WAO Global Hereditary Angioedema (HAE) Practice Parameter

Timothy J. Craig, DOProfessor of Medicine and Pediatrics

Distinguished EducatorChief, Allergy, Asthma, and Immunology

Program Director Director of Clinical Allergy and Respiratory Research

Pennsylvania State University College of MedicineHershey, Pennsylvania, USA

WAO Global Hereditary Angioedema Practice ParameterChair: Tim Craig, USA

General Advisor: Richard F. Lockey, USA  Steering Committee Members: Konrad Bork, Germany Tom Bowen, Canada Henrik Boysen, Belgium Marco Cicardi, Italy Henriette Farkas, Hungary Anete Grumach, Brazil (SLAAI) Connie Katelaris, Australia (APAAACI) Hilary Longhurst, UK William Lumry, USA (ACAAI) Marcus Maurer, Germany (EAACI) Bruce Ritchie, Canada Bruce Zuraw, USA (AAAAI) Emel Aygören Pürsün, Germany Inmaculada Martinez-Saguer, Germany

Sponsors of the WAO HAE ProgramCompany Financial Supporter

CSL Behring XX

Dyax XX

Viropharma XX

Shire XX (via Jerini)

Pharming (did not yet have a product on the market)

WAO Global Hereditary Angioedema Practice Parameter

OBJECTIVES:1.Produce an evidence based guideline for care of HAE patients throughout the world2.Develop a document that would be a reference for HCP3.To develop a document that could be used at the bedside4.Have a document that could be utilized in all countries5.Develop a guideline that would be approved by the global allergy community6.Develop a power point program for use by all members of the WAO7.Lastly, and most importantly, to improve care for the patients with Hereditary Angioedema and to improve access of therapies to all patients, in all countries around the world.

Is there a need for this?

ActiveCleaved: Inactive

What Is C1-Inhibitor?

Key regulator of fourbiochemical pathways

1. Complement 2. Contact 3. Fibrinolytic4. Coagulation

Human plasma protein …that mediates inflammation

C1-Inhibitor deficiency

can cause:– debilitating pain– disfiguring swelling– asphyxiation &

death

Autosomal Dominant Defect

Crowder JR, Crowder TR. Five generations of angioneurotic edema. Arch Inter Med 1917; 20:840-52

Bissler JJ, et al. Proc Assoc Am Physicians. 1997;109:164-173.Davis AE 3rd. Annu Rev Immunol. 1988;6:595-628.Verpy E, et al. Am J Hum Genet. 1996;59:308-319.Zuraw BL, Herschbach J. J Allergy Clin Immunol. 2000;105:541-546.

HAE Is Caused By C1 Inhibitor Mutations

C1-INH involved in 3 systems → C1-INH depletion

Kallikrein

HMW-K

Factor XII

Prekallikrein

Contact SystemContact System

C4C2

C1

Complement Complement SystemSystem

Increased vascular

permeability ANGIOEDEMA

C1-

INH

C1-

INH

C1-INH C1-INH C

1-IN

H

C

1-IN

H

C1-

INH

C1-

INH

Bradykinin

FibrinolyticFibrinolyticSystemSystem

Factor XIIa

Plasmin

Plasminogen

C1rs

C1-INH

C1INH gene +/+ +/+ -/- -/- -/-B2BKR gene +/+ +/+ +/+ +/+ -/-Evans blue No Yes Yes Yes YesC1INH therapy No No No Yes No

C1INH Null Mice and Vascular Permeability

Adapted from Han ED, et al. J Clin Invest. 2002;109:1057-1063.

In Vivo Generation of Kinins in HAE

From Nussberger J, et al. J Allergy Clin Immunol. 1999;104:1321-1322; with permission.

Actin stress fibersVE-cadherin

Nonstimulated

Stimulated

Increased vascular permeability

From Tiruppathi C, et al. Vascul Pharmacol. 2003;39:173-185; with permission.

How Does BK Cause Angioedema?

Common triggers of HAE attacks

Trauma Menstruation

Infection

Stress

Medications

AngioedemaAngioedema attack

• Conceptually divide intothree categories– Long-term prophylaxis

• Minimize attack frequency and severity

• Prevent hospitalizations and emergency room visits

– Short-term prophylaxis• Prevent attacks after trauma• Prevent attacks during

important life events

– Treatment of acute attacks• Terminate ongoing attack• Prevent morbidity and

mortality

Treatment of HAE

PK

Therapeutic Implications

Adapted from Zuraw BL. Immunol Allergy Clin North Am. 2006;26:691-708.

Drug Advantages Disadvantages Best use Status

Plasma-derivedC1-INH

• Extensive clinical experience

• Corrects the fundamental defect

• long half-life

• Infectious risk• Needs IV access• Limited supply

• Acute attacks• Short-term• Long-term

prophylaxis• Prodromes

• Berinert P: approved in EU, USA, Canada, Argentina

• Cinryze: approved in EU, USA

• Cetor in the EU, Turkey

RecombinantC1-INH

• Corrects the fundamental defect

• No human virus risk

• Scalable supply

• Needs IV access• Short half-life• Potential for

allergic reactions

• Acute attacks• Short

prophylaxis• Prodrome?

• Rhucin: approved in the EU

Ecallantide • More potent than C1-INH

• No infectious risk• Subcutaneous

administration

• Antibodies may cause allergic reaction or neutralization

• Short half-life

• Acute attacks in office

• Kalbitor: approved in the USA

Icatibant • No infectious risk

• Stable at room temperature

• Subcutaneous

• Short half-life• Local pain or

irritation

• Home treatment of acute attacks?

• Firazyr: approved in EU, USA, Brazil

In Summary

Global document is now being evidence based

From here it will go to the steering committee for approval

Than it will go to WAO leadership Finally out to all the Allergy

Associations for their approval Power Point slides will go through the

same process

Thank you.Questions?tcraig@psu.edu