Transcript Diapositive 1 - Moodle Lille 2

Hereditary Angioedema
Market
A MARKET WITH A LOT OF COMPETITORS.
By Philippe Breton
Alexia Dumoulin
Hortense Masias
Presentation of the pathology
What is an hereditary angioedema?
 Autosomal dominant disease
 Recurrent episodes of nonitching subcutaneous or submucosal
edema
 With no improvement with antihistamines, adrenaline or
corticosteroids
A debilibating disease…
 All HAE patients experience skin swelling
 But with variation in intensity :



temporaly disfiguring or disabling severe abdominal pain
pain vary depending on its location and severity
Frequency : every 7 to 14 days if untreated
potentially life threatening!
 Migration of the site of action during the episode
 Oropharynx : risk++
 Patients experienced 1 or more episodes of laryngeal attacks during
their lifetime: 50%
 Motality of untreated laryngeal
edema: 30%
Quinck’s edema!
Agostoni et al. J Allergy Clin Immunol. 2004; 114:S51-131
Average course of an attack
 Predictable course
 Presence of a prodrome in many cases (a tingling sensation)

1/3 accompanied by erythema marginatum, a nonpruritic rash
Epidemiology
 Prevalence :


1-2 cases / 50 000 (Orphan)
No differences known among ethnics groups
 Symptoms typically begin in childhood ( 2 or 3 years of age),
worsen around puberty,
and persist throughout life, with unpredictable severity.
 Origin of the attacks : unknown
 Potential trigger : stress, dental procedures, minor trauma
 Menstruation, pregnancy, oral contraceptives and hormone
replacement therapy worsen
Classification of HAE
 Over 150 different mutations on the C1-inhibitor gene :
75% of HAE patients but for 25% : new mutations
 Diagnostic based on a measurement of antigenic and functional
C1-inhibitor levels;
HAE type I
HAE type II
Numbers
85%
15%
Causes
C1 inh level
low
C1 inh level
normal but not
functional
First difficulty : the diagnostic

Antigenic and functional C1 INH levels
Persistently low antigenic C4 level

Often mis or underdiagnosed : ½ in the US
many HAE symptoms # allergies, headaches, colic, appendicitis
symptoms may be not recurrent or do not recur in the same location
various angioedema with similar clinical and laboratory data
Current treatments
Short-term and long-term prophylaxis
to minimize the frequency and severity of recurrent attacks
Drug class
Mechanism
Side effects
Androgens increase
production of C1-INH
Hepatocellular adenoma or carcinoma,
alterations in lipid profile, virilization,
muscle pains and cramps, depression…
Coagulation
inhibition
Muscle cramps, increased enzyme
concentrations in muscle, potential risk
of thrombosis
17α-alkylated androgens
(danazol)
Anti-fibrinolytic agents
(tranexamic acid)
Acute attack
halt the progression of the edema and alleviate the symptoms
Drug class
Administration
C1-INH concentrate
IV-hospital
Fresh frozen plasma
IV-hospital
Mechanism
Side effects
Increase C1-INH level
Without serious adverse effects
Contains C1-INH
Exposes the body to new
complement factors or
bradykinin precursors: aggravate
+ narcotic analgetics, steroids, spasmolytics and antiemetics for pain medication
HAE pathophysiology :
What is the best way to treat ?
Facteur XII
Kininogen
Prekallikrein
Facteur
XIIa
Kininogen
ANGIOEDEMA
Kallikrein
Bradykinin
Kallikrein
↑ Vascular permeability
↑ Fluids extravasation
↑ Vascular permability
↑ Fluids extravasation
↑ Vasodilatation
↑ Muscular contraction
Facteur XII
Kininogen
Prekallikrein
Facteur
XIIa
Kininogen
Kallikrein
Bradykinin
Kallikrein
↑ Vascular permability
↑ Fluids extravasation
↑ Vasodilatation
↑ Muscular contraction
Facteur XII
Kininogen
Prekallikrein
Facteur
XIIa
Kininogen
ANGIOEDEMA
Kallikrein
Bradykinin
Kallikrein
↑ Vascular permeability
↑ Fluids extravasation
↑ Vascular permability
↑ Fluids extravasation
↑ Vasodilatation
↑ Muscular contraction
C1 INH
Facteur XII
Kininogen
C1 INH Prekallikrein
C1 INH
Facteur
XIIa
C1 INH
Kininogen
Kallikrein
C1 INH
C1 INH
Bradykinin
Kallikrein
C1 INH
Facteur XII
Kininogen
C1 INH Prekallikrein
C1 INH
Facteur
XIIa
C1 INH
Kininogen
Kallikrein
C1 INH
C1 INH
Bradykinin
Kallikrein
What is the best way ?
 Global approach :
injection of C1 inhibitor like in some countries
C1-Inhibitor : A cornerstone protein
a serine esterase inhibitors of serpin
family
heavily glycosylated
478 AA
105 kDa
What is the best way ?
 Global approach :
injection of C1 inhibitor like in some countries
OR
 Specific approach :
targetted the predominant mediator of enhanced vascular permeability
Bradykinin
Nanopeptide generated by activation of the
contact system
Specific approach
 2 options :

