This document discusses the treatment of hereditary angioedema (HAE) from the past to the present and future. In the past, treatment for acute attacks was largely symptomatic and long-term prophylaxis included anabolic androgens and antifibrinolytics. Currently, treatment involves C1INH concentrates like Berinert and Cinryze for acute attacks and prophylaxis. Ecallantide, a plasma kallikrein inhibitor, is also approved to treat acute attacks. Future treatments may include recombinant human C1INH and icatibant.

1. HEREDITARYHEREDITARYHEREDITARYHEREDITARYHEREDITARYHEREDITARYHEREDITARYHEREDITARY
ANGIOEDEMAANGIOEDEMAANGIOEDEMAANGIOEDEMAANGIOEDEMAANGIOEDEMAANGIOEDEMAANGIOEDEMA
CHULEEPORN KONGMEESOOK , M.D.CHULEEPORN KONGMEESOOK , M.D.

2. OutlineOutline
•• TreatmentTreatment
PastPast
PresentPresent
FutureFuture

3. HAE with normal C1INHHAE with normal C1INH
•• No controlled treatment studiesNo controlled treatment studies
•• Corticosteroids and antihistaminesCorticosteroids and antihistamines
ineffectiveineffective
TreatmentTreatment
•• May respond to the same drugs as usefulMay respond to the same drugs as useful
in patients with HAE due to reducedin patients with HAE due to reduced
C1INHC1INH
Middleton'sMiddleton's allergy:principlesallergy:principles and practice 8th editionand practice 8th edition

4. NonhistaminergicNonhistaminergic idiopathicidiopathic angioedemaangioedema
•• Little is knownLittle is known
TreatmentTreatment
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5. 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
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6. Treatment : The pastTreatment : The past
Acute attacksAcute attacks
•• Abdominal attack : Aggressive IVAbdominal attack : Aggressive IV
replacement, control of pain and nauseareplacement, control of pain and nausea
withwith parenteralparenteral narcotic and antiemeticnarcotic and antiemetic
drugsdrugs
•• Airway attack :Airway attack : IntubateIntubate or emergencyor emergency
tracheotomytracheotomy
•• AngioedemaAngioedema of extremities : Not requireof extremities : Not require
treatmenttreatment
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7. Treatment : The pastTreatment : The past
LongLong--term prophylaxisterm prophylaxis
•• Goal : Decrease frequency and/orGoal : Decrease frequency and/or
severity of swelling attacksseverity of swelling attacks
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8. Treatment : The pastTreatment : The past
LongLong--term prophylaxisterm prophylaxis
•• Anabolic androgensAnabolic androgens
•• DanazolDanazol andand StanozololStanozolol (synthetic 17(synthetic 17--aa--
alkylated androgens )alkylated androgens )
2 mg2 mg StanozololStanozolol daily or ADdaily or AD
or 200 mgor 200 mg DanazolDanazol daily or ADdaily or AD
•• Precise mechanism be elucidatedPrecise mechanism be elucidated
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

9. Treatment : The pastTreatment : The past
LongLong--term prophylaxisterm prophylaxis
•• AntiAnti--fibrinolyticsfibrinolytics
•• EpsilonEpsilon aminocaproicaminocaproic acid (EACA oracid (EACA or
AmicarAmicar) and) and TranexamicTranexamic acidacidAmicarAmicar) and) and TranexamicTranexamic acidacid
•• Reserved for not tolerate anabolicReserved for not tolerate anabolic
androgensandrogens (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
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

10. Treatment : The pastTreatment : The past
ShortShort--term prophylaxisterm prophylaxis
•• Prevent attacks before expected trauma:Prevent attacks before expected trauma:
surgery or dental proceduressurgery or dental procedures
•• StanozololStanozolol 22 mg three times daily ormg three times daily or•• StanozololStanozolol 22 mg three times daily ormg three times daily or
danazoldanazol 200200 mg three times daily begunmg three times daily begun
55--77 days before proceduredays before procedure
•• 22 units of FFP several hours beforeunits of FFP several hours before
procedureprocedure
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

