant women)(children and pregnant women)

�� TranexamicTranexamic acid not available in USacid not available in US

�� EACA 1 gm orally 3EACA 1 gm orally 3--4 times per day4 times per day



ShortShort--term prophylaxisterm prophylaxis

•• Prevent attacks before expected trauma: Prevent attacks before expected trauma:

surgery or dental proceduressurgery or dental procedures

•• StanozololStanozolol 2 2 mg three times daily or mg three times daily or •• StanozololStanozolol 2 2 mg three times daily or mg three times daily or

danazoldanazol 200 200 mg three times daily begun mg three times daily begun

55--7 7 days before proceduredays before procedure

•• 2 2 units of FFP several hours before units of FFP several hours before

procedureprocedureBruce L Bruce L ZurawZuraw AllergyAllergy, , AsthmaAsthma & & ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

Treatment : The presentTreatment : The present

•• PlasmaPlasma--derived Cderived C11INH concentrates INH concentrates

��Pasteurized plasmaPasteurized plasma--derived Cderived C11INH INH concentrateconcentrate

��NanofilteredNanofiltered and pasteurized plasmaand pasteurized plasma

derived Cderived C11INH concentrateINH concentratederived Cderived C11INH concentrateINH concentrate

•• Plasma Plasma kallikreinkallikrein inhibitor: inhibitor: EcallantideEcallantide



Pasteurized plasmaPasteurized plasma--derived C1INHderived C1INH

ConcentrateConcentrate

•• BerinertBerinert (CSL Behring)(CSL Behring)

•• Licensed in Europe over 20 yearsLicensed in Europe over 20 years

•• Phase III study for acute attacks Phase III study for acute attacks •• Phase III study for acute attacks Phase III study for acute attacks

(I.M.P.A.C.T.1)(I.M.P.A.C.T.1)


Timothy Timothy J.CraigJ.Craig et alet al Allergy Allergy ClinClin ImmunolImmunol 2009;124:8012009;124:801--88


Pasteurized plasmaPasteurized plasma--derived C1INHderived C1INH

ConcentrateConcentrate

•• BerinertBerinert received approval from FDA for received approval from FDA for use in treatment of acute use in treatment of acute angioedemaangioedemaattacks in adolescent and adult HAE attacks in adolescent and adult HAE attacks in adolescent and adult HAE attacks in adolescent and adult HAE patientspatients

Bruce L Bruce L ZurawZuraw et al J Allergy et al J Allergy ClinClin ImmunolImmunol 20132013;;131131::14911491--33Bruce L Bruce L ZurawZuraw AllergyAllergy, , AsthmaAsthma & & ClinicalClinical ImmunologyImmunology 20102010; ; 66::11--88


NanofilteredNanofiltered and pasteurized and pasteurized

plasma derived Cplasma derived C11INH concentrateINH concentrate

•• CinryzeCinryze ((ViroPharmaViroPharma Incorporated)Incorporated)

•• Two separate randomized doubleTwo separate randomized double--blind blind placebo controlled studies of placebo controlled studies of CinryzeCinryzeplacebo controlled studies of placebo controlled studies of CinryzeCinryzeperformed in USperformed in US

Bruce L Bruce L ZurawZuraw AllergyAllergy, , AsthmaAsthma & & ClinicalClinical ImmunologyImmunology 20102010; ; 66::11--88

Bruce L Bruce L ZurawZuraw et al N et al N EnglEngl J Med 2010;363:513J Med 2010;363:513--2222


NanofilteredNanofiltered and pasteurized and pasteurized

plasma derived C1INH concentrateplasma derived C1INH concentrate

•• CinryzeCinryze received FDA approval for received FDA approval for prophylactic treatment in adolescent prophylactic treatment in adolescent and adult HAE patientsand adult HAE patientsand adult HAE patientsand adult HAE patients

•• Application for use of Application for use of CinryzeCinryze to treat to treat acute attacks of acute attacks of angioedemaangioedema is still is still pendingpending

Bruce L Bruce L ZurawZuraw et al J Allergy et al J Allergy ClinClin ImmunolImmunol 2013;131:14912013;131:1491--33Bruce L Bruce L ZurawZuraw AllergyAllergy, , AsthmaAsthma & & ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88


Plasma Plasma kallikreinkallikrein inhibitorinhibitor

•• EcallantideEcallantide

•• Recommended dose to treat Recommended dose to treat angioedemaangioedema attack : attack : 30 30 mg, mg, administered as three administered as three 1 1 ml SCml SCadministered as three administered as three 1 1 ml SCml SC

