1. C1 inhibitor Deficiency: Why does it happen and what does it look like?
Gina Lacuesta, MD FRCPC
Allergy and Clinical Immunology
Assistant Professor, Dalhousie University
Nov 29,2014

2. Disclosure and Thank You
CSL Behring -Berinert® Shire-Firazyr ® and Cinryze® -attended advisory boards, international meetings and worked with sales and medical representatives Board Member of CHAEN

3. objective
Review the definition and causes of angioedema – why are your doctors confused about this condition?
Review the pathophysiology of C1 inhibitor deficiency – today you are a medical student!
Review the clinical presentation of C1 inhibitor deficiency – does this sound like you?

4. Angioedema ANGIO – vessel EDEMA – swelling
Soft tissue swelling usually located around the eyes, lips, face, ears, tongue, hands, feet
Usually asymmetrical
In C1 inhibitor deficiency, intestinal angioedema is common with abdominal pain and urinary difficulties
Laryngeal edema can be life threatening

5. As opposed to….EDEMA
Swelling in dependant areas, ie feet, ankles, even sacral swelling, scrotal swelling, at end of day and around the eyes first thing in the morning
Related to fluid shifts/fluid retention/salt and water balance
Strongly associated with heart disease, liver disease, malnutrition, severe illness, ‘hormonal’ fluctuations

6. Picture of pitting edema

7. Non HAE Angioedema – causes
Allergy
Cause is easily identifiable
Food, drug, sting
Can be life threatening
Often associated with hives
Often easy to figure out the allergic culprit
With avoidance, most patients can live ‘normal’ lives
Responds to epinephrine, antihistamines and steroids

8. Non HAE Angioedema - causes
DRUGS
Aspirin/NSAIDs/anti-inflammatories
ACE- inhibitors
Well described phenomena; often forgotten about
Quinke’s edema
Uvula swelling only, repeatedly
Often as a rebound reaction to dryness in the throat
Occasionally, surgery used to correct

9. Non HAE Angioedema - causes
Infection
Mostly, viral related
Common, 1:10 will experience hives or angioedema, unexplained at least once in their lifetime
Usually short lived, ie lasting a few months maximum, most often benign

10. Non HAE Angioedema - causes
Chronic spontaneous/autoimmune
Often associated with hives
Can happen daily for months/years
Diagnosis of exclusion, ie. No other cause found
Benign, most easily managed with well tolerated medications, ie antihistamines
Newer treatments: Xolair ®, rarely immunosuppressants
Common condition

11. Angioedema- why are your doctors confused
Compared to the previous, C1 inhibitor deficiency is very rare, and rarely, if at all taught in medical school Doctors ARE aware of the other causes, and are AFRAID of the other causes EVERYONE wants the angioedema to be managed by steroids/antihistamines/epinephrine and AVOIDANCE of food!…but it doesn’t work that way

12. Why is diagnosing C1 inhibitor deficiency an issue?
Documented failure to recognize and diagnose HAE-22 year delay in survey by Frank et. al.
(Ann Int Med. 1976;84:580)
Delay still observed in recent survey
Age at diagnosis: 16.8 yrs (range 1-42 yrs)
Age when sx began: 7.8 yrs (range 1-18 yrs)
Delay in diagnosis: 9.1 yrs (range 0-32 yrs)
Failure to diagnose dramatically increases the risk
of significant M&M

13. HAE/C1 inhibitor deficiency

14. What is complement? Part of our INNATE immune system
Present in everyone as a PRIMITIVE defense mechanism against infection
As opposed to our ACQUIRED immune system which adapts based on our exposures, either via infection or vaccination
COMPLEMENT helps our ACQUIRED immune system do its job, therefore, the term COMPLEMENT

15. Picture of complement cascade

16. Importance of C1 inhibitor
Controls bradykinin formation
Bradykinin causes blood vessels to dilate and become permeable, ie leak fluid into the soft tissues, thus, swelling
If bradykinin is allowed to produce repeatedly, if it does not get broken down and destroyed, and if its receptor is not blocked….there will be increased chances of swelling, inflammation and pain

