1. WAO Global Hereditary Angioedema (HAE) Practice Parameter
Timothy J. Craig, DO
Professor of Medicine and Pediatrics
Distinguished Educator
Chief, Allergy, Asthma, and Immunology
Program Director
Director of Clinical Allergy and Respiratory Research Pennsylvania State University College of Medicine
Hershey, Pennsylvania, USA 1

2. WAO Global Hereditary Angioedema Practice Parameter
Chair: 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

3. Sponsors of the WAO HAE Program
Company
Financial Supporter
CSL Behring XX
Dyax
Viropharma
Shire
XX (via Jerini)
Pharming
(did not yet have a product on the market)

4. WAO Global Hereditary Angioedema Practice Parameter
OBJECTIVES:
Produce an evidence based guideline for care of HAE patients throughout the world
Develop a document that would be a reference for HCP
To develop a document that could be used at the bedside
Have a document that could be utilized in all countries
Develop a guideline that would be approved by the global allergy community
Develop a power point program for use by all members of the WAO
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.

5. Is there a need for this?

6. Active
Cleaved: Inactive

7. Human plasma protein …that mediates inflammation
What Is C1-Inhibitor?
Human plasma protein …that mediates inflammation
C1-Inhibitor deficiency
can cause:
debilitating pain
disfiguring swelling
asphyxiation & death
Key regulator of four
biochemical pathways
Complement
Contact
Fibrinolytic
Coagulation

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

9. HAE Is Caused By C1 Inhibitor Mutations
Bissler JJ, et al. Proc Assoc Am Physicians. 1997;109:
Davis AE 3rd. Annu Rev Immunol. 1988;6:
Verpy E, et al. Am J Hum Genet. 1996;59:
Zuraw BL, Herschbach J. J Allergy Clin Immunol. 2000;105: 9

10. Increased vascular permeability  ANGIOEDEMA
C1-INH involved in 3 systems → C1-INH depletion
Factor XII
Factor XIIa
C1-INH C1
Contact System
C1-INH
Prekallikrein
Complement System
HMW-K C4 C2
Kallikrein
C1rs
C1-INH
C1-INH
C1-INH
Plasminogen
Animation script
Opening: Triggers, such as trauma and infection, activate the complement system.
Click 1: Triggers also activate the contact system and the fibrinolytic system. In a normal person, C1-INH regulates these systems by blocking pathways. This prevents the systems from becoming over-active.
Click 2: Patients with HAE have low reserves of C1-INH. Once depleted, the systems will be unopposed, resulting in an over-production of bradykinin. Bradykinin is believed to be responsible for the swelling symptoms.
Click 3: If C1-INH is replenished, bradykinin production will be controlled and balance can be restored (optional).
This slide illustrates some of the processes involved in activation of the complement, contact, and fibrinolytic system
Clinically, attacks of HAE appear to have a number of environmental and pathophysiological triggers: prolonged mechanical pressure, trauma, emotional stress, drug therapy
Chronically low levels of C1-INH—approximately 30% of normal—suggest the possibility of complement and contact systems activation even during apparently symptom-free periods, so-called autoactivation of the plasma cascade systems. Any further reductions in available C1-INH would be associated with development of angioedema symptoms during an HAE attack
Chronic, low-level activation of the complement pathway could lead to the inappropriate activation of the contact pathway via activation of factor XI and kallikrein. Vascular permeability and edema would result from the rapid and excessive synthesis of bradykinin
Activation of factors and proteases may modulate between and among systems
Plasmin and plasminogen in the fibrinolytic pathway may serve to activate C1 in the complement pathway, while factor XIIa or kallikrein in the contact pathway may generate plasmin from plasminogen in the fibrinolytic pathway
Bradykinin
Plasmin
Fibrinolytic System
Increased vascular permeability  ANGIOEDEMA

11. C1INH Null Mice and Vascular Permeability
C1INH gene / / / / /-
B2BKR gene / / / / /-
Evans blue No Yes Yes Yes Yes
C1INH therapy No No No Yes No
Adapted from Han ED, et al. J Clin Invest. 2002;109: 11

12. In Vivo Generation of Kinins in HAE
From Nussberger J, et al. J Allergy Clin Immunol. 1999;104: ; with permission. 12

13. How Does BK Cause Angioedema?
Increased vascular permeability
VE-cadherin
Actin stress fibers
Nonstimulated
Stimulated
From Tiruppathi C, et al. Vascul Pharmacol. 2003;39: ; with permission. 13

14. Common triggers of HAE attacks
Trauma
Menstruation
Angioedema
Angioedema attack
Infection
Medications
Medications: ACEI, OCPs (estrogen), ARBs
Stress

19. Treatment of HAE Conceptually divide into three 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
Slide 19
Conventional treatment of HAE hasn’t significantly changed in almost 40 years. The general approach to treatment can be classified into three goals: long-term prophylaxis, short-term prophylaxis, and treatment of acute attacks. 19

20. Therapeutic ImplicationsPK
Adapted from Zuraw BL. Immunol Allergy Clin North Am. 2006;26: 20

21. Long-term prophylaxis Prodromes
Drug
Advantages
Disadvantages
Best use
Status
Plasma-derived
C1-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
Recombinant
No human virus risk
Scalable supply
Short half-life
Potential for allergic reactions
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
Acute attacks in office
Kalbitor: approved in the USA
Icatibant
Stable at room temperature
Subcutaneous
Local pain or irritation
Home treatment of acute attacks?
Firazyr: approved in EU, USA, Brazil
Slide 21
How do the newer drugs compare with each other?
Plasma-derived C1-INH is clearly very effective and has an excellent safety record; however, it is not convenient for home use and carries the theoretical risk of infection. The lack of convenient home use is less of an issue for prophylaxis and, as mentioned, Cinryze is already approved for prophylactic use.
Recombinant C1-INH has a profile similar to plasma-derived C1-INH except that it does not have the same concern about viral safety; however, the shorter half-life makes prophylaxis more problematic, and the risk of allergic reactions is unknown but likely small.
Ecallantide does not have any infectious risk and can be conveniently administered by subcutaneous injection. The risk of allergic reactions, however, precludes its home use at the present time.
Icatibant also doesn’t have an infectious risk and can be conveniently administered by subcutaneous injection. It could conceivably be self-administered at home; however, the failure of the US phase III study means that it is unlikely to be approved in the short-term. 21

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26. 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

27. Thank you.
Questions?