11. Treatment : The presentTreatment : The present
•• PlasmaPlasma--derived Cderived C11INH concentratesINH concentrates
Pasteurized plasmaPasteurized plasma--derived Cderived C11INHINH
concentrateconcentrate
NanofilteredNanofiltered and pasteurized plasmaand pasteurized plasma
derived Cderived C11INH concentrateINH concentratederived Cderived C11INH concentrateINH concentrate
•• PlasmaPlasma kallikreinkallikrein inhibitor:inhibitor: EcallantideEcallantide
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12. Treatment : The presentTreatment : The present
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 attacksPhase III study for acute attacks•• Phase III study for acute attacksPhase III study for acute attacks
(I.M.P.A.C.T.1)(I.M.P.A.C.T.1)
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

13. TimothyTimothy J.CraigJ.Craig et alet al AllergyAllergy ClinClin ImmunolImmunol 2009;124:8012009;124:801--88

14. TimothyTimothy J.CraigJ.Craig et alet al AllergyAllergy ClinClin ImmunolImmunol 2009;124:8012009;124:801--88

15. TimothyTimothy J.CraigJ.Craig et alet al AllergyAllergy ClinClin ImmunolImmunol 2009;124:8012009;124:801--88

16. Treatment : The presentTreatment : The present
Pasteurized plasmaPasteurized plasma--derived C1INHderived C1INH
ConcentrateConcentrate
•• BerinertBerinert received approval from FDA forreceived approval from FDA for
use in treatment of acuteuse in treatment of acute angioedemaangioedema
attacks in adolescent and adult HAEattacks in adolescent and adult HAEattacks in adolescent and adult HAEattacks in adolescent and adult HAE
patientspatients
Bruce LBruce L ZurawZuraw et al J Allergyet al J Allergy ClinClin ImmunolImmunol 20132013;;131131::14911491--33
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 20102010;; 66::11--88

17. Treatment : The presentTreatment : The present
NanofilteredNanofiltered and pasteurizedand pasteurized
plasma derived Cplasma derived C11INH concentrateINH concentrate
•• CinryzeCinryze ((ViroPharmaViroPharma Incorporated)Incorporated)
•• Two separate randomized doubleTwo separate randomized double--blindblind
placebo controlled studies ofplacebo controlled studies of CinryzeCinryzeplacebo controlled studies ofplacebo controlled studies of CinryzeCinryze
performed in USperformed in US
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 20102010;; 66::11--88

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

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

21. Treatment : The presentTreatment : The present
NanofilteredNanofiltered and pasteurizedand pasteurized
plasma derived C1INH concentrateplasma derived C1INH concentrate
•• CinryzeCinryze received FDA approval forreceived FDA approval for
prophylactic treatment in adolescentprophylactic treatment in adolescent
and adult HAE patientsand adult HAE patientsand adult HAE patientsand adult HAE patients
•• Application for use ofApplication for use of CinryzeCinryze to treatto treat
acute attacks ofacute attacks of angioedemaangioedema is stillis still
pendingpending
Bruce LBruce L ZurawZuraw et al J Allergyet al J Allergy ClinClin ImmunolImmunol 2013;131:14912013;131:1491--33
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

22. Treatment : The presentTreatment : The present
PlasmaPlasma kallikreinkallikrein inhibitorinhibitor
•• EcallantideEcallantide
•• Recommended dose to treatRecommended dose to treat
angioedemaangioedema attack :attack : 3030 mg,mg,
administered as threeadministered as three 11 ml SCml SCadministered as threeadministered as three 11 ml SCml SC
•• 22 separate RDBPC phase III studiesseparate RDBPC phase III studies
EDEMAEDEMA 33
EDEMAEDEMA 44
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