18. C1 inhibitor deficiency

20. Complement profiles

21. HAE nomenclature
HAE Type 1 – HAE due to C1 deficiency with low levels and functional assay
HAE Type 2 – HAE due to C1 dysfunction with normal levels and low functional assay
HAE Type 3 – HAE with normal C1 levels and functional assay

22. HAE type 1 and 2
1:50,000
Autosomal dominant; mutations of the SERPING1 gene
25% de novo mutation rate
Bradykinin is the main mediator of swelling
Bradykinin produced when kallikrein cleaves HMW kininogen.
Kallikrein activated by factor XII
Kallikrein and factor XII both normally inhibited by C1 inhibitor.

23. Features of HAE-Normal C1INH Compared to HAE-C1INH Deficiency – Bork 2007
Normal C1INH protein level and activity
Predominantly women clinically affected
Symptom onset in adulthood more common, rarely
affects children
Less frequent symptoms with longer symptom-free
Intervals
Facial and lip swelling more frequent
Recurrent tongue swelling a cardinal symptom
Many patients have only skin swelling
Abdominal attacks less frequent
Asphyxiation due to airway involvement occurs
No erythema marginatum; hemorrhages into skin
swelling has been observed

26. How patients present
Angioedema without urticaria, can have non-pruritic serpiginous rash
Angioedema mostly face, limbs, gut
Can have profound pain syndromes, vomiting, diarrhea, voiding difficulties
Attacks prolonged but do not occur daily; latency period
“Average” untreated patient will swell q10-14 days, lasting 48-72h
Enormous range of severity between patients
Substantial morbidity seen in patient surveys
Risk of death from laryngeal angioedema, mortality rate of 30% if left untreated

27. Most attacks affect the skin or abdomen
Angioedema most commonly involves the abdomen⁴, face, extremities, genitals, and larynx.¹
Skin attacks are the most common and usually manifest as disfiguring, nonpitting, and sometimes painful skin swelling affecting most commonly the extremities, face, and genitals.²
Abdominal attacks occur in 70%-80% of patients with recurrent abdominal pain caused by edema in the stomach or intestinal wall and free fluid in the peritoneal cavity.³
Laryngeal attacks occur at least once in a patient’s lifetime in 50% of the cases. These attacks are usually classified as severe—as airway obstruction could be fatal—with mortality rates as high as 30% if left untreated or undiagnosed.2, 4
The probability that a given attack will involve the skin or abdomen is nearly 50% each. All other attack locations, including genitourinary and laryngeal attacks, account for only 3.6% of attacks.⁴
1. Khan D A, Allergy Asthma Proc 2011; 32:1-10; 2. Banerji A,Allergy Asthma Proc 2011; 32: ; 3. Caballero T, J Investig Allergol Clin Immunol 2011;21(5): 333 ; 4. Bork K. et al. Am J Med 2006; 119:267-74

28. Frequency of HAE Attacks
Attack frequency, severity, and course vary among patients, and even for a single patient depending on stage of life1,2,3
Less than one attack per year to more than 26 attacks per year
Mean of 27 attacks /year
Median 12 attacks/ year per patient
In some rare cases, patients can experience more than 100 attacks per year
No evident correlation between:
Attack frequency and plasma levels of C1-INH
Number of attacks from one year and the next
Frequency of attacks in family members
Although precipitated by known factors, attacks may occur without obvious trigger1,3
The frequency at which HAE attacks occur spans a broad range among patients and may also vary in the same patient during different stages of life. Reported rates range from <1 attack per year to >26 attacks per year. A recent study in 457 patients with HAE in the United States found that patients experienced an average of 27 attacks per year.
In some cases, patients can experience >100 attacks per year. A survey of untreated patients with HAE in Italy found that nearly one-third had >1 attack per month, 40% had 6 to 11 attacks per year, and the remaining 30% had either no or infrequent attacks.
[Agostoni 2004, p S57b; Levy 2006, p 6a]
1 Gompels MM, et al. Clin Exper Immunol ;139(3): Kaplan AP. J Allergy Clin Immunol. 2010;126(5): Frank MM Ann Intern Med. 1976;84:580ñ593

