HAE management and future perspectives Marcus Maurer Allergie-Centrum-Charité Department of Dermatology and Allergy Charité - Universitätsmedizin Berlin Germany
Disclosure of Significant Relationships with Commercial Companies and Organizations Funding of Research by Deutsche Forschungsgemeinschaft (DFG), EU (FP7, COST), European Centre of Allergy Research Foundation (ECARF), Urticaria Network e.v. (UNEV), Bayer, Leo, Novartis, Riemser, Uriach. Speaker and/or Advisor for Almirall Hermal, Bayer, BioCryst, CSL Behring, Dyax, FAES, Genentech, Leo, Merckle Recordati, Moxie, MSD, Novartis, Riemser, Sanofi Aventis, Shire, Takeda, UCB, and Uriach. 9 / 2016, for past five years
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Craig et al. World Allergy Organ J. 2012; 5: 182-199
WAO/EAACI guidelines for the management of hereditary angioedema Global, evidence-based, GRADE approach 20 recommendations, 2 levels of strength 7 sections Craig et al. World Allergy Organ J. 2012; 5: 182-199
WAO/EAACI guidelines for the management of hereditary angioedema Definitions, Nomenclature, and Classification Pathophysiology Diagnosis Therapy of HAE-1/2 Management of HAE-1/2 in children Management of HAE-1/2 in pregnancy & lactation Patient support, home therapy, self administration, and other management considerations Craig et al. World Allergy Organ J. 2012; 5: 182-199
WAO/EAACI guidelines for the management of hereditary angioedema Definitions, Nomenclature, and Classification Pathophysiology Diagnosis Therapy of HAE-1/2 Management of HAE-1/2 in children Management of HAE-1/2 in pregnancy & lactation Patient support, home therapy, self administration, and other management considerations Craig et al. World Allergy Organ J. 2012; 5: 182-199
Coagulation Kininogen Prekallikrein C1 XIIa Kallikrein XII C1 C4 Bradykinin Angioedema
Coagulation Kininogen Prekallikrein C1 XIIa Kallikrein XII C1 C4 Bradykinin Angioedema
Coagulation Kininogen Prekallikrein C1 XIIa Kallikrein Ecallantide XII C1 C4 Bradykinin Angioedema
Coagulation Kininogen Prekallikrein C1 XIIa Kallikrein Ecallantide XII C1 C4 Bradykinin Angioedema
Concepts and products for the treatment of HAE On-demand treatment Long term prophylaxis Craig et al. World Allergy Organ J. 2012; 5: 182-199
Concepts and products for the treatment of HAE On-demand treatment pdc1-inh (Berinert) pdc1-inh (Cinryze) rhc1-inh (Ruconest) Icatibant (Firazyr) Ecallantide (Kalbitor) Long term prophylaxis pdc1-inh (Cinryze) Attenuated androgens Tranexamic acid Craig et al. World Allergy Organ J. 2012; 5: 182-199
Concepts and products for the treatment of HAE On-demand treatment pdc1-inh (Berinert) pdc1-inh (Cinryze) rhc1-inh (Ruconest) Icatibant (Firazyr) Ecallantide (Kalbitor) Craig et al. World Allergy Organ J. 2012; 5: 182-199
Recommendation 2 We recommend that all attacks are considered for on-demand treatment. We recommend that any attack affecting or potentially affecting the upper airway is treated. (20/20) WAO/EAACI guidelines for the management of hereditary angioedema: 2016 revision and update
Recommendation 3 We recommend that attacks are treated as early as possible. (20/20) WAO/EAACI guidelines for the management of hereditary angioedema: 2016 revision and update
Early treatment with 20IU/kg of C1-INH (Berinert) reduces the time to complete attack resolution <6 hours 6 hours 20 IU/kg C1-INH (n = 20) Placebo a (n = 24) 20 IU/kg C1-INH (n = 22) Placebo a (n = 17) Time to complete resolution, h 2.8 (0.8-52.0) 8.0 (0.3-77) 7.9 (0.5-81.5) 6.2 (0.9-104.9) Craig et al. Ann Allergy Asthma Immunol 2013; 111: 211-5. If onset of symptom relief did not occur within 4 hours, patients received additional treatment with 20 IU/kg of C1-INH.
Early treatment with 20IU/kg of C1-INH (Berinert) reduces the time to onset of relief Craig et al. Ann Allergy Asthma Immunol 2013; 111: 211-5. If onset of symptom relief did not occur within 4 hours, patients received additional treatment with 20 IU/kg of C1-INH.
