Current issues in Hereditary Angioedema (HAE) - Ipopi

Current issues in Hereditary
Angioedema (HAE)
Dr Hilary Longhurst
Barts and The London Hospital
London
UK

Current issues in HAE
• Overview of HAE
• New/ newly licensed drugs
– C1 inhibitor (Berinert, Cetor, Cinryze)
– Recombinant C1 inhibitor (Rhucin)
– Icatibant (Firazyr)
– Ecallantide (DX88; Kalbitor)
• Rational use of preventatıve medıcatıon
– Danazol/ stanozolol/ oxandrolone
• General issues

What is HAE (Hereditary
• HAE 1 or 2
.. Lack of C1 inhibitor
protein
angioedema)
• HAE 3
..similar symptoms but
not C1 inhibitor deficiency
• AAE (acquired
angioedema)
– Lack of C1 inhibitor
developing in later life

HAE- C1 ınhıbıtor defıcıency
• Swellıngs of
hands/ feet /
face/other areas
• Swellıngs of
ıntestıne
‘abdomınal
attacks’
• Swellıngs of
larynx/throat

C1 inhibitor controls inflammation
• Complement
• Bradykinin
• Clotting/ anticlotting

Prevention vs treatment
Prevention (prophylaxis)
Treatment
•C1 inhibitor (‘Berinert’,
‘Cetor/Cinryze’)
•Icatibant (‘Firazyr’)
•(Ecallantide/ ‘Kalbitor’)
•(Recombinant C1
inhibitor ‘Ruconest’)
– Danazol/stanozolol/
oxandrolone “attenuated
androgens”
– Tranexamic acid
Tablets
Injections

What have we learnt about the new
• C1 inhibitor (Berinert)
treatments
We need to use a higher dose- 3 vials for an
average sized person
25 kg 4 st 1 vial (500 units)
50kg 8 st 2 vials (1000 units)
75 Kg 12 st 3 vials (1500 units)
100 kg 16 stone 4 vials (2000 units)

C1 inhibitor- dosage issues
Mrs A 33 yrs
• 8 years – hand/ feet swellings
• 3 facial swellings
– 2003- 7 days in hospital
– 2009- 4 days in hospital, laryngeal obstruction
– 2010- associated with abdominal pain,
vomiting
• Treated on day 3 with 500 units C1 inhibitor
• Resolution after 4 further days

• Berinert (C1 inhibitor)
trials
– 20 U/kg (ie at least 3 vials)
– Much quicker response
and recovery at this dose
– Recommend this dose for
most people
– esp. extensive, established
or laryngeal attacks
– [May be able to use lower
doses for self
administration, or v
tiny/early swellings]

• Cinryze (C1 ınhıbıtor) acute trials
– 1000 units with second 1000 U dose after 1
hour
– Not equivalent to 2000 units up front
– Recommended dose 2000 units

Treatment of C1 inhibitor deficiency
-Rhucin/Ruconest
• Recombinant C1 inhibitor
– Not blood product
• Higher dose possible
– 50U/ kg c.f. 20U/kg with Berinert
• Purified from rabbit milk
– Anaphylaxis in one severely rabbit allergic ‘normal’ volunteer
– Otherwise v well tolerated
– No significant antibody production
• Short half life

Icatibant (Firazyr)
• Subcutaneous bradykinin inhibitor
– Local pain & swelling ‘giant bee-sting’
– Almost anyone can learn
– Risks: large swelling, patient with frequent attacks
• Ideal for self administration
• Speed of onset of relief and resolution broadly equivalent
to C1 inhibitor
t=0 min t=30 min

Icatibant (Firazyr)
• Recurrent attacks
– Usually slow onset
– May occasionally be fast
– 10% need retreatment
• Risk of recurrence increased if:
– Large swelling/severe attack
– Late in course of attack
– Very frequent attacks (>1/week)
Always have second syringe available- will be effective