29. C1 inhibitor deficiency- acquired form AAE-symptoms the same
no family history
later onset, usually after age 60
often associated with hematological malignancies, ie lymphoma, monoclonal gammopathy, or autoimmune diseases
Often with low C1q levels
Mechanism felt to be autoimmune, increased metabolism of C1 inhibitor, unknown
Mainstay is to treat the underlying condition, but also to be aware of usual C1 inhibitor treatment, can become resistant to treatment, requiring increasing doses of C1 inh replacement
Rarer than HAE

30. Health-Related QOL Decreases in Patients With HAE
Normative Population
P<.0001
P<.0001
Patients With HAE
49.6
± 9.9
49.4
± 9.8 60
43.7
± 10.2
42.6
± 10.1 50 40
Mean SF-12 Score 30 20 10
Physical Component Summary
Mental Component Summary
In a survey of 457 patients with HAE, patients reported significant reduction in health-related quality of life.
One component of the survey, the 12-Item Short Form (SF-12) Health Survey, consisted of 12 questions about health-related functioning over the prior 4 weeks.
Survey outcomes included two summary scores: a Mental Component Summary (MCS-12) and a Physical Component Summary (PCS-12). For each, a higher score represents higher functioning.
Compared with population norms, patients with HAE had lower mean scores across all components of the SF-12 Health Survey.
Patients with HAE had a mean overall PCS-12 score of 43.7 (SD ± 10.2, P<.0001) vs 49.6 (SD ± 9.9, P<.0001) for population norms.
Up to 70% of patients with HAE reported that the disease had affected their educational and career goals, possibly due to elevated levels of anxiety and depression.
Patients with HAE suffer activity impairment comparable with impairments suffered by patients with severe asthma and Crohn’s disease.
Reference
Lumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT. The humanistic burden of hereditary angioedema: impact of health-related quality of life, productivity, and depression. Allergy Asthma Proc.2010;31(5):
Patients with HAE are also significantly more likely to experience symptoms of depression compared with population norms (P<.0001)
Up to 70% of patients report that HAE has affected their educational and career goals and that they may be unable to realize their potential due to high levels of anxiety and depression
Patients with HAE experience a decline in productivity comparable with patients with severe asthma or Crohn’s disease
QOL=quality of life; SF-12=Short Form Health Survey.
Adapted from Lumry WR, et al. Allergy Asthma Proc. 2010;31(5):
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31. Days Missed During Most Recent HAE Attackb
HAE Attacks Adversely Impact Work, School, and Leisure Activities
Patients Affecteda
Days Missed During Most Recent HAE Attackb
Work Days (n=156)
School Days (n=12)
Leisure Days (n=271)
Work Days (n=308)
School Days (n=27)
Leisure Days (n=457)
3.3
±14.4
1.9
±0.8
2.7
±3.0 51 44 59 10 20 30 40 50 60 70
Patients Missing Days (%) 2 4 6
Mean Number of Days Missed
In a survey of 457 patients with HAE, patients reported that HAE significantly impacted their ability to work and gain an education.
51% of employed patients missed at least 1 day of work due to their most recent HAE attack.
44% of student patients missed at least 1 day of school due to their most recent HAE attack.
59% of patient respondents reported that they missed at least 1 day of leisure activities due to their most recent HAE attack.
Across all patients, the most recent HAE attack caused a mean number of 3.3 (SD ± 14.4) days of missed work, 1.9 (SD ± 0.8) days of missed school, and 2.7 (SD ± 3.0) missed leisure days.
Reference
Lumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT. The humanistic burden of hereditary angioedema: impact of health-related quality of life, productivity, and depression. Allergy Asthma Proc. 2010;31(5):
aNumber of patients affected during most recent attack of HAE. bMean number of days missed during most recent attack of HAE.
Lumry WR, et al. Allergy Asthma Proc. 2010;31(5):
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33. Management of C1 inhibitor deficiency
Gina Lacuesta, MD FRCPC
Allergy and Clinical Immunology
Assistant Professor, Faculty of Medicine
Dalhousie University
Nov 29, 2014

34. Objectives What are the goals of care?
What did treatment look like BEFORE and what was the problem?
What does treatment look like now?
What can we do better?

