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

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

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)

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.

Is there a need for this?

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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

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

HAE Is Caused By C1 Inhibitor Mutations 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. 9

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

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;109:1057-1063. 11

In Vivo Generation of Kinins in HAE From Nussberger J, et al. J Allergy Clin Immunol. 1999;104:1321-1322; with permission. 12

How Does BK Cause Angioedema? Increased vascular permeability VE-cadherin Actin stress fibers Nonstimulated Stimulated From Tiruppathi C, et al. Vascul Pharmacol. 2003;39:173-185; with permission. 13

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

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

Therapeutic Implications PK Adapted from Zuraw BL. Immunol Allergy Clin North Am. 2006;26:691-708. 20

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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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