Living with hereditary angioedema:
L’s story
• 2002 17 years
– Weekly swellings- mainly peripheral
– Tranexamic acid 2g od- bd some help
– Starting first job
• 2003
– Reduced hours at work because of frequent HAE-related symptoms: low mood
– Treatment of severe abdominal attacks in hospital
– Unwilling to take attenuated androgens because of fear of virilisation
– Difficulties with employer- asking about sickness benefits
• 2004
– New job at Marks & Spencer’s (M&S ‘Britain’s favourite department store’)
– Less stressful: no attacks in 3 months after starting work
– 1 st attack for 3 months- swelling of hands, feet and abdomen- didn’t seek hospital care
– 1 day off work
– M&S policy: After 3 days off work, employee receives verbal warning. Dismissal possible for
repeated time off.

Living with hereditary angioedema:
L’s story
• 2005
– Severe abdominal attack – treated in hospital. Delay in receiving
treatment, poor response, patient admitted overnight.
– ‘Mild angioedema’ affecting arms, legs, abdomen or neckuntreated
– PCT considering funding C1 inhibitor for L to hold at home.
• 2006
– Facial angioedema, New Year’s Eve. Treated in hospital with C1
inhibitor
– No other attacks
– Working in car showroom

Living with hereditary angioedema:
L’s story
• 2008
– Severe abdominal attacks 4 times per year. Treated in A&E- but
delays are common. Peripheral attacks monthly.
– Home C1 inhibitor training recommended.
– Working part time
• 2008
– Pregnant, stopped tranexamic acid. 3 attacks requiring hospital
treatment in 9 weeks.
– C1 inhibitor prophylaxis discussed but not implemented. Early
maternity leave.
• 2009
– 6 days off work in 6 months- lost job, looking for work

L’s story: 25 year old with HAE
• 2010
– Mainly abdominal attacks, every 2-3 weeks
– Last 3-4 days
– Severe abdominal pain, distension, vomiting,
faintness and sometimes loss of consciousness.
– Followed by severe fatigue
– Unable to do household duties for 3-4 days
– Husband, mother or father need to take a day off
work to care for L and her baby on day when
symptoms are worst.
• 3-4 hospital attendances only
• Looking for work

L’s story
•2 nd March 2010
– Severe abdominal pain & vomiting
– Symptoms had started 2 days previously, not
improving
– Given icatibant 30mg sc
– Symptoms started to improve within 30 mins
– Discharged after 2 hours
– Fully recovered by the next day

L’s story
•15 th March 2010- 2 weeks later….
– Awoke with severe abdominal pain.
– Self administered backup icatibant
– Similarly good response- but at onset of
attack
– Able to get up and resume normal duties
– Husband amazed
– ‘Like magic’ ‘life changing’

Treatment of C1 inhibitor deficiency
-icatibant (Firazyr)
Mean VAS scores vs. time for the primary symptom
Mean VAS [mm]
100
90
80
70
60
50
40
30
20
10
0
Icatibant (JE049 #2102)
Tranexamic acid
Icatibant (JE049 #2103)
Placebo
0 1 2 3 4 5 6 7 8 9 10 11 12
Time point [h]

Treatment of C1 inhibitor deficiency
-ecallantide (DX88; Kalbitor)
• Effectıve
• Subcutaneous
– Kallikrein inhibitor
– Produced in pichia pastoris (recombinant
protein)
• Short half life
– 2 hours
Avaılable ın USA

‘Acute dosing reactions’-ecallantide
(DX88; Kalbitor)
• 8 reports of anaphylactoid reactions (~514 treatments)
– May occur during first treatment
– Rhinitis, sneezing, itchy throat, laryngeal oedema, hypotension
– Some treated with adrenaline etc.
• Cause uncertain
– No relation of antibodies to risk of reactions
• 3 antiecallantide/7 anti-pichia (1 IgE)/1 antiecallantide & -pichia antibodies (8% of
180 patients tested)
– ‘Desensitisation’ in 6 of 8 patients-successful in 5
FDA recommends not to be used for self administration
Schneider JACI 2007; Zuraw Expert opinion invest
drugs 2008; Caballero, personal communication
2005