35. Previous goals of care Make the right diagnosis!
Recognize that the condition is hereditary and screen the family
Keep the patients ALIVE
Keep the patients out of the ER

36. New goals of care Improving quality of life
Treatment should aim to maximize patient health by
Aborting acute attacks to prevent morbidity and mortality
Minimize significant side effects
Avoid disruption of normal life, ie school, work, family life

37. PAST treatment

38. Past treatment: side effects

39. In with the NEW….US data

40. In Canada: June 2010 : Berinert® fully approved for use in HAE
2012: Cinryze® approved in Canada, still waiting for its full release
2014: Firazry® approved in Canada

41. In Maritimes: 2011
First patient on prophylactic Berinert, early Spring 2011
4 patients being arranged
In Hospital treatment only…thus far

42. In Maritimes: 2013
NS: 5 patients on prophylaxis( 4 self infusion/1 in hospital )
NB: 1 patient on prophylaxis( line in place, home)
PEI: 1 patient on prophylaxis (line in place, in hosp)
NS: 1 patient on demand(self), 1 due to be taught
NB: 1 patient on demand (self)

43. In Maritimes: 2013
Still some patients on oral medications for on demand and prophylaxis and this works well for them
5 acquired C1 inhibitor deficiency patients, 1 of which is on prophylaxis.

44. In Maritimes: 2014 NS: 8 patients on Prophylaxis with Berinert
NB: 1 patient on Prophylaxis with Berinert
PEI: 1 patient on prophylaxis with Berinert
10 others On Demand Berinert treatment, or prophylaxis with medications
6 with Firazyr On Demand, a few others in the works for approval

46. C 1 inhibitor

47. C1 inhibitor –eliminates the underlying cause by replacing the deficient protein
Berinert®-CSL Behring
Cinryze®- Shire
20U/kg, slow IV push
<50kg 1000U, >50kg 1500U
Indicated for acute attacks
Half life 32-47h
Well tolerated
Off label use with high doses in neonates resulted in thrombotic events
1000U, slow IV push, not based on weight
Indicated for long term, routine prevention
Half life 48+/- 10h
Well tolerated

48. IMPACT2- International Multicenter Prospective Angioedema C1 inhib Craig, T. et al, Allergy, 2011
57 patients, 975 HAE attacks
Open label extension of placebo controlled IMPACT1 trial
Median time to onset of symptom relief of 15min for laryngeal attacks, 20 min for abdominal attacks, 28 min for facial attacks and 31 minutes for peripheral attacks

49. Nanofiltered C1 inhibitor in HAE- Zuraw, et al, Am J Med, 2012
Open label multi center extension study, 146 patients with HAE treated for 2.6y with prophylaxis Cinryze® 1000U every 3-7 days
93.7% reduction in attacks compared with historical rate of attacks
87.7% had 1 attack or less per month
34.9% had no attacks
Twice weekly seemed to have the best control, though sub group responded to once a week, no predictors found

50. C1 inhibitor self infusion-Maritimes
Currently, all teaching has been done by hemophilia nursing, with follow up and support as needed
Berinert® does come with option to be taught by private nursing
??Cinryze® to have a comprehensive training program established, based on education and training practices already used in the US, My PathTM, with ongoing support