Early treatment with Icatibant reduces the duration of HAE attacks Duration of attack (h) 30 p<0.001 p<0.001 p<0.001 25 20 20.2 23.5 15 16.8 10 5 6.1 7.2 8.0 0 <1 1 <2 2 <5 5 Treatment after onset (h) Maurer M, et al. PLoS One. 2013;8(2):e53773. 1
Recommendation 4 We recommend that HAE attacks are treated with either C1-INH, ecallantide, or icatibant. (18/20) WAO/EAACI guidelines for the management of hereditary angioedema: 2016 revision and update
Adjuvant therapy: Pain management, intravenous fluids, supportive care How should we treat? Icatibant, Ecallantide, C1-INH Solvent detergent treated plasma (SDP) Fresh frozen plasma (FFP If not available If not available In progressive upper airway edema: Consider early intubation, tracheotomy Craig et al., World Allergy Organ J. 2012; 5: 182-199
Recommendation 6 We recommend that all patients have sufficient medication for on-demand treatment of two attacks and carry on-demand medication at all times. (20/20) WAO/EAACI guidelines for the management of hereditary angioedema: 2016 revision and update
On demand treatment (ODT) of HAE Every patient should...be prescribed or provided with ODT be informed to carry ODT at all times...always have enough ODT to treat 2 attacks be offered self medication training...receive 24 h help line number...receive emergency pass
Concepts and products for the treatment of HAE Long term prophylaxis pdc1-inh (Cinryze) Attenuated androgens Tranexamic acid Craig et al. World Allergy Organ J. 2012; 5: 182-199
Recommendation 8 We suggest prophylaxis be considered for patients who face events in life that are associated with increased disease activity. (19/20) WAO/EAACI guidelines for the management of hereditary angioedema: 2016 revision and update
Recommendation 9 We recommend that patients are evaluated for long term prophylaxis at every visit. Disease burden and patient preference should be taken into consideration. (20/20) WAO/EAACI guidelines for the management of hereditary angioedema: 2016 revision and update
Recommendation 10 We recommend the use of C1-Inhibitor for first line long term prophylaxis. We suggest to use androgens as second-line long-term prophylaxis. (13/20) WAO/EAACI guidelines for the management of hereditary angioedema: 2016 revision and update
Recommendation 11 We suggest adaptation of long-term prophylaxis in terms of dosage and/or treatment interval as needed to minimize burden of disease. (20/20) WAO/EAACI guidelines for the management of hereditary angioedema: 2016 revision and update
The Angioedema Activity Score (AAS) Why? Who? How? How long? Assess disease activity in patients with recurrent angioedema Documentation by patient Evaluation by physician / aptient Prospective Usually 4 weeks (AAS28) Weller et al. Allergy 2013; 68: 1185-92
The Angioedema Activity Score (AAS) Weller et al. Allergy 2013; 68: 1185-92
The Angioedema Activity Score (AAS) Weller et al. Allergy 2013; 68: 1185-92
AAS7 score The Angioedema Activity Score (AAS) 60 50 n.s. 40 *** 30 *** 20 10 *** 0 None Mild Moderate Severe Very Severe Patients global self-rated disease activity Weller et al. Allergy 2013; 68: 1185-92
The Angioedema Activity Score (AAS) Disease activity Low < 25 Moderate 25-75 High > 75 Weller et al., Allergy 2013; 68: 1185-92
www.moxie-gmbh.de Weller et al., Allergy 2013; 68: 1185-92
www.moxie-gmbh.de 9/2016 The Angioedema Activity Score (AAS) UK Denmark Sweden Canada (English) Canada (French) Germany Poland Russia USA (English) The Netherlands Spain Portugal Hungary Romania Slovakia China Japan Mexico USA (Spanish) France Italy Macedonia Bulgaria Turkey Israel (Hebrew) India Taiwan Brazil Greece Australia translation completed translation in progress
Hereditary Angioedema Side Effects of Inefficient Treatment Stria distensae due to treatment with systemic glucocortiocoids
Common triggers of HAE attacks Trauma Menstruation Angioedema Angioedema attack Medications Infection Stress
Medications to avoid in HAE patients Estrogen birth control Estrogen hormone replacement ACE-inhibitors
The future of HAE treatment
Coagulation Kininogen Prekallikrein C1 XIIa Kallikrein Ecallantide XII C1 C4 Bradykinin Angioedema
Coagulation Kininogen Prekallikrein C1 XIIa Kallikrein Ecallantide DX-2930 Avoralstat BCX7353 XII C1 C4 Bradykinin Angioedema
Role of Plasma Kallikrein in HAE Stimulus Prekallikrein Factor XIIa Plasmin Kallikrein High-Molecular-Weight Kininogen Bradykinin BK receptor Vasodilatation, nonvascular smooth muscle contraction & edema
Avoralstat Small-molecule inhibitor of human plasma kallikrein Orally available OPUS1 trial: Attack rates lower than placebo (p<0.001) Quality of life improved (p=0.004) Aygören-Pürsün et al., J Allergy Clin Immunol. 2016; 138: 934-936
DX-2930 Fully human monoclonal antibody inhibitor of human plasma kallikrein Subcutaneous Phase1b trial: Attack rates lower than placebo
Coagulation Kininogen Prekallikrein C1 XIIa Kallikrein Ecallantide DX-2930 Avoralstat BCX7353 XII CSL312 C1 C4 Bradykinin Angioedema
CSL312 Fully human IgG4 antibody inhibitor of FXIIa Subcutaneous CSL312 potently inhibits Bradykinin generation
CSL312 inhibits FXIIa in normal and HAE human plasma
Coagulation Kininogen Prekallikrein C1 XIIa Kallikrein Ecallantide DX-2930 Avoralstat BCX7353 XII CSL312 C1 C4 Bradykinin Angioedema
HAE: What to remember Rare, dangerous and underdiagnosed Readily diagnosed (when you think of it ) Novel and improved treatment options ODT: The earlier, the better
HAE management and future perspectives Marcus Maurer Allergie-Centrum-Charité Department of Dermatology and Allergy Charité - Universitätsmedizin Berlin Germany
Division of of Dermatological Allergology www.allergie-centrum-charite.de www.allergie-centrum-charite.de Director of the Department of Dermatology and Allergy of Charité Universitätsmedizin Berlin: Professor. Dr. med. Dr. h.c. Torsten Zuberbier marcus.maurer@charite.de