24. MarcoMarco CicardiCicardi et alet al NN EnglEngl J Med 2010;363:523J Med 2010;363:523--3131

25. MarcoMarco CicardiCicardi et alet al NN EnglEngl J Med 2010;363:523J Med 2010;363:523--3131

26. MarcoMarco CicardiCicardi et alet al NN EnglEngl J MedJ Med 20102010;;363363::523523--3131

27. Treatment : The presentTreatment : The present
PlasmaPlasma kallikreinkallikrein inhibitor :inhibitor : EcallantideEcallantide
•• Based on data from both Phase IIIBased on data from both Phase III
studies, approval for use ofstudies, approval for use of ecallantideecallantide
to treat acute HAE attacks in patientsto treat acute HAE attacks in patients
aged >aged >1616 ((granted on Decembergranted on December 2 20092 2009))
•• Black box warning on anaphylacticBlack box warning on anaphylactic
potential and requiring that the drug bepotential and requiring that the drug be
administered by health care provideradministered by health care provider
Bruce LBruce L ZurawZuraw et al J Allergyet al J Allergy ClinClin ImmunolImmunol 2013;131:14912013;131:1491--33
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

28. Treatment : The futureTreatment : The future
•• Recombinant human CRecombinant human C11INHINH
•• IcatibantIcatibant
•• Other future directionsOther future directions
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

29. Recombinant human CRecombinant human C11INHINH
•• RhucinRhucin ((PharmingPharming NV)NV)
•• Two separate phase III studiesTwo separate phase III studies
Treatment : The futureTreatment : The future
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 20102010;; 66::11--88

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

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

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

33. IcatibantIcatibant ((FirazyrFirazyr, Shire), Shire)
•• Administered subcutaneously as aAdministered subcutaneously as a
singlesingle 3030 mg injectionmg injection
•• Two RDBPC phase III studyTwo RDBPC phase III study
FASTFAST--11
Treatment : The futureTreatment : The future
FASTFAST--11
FASTFAST--22
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

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

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

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

37. IcatibantIcatibant
•• Approved for use for acute attacks inApproved for use for acute attacks in
the European Unionthe European Union
•• The FDA disapproved the application forThe FDA disapproved the application for
Treatment : The futureTreatment : The future
•• The FDA disapproved the application forThe FDA disapproved the application for
licensure, and new RDBPC phase III triallicensure, and new RDBPC phase III trial
(FAST(FAST33) is ongoing) is ongoing
Bruce LBruce L ZurawZuraw et al J Allergyet al J Allergy ClinClin ImmunolImmunol 2013;131:14912013;131:1491--33
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

38. Other future directionsOther future directions
•• Administering CAdministering C11INH concentrate byINH concentrate by
subsub--cutaneouscutaneous infusioninfusion
•• Inhibition of factor XII activity mightInhibition of factor XII activity might
Treatment : The futureTreatment : The future
•• Inhibition of factor XII activity mightInhibition of factor XII activity might
preventprevent bradykininbradykinin generationgeneration
•• Orally availableOrally available bradykininbradykinin receptorreceptor
antagonistsantagonists
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

39. Other future directionsOther future directions
•• CombinedCombined bradykininbradykinin BB22 and Band B11
receptor antagonismreceptor antagonism
•• Gene repair or intracellular traffickingGene repair or intracellular trafficking
Treatment : The futureTreatment : The future
•• Gene repair or intracellular traffickingGene repair or intracellular trafficking
for molecular correction of defects infor molecular correction of defects in
HAEHAE
Bruce LBruce L ZurawZuraw AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 20102010;; 66::11--88

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

41. TreatmentTreatment
Middleton'sMiddleton's allergy:principlesallergy:principles and practiceand practice 88th editionth edition

42. TreatmentTreatment
Middleton'sMiddleton's allergy:principlesallergy:principles and practice 8th editionand practice 8th edition

43. TreatmentTreatment
Middleton'sMiddleton's allergy:principlesallergy:principles and practiceand practice 88th editionth edition

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

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

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

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

48. KonradKonrad BorkBork AllergyAllergy,, AsthmaAsthma && ClinicalClinical ImmunologyImmunology 2010; 6:12010; 6:1--88

49. THANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOUTHANK YOU

50. Middleton'sMiddleton's allergy:principlesallergy:principles and practiceand practice 88th editionth edition

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