51. Icatibant

52. Characteristics of Icatibant
Synthetic decapeptide with structure similar to bradykinin
Indicated for the treatment of acute attacks of HAE in adults with C1-esterase inhibitor deficiency
Delivered by subcutaneous (SC) injection in the abdomen
Provided in a single-use, pre-filled syringe containing 30 mg (10 mg/mL) that can be stored at room temperature H 2 N O S C 3 n
Shire Human Genetic Therapies (Canada) Inc. Firazyr Product Monograph. June 4, 2014.
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53. Endpoints Measure Onset and Resolution of Symptoms
Symptom severity of a treated attack
Time
t=0
Time course of a treated attack
Beginning of attack
Almost complete symptom relief
(All VAS < 10mm)
Treatment administration
Initial symptom improvement
earliest of 3 consecutive measures
Onset of symptom relief
(VAS )
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54. FAST 2: Time to Onset of Primary Symptom Relief Primary endpoint
100%
Median
95% CI
p-value
Icatibant
2.0
<0.001
Tranexamic Acid
12.0
90%
80%
70%
60%
Tranexamic Acid
% of Patients
Not Achieving Symptom Relief
50%
40%
30%
20%
In FAST-2, Icatibant was effective in the treatment of acute HAE with primary endpoint showing consistent onset of primary symptom relief in 2 hours compared to median time to onset of 10.1 hours with tranexamic acid, which was statistically significant.
To show you consistency of response, let‘s look as some other measures...
10%
Icatibant 0% 12 24 36 48
Hours After Treatment
Primary symptom relief is defined as a reduction of at least 30% from pre-treatment in the score for primary VAS; has to sustain for 3 consecutive non-missing measurements
Cicardi M, et al. N Engl J Med. 2010;363: Erratum in: N Engl J Med. 2010;363:1468.
ITT non-laryngeal population
VAS
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55. FAST-3: Study Design and Patient Disposition
First eligible attack
(n=98)
Laryngeal attack
(n=10)
Abdominal and/or cutaneous attack
(n=88)
Moderate to severe attack
Mild to moderate attack
Severe attack
Double-blind treatment:
Icatibant vs placebo
(n=43) (n=45)
Double-blind treatment:
Icatibant vs placebo
(n=3) (n=2)
Open-label treatment:
icatibant
(n=5)
Treatment of subsequent attacks (cutaneous, abdominal, or laryngeal)
Open-label extension phase Icatibant 30 mg SC up to 3 x per attack; no more than 8 injections per month
(n=82 pts)
Lumry W et al. Ann Allergy Asthma Immunol. 2011; 107:
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56. FAST-3: Time to Onset of Symptom Relief Primary endpoint
100%
Median
95% CI
p-value
Icatibant
2.0
1.5, 3.0
<0.001
Placebo
19.8
6.1, 26.3
90%
80%
70%
60%
Placebo (n=45)
% of Patients
Not Achieving Symptom Relief
50%
40%
30%
20%
Icatibant (n=43)
We have used Kaplan Meier Curves to show the progress of patients as they respond to treatment over time.
This also allows you to see the response of every patient in the trial.
The y- axis shows the percentage of patients who have not yet met the target endpoint.
So as we move from the left to right, we are showing you each patient as they respond to therapy and hit the target endpoint.
This Kaplan- Meier curve from the FAST 3 trial shows the primary endpoint of time to onset of symptom relief based on the composite VAS score, the VAS-3,
It shows the rapid drop in the graph for the icatibant treated patients as each patient reaches the endpoint.
Icatibant was significantly better than placebo in treatment of HAE attacks.
In the analyses of these cutaneous and abdominal attacks, Icatibant patients had onset of symptom relief based on the composite VAS-3 in median 2 hrs
compared to placebo patients where relief was not seen for median of 19.8 hr.
Next, if you look at the Kaplan Meier curve for time to onset of symptom relief based on the primary single VAS……
10% 0% 12 24 36 48
Hours After Treatment
ITT population
VAS 3
(abdominal pain, skin pain, and skin swelling)
Onset of symptom relief is defined as a 50% reduction from pre-treatment in VAS 3 score; has to sustain for 3 consecutive non-missing measures
Lumry W et al. Ann Allergy Asthma Immunol. 2011; 107:
Shire Human Genetic Therapies (Canada) Inc. Firazyr Product Monograph. June 4, 2014.
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57. FAST-3: Time to Almost Complete Symptom Relief Secondary endpoint
100%
Median
95% CI
p-value
Icatibant
8.0
5.0, 42.5
0.012
Placebo
36.0
29.0, 50.9
90%
80%
Placebo
70%
60%
% of Patients
Not Achieving Symptom Relief
50%
40%
Icatibant
30%
20%
Icatibant accelerated resolution of attacks as measured by almost complete symptom relief at a median of 8 hr compared to placebo (median 36.0 h) as shown on this Kaplan-Meier that has now been extended to 120 hours on the x-axis.
This faster time to near resolution of attacks reduced the amount of time that patients experienced the debilitating symptoms of HAE.
Now that we have looked at the most recently completed and definitive trial,
10% 0% 10 20 30 40 50 60 70 80 90
100
110
120
Hours After Treatment
ITT population
VAS 3
(abdominal pain, skin pain, and skin swelling)
Almost complete symptom relief is defined as all VAS scores ≤ 10 mm; has to sustain for 3 consecutive non-missing measurements
Lumry W et al. Ann Allergy Asthma Immunol. 2011; 107:
Shire Human Genetic Therapies (Canada) Inc. Firazyr Product Monograph. June 4, 2014.
Shire Proprietary & Confidential Information