•• 2 2 separate RDBPC phase III studiesseparate RDBPC phase III studies

�� EDEMA EDEMA 33

�� EDEMA EDEMA 44


Marco Marco CicardiCicardi et alet al N N EnglEngl J Med 2010;363:523J Med 2010;363:523--3131

Marco Marco CicardiCicardi et alet al N N EnglEngl J Med J Med 20102010;;363363::523523--3131


Plasma Plasma kallikreinkallikrein inhibitor : inhibitor : EcallantideEcallantide

•• Based on data from both Phase III Based on data from both Phase III studies, approval for use of studies, approval for use of ecallantideecallantideto treat acute HAE attacks in patients to treat acute HAE attacks in patients aged >aged >16 16 ((granted on December granted on December 2 20092 2009))

•• Black box warning on anaphylactic Black box warning on anaphylactic potential and requiring that the drug be potential and requiring that the drug be administered by health care provideradministered by health care provider


Treatment : The futureTreatment : The future

•• Recombinant human CRecombinant human C11INHINH

•• IcatibantIcatibant

•• Other future directionsOther future directions


Recombinant human CRecombinant human C11INHINH

•• RhucinRhucin ((PharmingPharming NV)NV)

•• Two separate phase III studies Two separate phase III studies



Bruce L Bruce L ZurawZuraw et alet al J Allergy J Allergy ClinClin ImmunolImmunol 2010;126:8212010;126:821--77

IcatibantIcatibant ((FirazyrFirazyr, Shire), Shire)

•• Administered subcutaneously as a Administered subcutaneously as a single single 30 30 mg injection mg injection

•• Two RDBPC phase III study Two RDBPC phase III study

�� FASTFAST--11


�� FASTFAST--11

�� FASTFAST--22


M. M. CicardiCicardi et alet al N N EnglEngl J Med J Med 20102010;;363363::532532--4141

M. M. CicardiCicardi et alet al N N EnglEngl J Med 2010;363:532J Med 2010;363:532--4141

IcatibantIcatibant

•• Approved for use for acute attacks in Approved for use for acute attacks in the European Unionthe European Union

•• The FDA disapproved the application for The FDA disapproved the application for


•• The FDA disapproved the application for The FDA disapproved the application for licensure, and new RDBPC phase III trial licensure, and new RDBPC phase III trial (FAST(FAST33) is ongoing) is ongoing


Other future directionsOther future directions

•• Administering CAdministering C11INH concentrate by INH concentrate by subsub--cutaneouscutaneous infusion infusion

•• Inhibition of factor XII activity might Inhibition of factor XII activity might


•• Inhibition of factor XII activity might Inhibition of factor XII activity might prevent prevent bradykininbradykinin generationgeneration

•• Orally available Orally available bradykininbradykinin receptor receptor antagonists antagonists


Other future directionsOther future directions

•• Combined Combined bradykininbradykinin BB2 2 and Band B1 1 receptor antagonismreceptor antagonism

•• Gene repair or intracellular trafficking Gene repair or intracellular trafficking


•• Gene repair or intracellular trafficking Gene repair or intracellular trafficking for molecular correction of defects in for molecular correction of defects in HAEHAE


Larisa V. Larisa V. BuyantsevaBuyantseva et al et al AsainAsain PacPac J J AllergyAllergy ImmunolImmunol 20122012; ; 3030::8989--9898

TreatmentTreatment

Middleton's Middleton's allergy:principlesallergy:principles and practice and practice 88th editionth edition

TreatmentTreatment


Timothy Craig et al WAO Journal Timothy Craig et al WAO Journal 20122012; ; 55::182182––199199

Tom Bowen et al Tom Bowen et al AllergyAllergy, , AsthmaAsthma & & ClinicalClinical ImmunologyImmunology 20102010; ; 66::11--88

Tom Bowen et al Tom Bowen et al AllergyAllergy, , AsthmaAsthma & & ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

Tom Bowen et al Tom Bowen et al AllergyAllergy, , AsthmaAsthma & & ClinicalClinical ImmunologyImmunology 20102010; ; 66::11--88

KonradKonrad Bork Bork AllergyAllergy, , AsthmaAsthma & & ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

THANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOU

hereditary angioedema ii

Health & Medicine