Self administration
C1 ınhıbıtor or ıcatıbant
• Access to acute treatment (via
self admin)
– estimate ~95% attacks treated
– Freedom from symptoms
achievable
– ‘political’ difficulties
• No rapid access to acute
treatment
– Estimate ~ 5-25% attacks
treated
– Acceptance
– unpredictable reversible
disability
– Loss of opportunity
– ‘Blight’ on life

Prophylaxis: C1 inhibitor

C1 inhibitor controls local
Healthy HAE
Inflammatory HAE
inflammation
‘Inflammatory’
non HAE
Healthy non-HAE
Control of local oedema
Local C1 inhibitor function

Steroids
• Naturally occurrıng steroıds:
–Cortısol
– Oestrogen/Progesterone/Testosterone
•Steroıd medıcatıons
– Attenuated androgens/Anabolic steroids
• E.g. Danazol, stanozolol, oxandrolone
– Prednisolone (taken for asthma, some forms
of arthritis etc)

Rational use of steroids….

Mr B 15 yrs
• Swellings once/ month- usually abdominal
– 1 day off school
– 2-3 days ‘under the weather’
– FFP at local hospital once/ month
• Tranexamic acid 500mg twice daily
– Slight reduction in severity & frequency of attacks
• GCSEs coming up
Grandfather and great-grandfather died of HAE

Mr B 15 years
• Unwilling to train for C1 inh self-admin
• Danazol 200mg daily on temporary basis
over exams

Mrs B 45 years
• Swellings once/ month- usually abdominal
• Some facial swellings
• 2 days off school
• 2-3 days ‘under the weather’
• FFP at local hospital once/ month
– Prodromal rash/ fatigue
• Tranexamic acid 500mg twice daily
– Slight reduction in severity & frequency of
attacks

Mrs B 42 years
• Danazol 100 mg at prodromal symptoms
– One or two doses prevent attack
– Initially danazol needed every month- now
virtually never
• C1 inhibitor for acute attacks in hospital:
– 1 /year

Rational use of androgens
• Better guidelines*
• Low dose
– Max. 200mg danazol daily, 4 mg stanozolol
• Alternatives to danazol
– Stanozolol, oxandrolone, (tibolone)
• Intermittent usage/ self management
Life transforming
(Still need acute treatment)
*2010 International consensus algorithm for the
diagnosis, therapy and management of hereditary
angioedema http://www.aacijournal.com/content/6/1/24

Need to control acute attacks

Poorer nations/ patients without
insurance
• Access to (diagnosis &) treatment
– Oral prophylaxis
–Acute
• ‘recycling’ of expired treatments
• Companies –access programmes
• Post trial participants
–Patıent representation for emerging nations

What does everyone want
• Patients
– Freedom from symptoms
– Ability to prevent & treat
attacks
– Avoid side effects
• Companies
– Profit
• Effective drugs
• Minimal side effects
• Drug better than
competitors
– Welfare of patients
• Doctors
– Healthcare/welfare of patients
(and society)
– Good income
– Status
– Time with family
– Freedom from administrative
hassle
– Paternalistic/partnership
• Funding authorities
– Remain within budget
– Make a ‘surplus’/ ‘profit’
– Welfare of patients

Working with…
•Doctors
– Attitudes
– Consensus documents
• Pharmaceutical companies
–Trıals
– Access programmes
• Publicity
– HAE- personal stories- lay press
– Medical publications/ conferences

Recent initiatives
• World consensus document published July 2010
– Earlier treatment of acute attacks
– New treatments
• C1 inhibitor, icatibant, ecallantide
– FFP (plasma) obsolete
– Lower doses of danazol/stanozolol
– Self administration available for everyone who wants it
– http://www.aacijournal.com/content/6/1/22 or 24
• Trials of self-administration of icatibant
• Subcutaneous C1 inhibitor
• Higher doses of C1 inhibitor
• rC1 inhibitor for Europe-early 2011
• Ecallantide for Europe- 2011
• USA patient-led database
• Icatibant outcome survey