58. Events including open label extension trial
FAST-3: Icatibant Laryngeal Attack Efficacy Comparable to Abdominal or Cutaneous
Laryngeal Treated
Events including open label extension trial
Icatibant
(N=27attacks)
Median time to onset of symptom relief as measured by VAS-5; hours (95% CI)
2.2
(1.5, 3.5)
Median time to onset of primary symptom relief; hours (95% CI)
Median time to almost complete symptom relief; hours (95% CI)
6.2
(3.0, 24.3)
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59. Laryngeal Attacks: Time to Initial Symptom Improvement
% of Patients
Not Achieving Symptom Relief
First laryngeal attack
ISE Table 11.5
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60. FAST OLE: Analysis of HAE Attacks Requiring Reinjection of Icatibant
More than 90% of HAE attacks were treated with a single icatibant injection regardless of location.
Icatibant reinjection was infrequent and appeared to be independent of patient age, patient sex, HAE type, and initial attack severity.
0.5%
0.9%
90.4% 8%
91.8%
7.3%
1.1%
All attacks
Laryngeal Attacks
Analysis of pooled data from all FAST OLE studies.
Total # pts in FAST OLE: 225. Total # of attacks treated: 1149
Total # pts with laryngeal attacks in FAST OLE: 52. Total # of attacks treated: 110
1 injection
2 injections
3 injections injection + other acute HAE treatment
Bernstein JA, et al. Poster presented at: American College of Allergy, Asthma and Immunology (ACAAI) 2013 Annual Scientific Meeting; November 7-11, 2013; Baltimore, MD. Poster P90. Berstein et al. Poster presented at AAAAI 2014

61. Safety Profile
Shire Human Genetic Therapies (Canada) Inc. Firazyr (icatibant) Product Monograph. June 4, 2014.

62. Safety Profile
The overall incidence of serious adverse events (SAEs) was low in the clinical development program
In the Phase I and II studies, only 2 SAEs were reported within 14 days of FIRAZYR treatment (manic episode, HAE); these were judged as not related/probably not related to treatment.
In the controlled part of the three Phase III studies, only one SAE (cystitis) was reported within 14 days of dosing with FIRAZYR. This event was judged as not related to treatment.
In the repeated treatment part of the Phase III studies, safety was evaluated for up to 15 FIRAZYR-treated attacks for patients. Sixteen patients experienced a total of 22 SAEs that occurred within 14 days of FIRAZYR administration. The only SAE that occurred in more than one patient was worsening or recurrence of HAE. Two SAEs were considered by the investigator as related to FIRAZYR treatment (events of arrhythmia and noncardiac chest pain).
Shire Human Genetic Therapies (Canada) Inc. Firazyr (icatibant) Product Monograph. June 4, 2014.

63. Injection Site Reactions are Common but Transient and Self-resolving
Photos courtesy of Dr M Bas, Klinikum Rechts der Isar der TechnischenUniversität München, Munich, Germany
Represents moderate severity reaction 63
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64. Icatibant Safety Profile in Open-Label Use
AEs in open-label extension of phase III controlled trials (N=225) were similar in frequency and nature to those observed in the controlled / blinded phase of the trials
Rash, nausea, headache, worsening or recurrence of HAE
Self-administered icatibant (N=98) displayed a safety profile similar to that of HCP-administered icatibant
No hypersensitivity or anaphylactic reactions were reported in clinical trials
No association between anti-icatibant antibodies and efficacy was observed
Shire Human Genetic Therapies (Canada) Inc. Firazyr Product Monograph. June 4, 2014. 64
CONFIDENTIAL 64

65. Ecallantide-Kalbitor® not available in Canada

66. Kallikrein inhibitor
Inhibits cleavage of HMW kininogen to bradykinin and therefore prevents progression of angioedema attack
Ecallantide- Kalbitor®- Dyax.
30mg sc injection, half life 1-2hours
Has had reported anaphylaxis

67. Attenuated Androgens Danazol, stanazolol, oxandrolone
Contraindicated in pregnancy, lactation, cancer, hepatitis, childhood
Significant side effects of virilization, weight gain, acne, hair growth, altered libido, voice deepening, decreased breast size, menstrual irregularities, HTN, atherosclerosis, increased liver enzymes, cholestasis, HCC
Dose varies from 100mg EOD, to 200mg TID, adjusting to clinical response
More effective than antifibrinolytic agents

68. Antifibrinolytic agents
Used in more in pediatric population, as a safer alternative to androgens, but evidence of efficacy lacking
Side effects mostly GI, theoretical risk of increased thrombosis
Dosing 30-50mg/kg in divided doses 2-3 times /day to max of 6g

71. WAO Guideline Consensus meeting in Turkey 2011
Published in WAO Journal DEC 2012

75. Short term/preprocedural prophylaxis
Evidence is lacking, but generally considered to be a strong recommendation
Dental/intraoral surgery, any procedure requiring intubation, with upper airway or pharynx manipulation, bronchoscopy or endoscopy
History of frequent swellings, swelling after a similar procedure in the past
Stressful periods, concurrent infections
C1 inhibitor U/kg 1-6 hours before procedure, with on demand treatment available also
Other options: Androgens or tranexamic acid

77. Long term prophylaxis
Use of regular medication to prevent episodes of angioedema
Takes into consideration severity of disease, frequency of attacks, patients' quality of life, availability of resources, failure to achieve adequate control with on demand therapy
If more than 1 severe attack occurs per month, or treatment for severe attack is not sufficiently effective
Choice between C1 inhibitor replacement, androgens, antifibrinolytic agents

83. Management Counseling about their disease, genetics
Refer to patient support HAE groups
Carry letters identifying them as a C1 inhibitor deficiency patient, urgency and how to treat
Baseline viral studies and liver function studies; Hepatitis A and B vaccine, influenza vaccine

86. Management
Depending on long term drug treatment- labs and radiology to monitor side effects
Education regarding MEDS to avoid ( ACE inhibitors for blood pressure, estrogen supplements/birth control), potentially exacerbating situations(fatigue, stress, dental work, surgery, infection, etoh, menses etc)

87. Management C1 inhibitor to be stocked at home hospital
Patients educated to be vigilant about keeping relations with blood bank, especially in remote areas

88. Long term care for HAE patients
procedures
timing
Develop action plan
Provide with HAE emergency card
Provide with 2 doses of on demand therapy
Screen family
Hep B, C HIV screening
Assessment by HAE specialist
Influenza vaccine
If androgens used:
LFT,CBC,Lipids, UA
Cardiac RF
U/S liver
At diagnosis and annually
At diagnosis
At diagnosis, annually if using blood product
Annually
Start and q 6 months
Start and q6 months
Start and q 12 months
Craig, et al, WAO Journal, Dec 2012

91. Pediatric population
Attacks usually occur during school age years, in 50% of cases between age 5-11
Upper airway is rarely the initial presentation
Erythema marginatum is more frequent and often mistaken for urticaria
Pre-natal testing is not recommended
Testing at birth is not recommended, due to false negative testing

92. Pediatric population
If symptomatic, still need a treatment plan and on demand therapy
Ecallantide and icatibant are not licensed for use in children
C1 inhibitor best choice for on demand therapy
Antifibrinolytics(20-40mg/kg) chosen over androgens because of side effect profile.
Common triggers include infection and mechanical trauma
Vaccination recommended to reduce infection
Avoid use of oral estrogen contraception
Educate all caregivers

93. Pregnancy
Can either mitigate, worsen or not change the frequency of attacks at all
C1 inhibitor replacement is the recommended first line therapy.
Short term prophylaxis is recommended during any procedures including amniocentesis, chorionic villus sampling, surgical abortion.
Not necessary with uncomplicated natural delivery, but should be available for 72hours port partum

94. Pregnancy C1 inhib should be given prophylactically if:
HAE is known to be severe
Frequent swellings in 3rd trimester
History of vaginal edema with mechanical trauma
If intubation necessary
With forceps or vacuum extraction needed
C- section
Androgens not recommended in pregnancy due to effects on the fetus, also not recommended during breastfeeding
Tranexamic acid can be used if C1 inhibitor not available

95. AAE management
Essentially the same principles, except treatment for underlying condition plays an important role
May have some benefit from antihistamines, steroids as can also have an autoimmune histamine mediated angioedema along with AAE
Can use either Icatibant or C1 inhibitor -On Demand, though not formally studied
If prophylaxis required, can become “resistant” to C1 inhibitor replacement of may need higher than usual dosing

96. After these presentations, you should be able to:
Define and classify HAE
Know what tests are ordered to diagnose HAE/AAE. Know what other conditions your drs are thinking about and how to differentiate from them
Discuss management strategies, ie on-demand, short term and long term prophylaxis
How the appropriate medications and replacement are prescribed
What information is important to patients and primary physicians about follow up, meds to avoid, when to be vigilant
Discuss special circumstances, ie pediatric population, pregnancy
Acquired angioedema
Recognize and refer to international and national guidelines
Be an EXPERT in HAE

97. What else can we do? 2011: Train and recruit more immunologists
Educate local physicians/ER/nurses
Maintain good working relationships with blood banks
Set up self treatment program
If not a candidate for self treatment program, have a plan for treatment of acute swelling attacks….stay on top of C1 stock in local hospitals
2013:
Consider participating in upcoming trials
Now there is CHOICE in effective, safe treatments…how do we make those choices?
Be responsible with the products that we use

98. What else can we do? EDUCATE, EDUCATE, EDUCATE
Lobby for coverage and access for all patients
Comprehensive care clinics
Look forward to more sc products, ? Oral products

99. questions
How soon into an HAE attack do I take the first Firazyr injection?
If I take the first injection early enough, should it stop the attack from worsening?
In order to judge if Firazyr is going to be an effective treatment in decreasing an attack, would I have to use it during a couple of HAE attacks to assess the results? I used it once and I was still not well for 2-3 days afterwards.

100. questions
If the Firazyr did not decrease my swelling after the first dose, how long should I wait before I go to the hospital?
Can I take Berinert between the first dose of Firazry and the second dose of Firazyr when the first dose did not stop or decrease my swelling?
If I have to try the second dose of Firazyr before taking berinert, how long do I have to wait after I take the second Firazyr to take Berinert?

101. questions
Does Firazyr have the same drug components/ingredients in it as Berinert?
I keep Firazyr in the fridge at a temperature above 2 degrees. What temperature should it be at when I administer it? For example, should I let it sit out of the fridge for a little while before I use it?

102. questions
What is the experience of patients who have taken Firazyr ? for example how long did it for them to feel the swelling decreasing? How long did it take for the swelling to be gone completely? Have they had any side effects from it? If so what were they?
For patients who took long term Danazol and is now off it, are there any tests as follow up that they should have done ?

103. Canadian websites HAE Canada's Physician Website: www.chaen-rcah.ca