Inhibitor of kallikrein
Competitive bradykinin
B2 receptor antagonist

New developments
Several options for 5 companies
C1 inhibitor
Bradykinin pathway
Derived plasma
Inhibitor of kallikrein
Cinryze
Ecallantide
DX-88
Berinert
Competitive bradykinin B2
receptor antagonist
Recombinant
Rhucin
Icatibant
Firazyr®
A. Increase C1 inhibitor level
C1 inhibitor
3 competitors
Potential
indications
(US)
Status
Adm
Derived
from
Berinert
Acute attacks
Drug administration:
300,000 doses
Use in Europe for 20
years
IV
Plasma
Cinryze
(Cetor)
Acute attack
AND
prophylaxis
Cetor Marketed in
netherlands since 1972
Cinryze similar for US
Market
IV
3h*
Plasma
IV
Transgenic
rabbit milk
Product
Rhucin
Packaging
Acute attack
Negative
opinion from
EMEA
(Mars 2008)
C1 inhibitor
3 competitors
Product
Results
Time of action
Anticipated
side effects
Berinert
Decrease
frequency and
severity
Begins after
30-60min;
Lasts 1-2 days
Anaphylaxis;
Transmission
infectious agent
Decrease
frequency and
severity
Begins after
30-60min;
Lasts 3-4 days
Anaphylaxis;
Transmission
infectious agent
Inflammation;
Myocardite
infarctus
Anaphylaxis;
autoAb?
Antibodymediated
rejection in
kidney
transplantation
Cinryze
Rhucin
Decrease
frequency and
severity
Begins after
30-60min;
Lasts 3 hours
Other
indications
C1 inhibitor
Production
 C1 inhibitor plasma derived plasma serum donors:
+ detergents to destroy the membranes of enveloped virus
+ heat treatment to reduce the possibility of viral contamination
+ nanofiltration to remove agents largers than 15 nm
 Recombinant C1 inhibitor :



the human gene for C1 inhibitor has been cloned and introduced into rabbits
then the human protein is secreted in the milk of the lactating rabbit
the milk can be collected and the human protein isolated.
Warning:
the rabbit-produced C1 inhibitor is glycosylated differently than the
normal human protein, it has a much shorter half-life in the recipient
than the native protein activation of C1.
B. Action on bradykinin
B1. Ecallantide :
a kallikrein inhibitor
Ecallantide
Ecallantide DX-88
a phage display discovery
 An rapid, effective and focused discovery method


genetic material is inserted into a phage gene
Kunitz inhibitor sequence modified on reactive bond region
DX-88 : primary sequence differing from the parental protein by only 7 AA
AA of the Kunitz domain varied were those known to make
contact with the serine protease
a peptide is made and exposed on the phage surface
each phage receives a different gene,
so each expresses a single protein or
peptide  collection of phage displaying = library
bacteriophage display library of 109 variants
of the first Kunitz domain
From Dyax.com
Ecallantide DX-88
a phage display discovery
exposition to an immobilized target (receptor or enzyme)
The Kunitz domain display library was used in three rounds of selection against plasma
Kallikrein

o
some members of the library will bind to the target
Reduced the diversity from 109 to 20 distinct Kunitz domains
An enzyme inhibition assay was used to select the
most potent, Ecallantide
Ecallantide inhibits plasma kallikrein with high potency
and has a low potency towards other proteases
o
wash the immobilized target to remove phages that did not bind
o
phage replication in bacteria
o
sequencing of the phage DNA to identify the protein
From Dyax.com
Ecallantide DX-88
an inhibitor of kallikrein
A first-in-class compound :
a potent, specific and tight-binding kallikrein inhibitor
- small recombinant protein
- 60-amino acid polypeptide
- 7054 Daltons
 Mechanism : blocks bradykinin production
 Effective acute treatment for all types of attacks
 3x 1mL or 2x 1,5mL SC injections; requires
refrigeration prior to use
 Well-tolerated : nausea, vomiting, headache;
Safety profile: non blood derived product
Ecallantide DX-88
an inhibitor of kallikrein
 Phase III trials : EDEMA3 (completed in November 2006)
EDEMA4 (completed in June 2008)
primary endpoint : symptom improvement at four hours
EDEMA4 : under a special protocol assessment (SPA)
to further support the validity of the patient reported outcome methodology
and to confirm efficacy and safety
Efficacy determined by :
 Treatment Outcome Score (TOS) = an overall measure of response to treatment
 Mean Symptom Complex Severity score=measure symptoms severity at a specific point in
time
 Successful response at 4 hours (P < 0.001) - Efficacity in 30mn
B. Action on bradykinin
B2. Icatibant :
a competitive bradykinin
B2 receptor antagonist
Icatibant
Icatibant- Firazyr®
a bradykinin B2 receptor antagonist
A first-in-class compound :
a potent, competitive and synthetic peptidomimetic.
- Decapeptide
- Similar to bradykinin
- Four unnatural amino acids
Synthesis
Cost !
• Mechanism : prevents bradykinin action
• Effective treatment for all types of attacks
• Administration with a medicine staff, in hospital;
ready-to-use pre-filled syringes for SC route
(Biodisponibility = 97 %. - Efficacity in 30 min)
• Contains 30 mg of icatibant acetate = 3mL
1395 $ for one injection !!
Icatibant- Firazyr®
a bradykinin B2 receptor antagonist
 Well tolerated: no drug related side effects / safety profile: non blood derived
 2 Phases III trials : FAST 1 and FAST 2 :
primary endpoint : patient reported time to onset of symptom relief as a VAS (visual analog score)
FAST 1 : US + Canada + Australia + Argentina,
56 patients randomized to Icatibant (2,5 hours) or placebo (4,6 hours) ► p =0,131
FAST 2 : Europe + Israel,
74 patients compared Icatibant (2 hours) to tranexamic acid (12 hours) ► p <0.001
 2008: Approbation by EMEA
FDA issued a non approval letter
Comparaison : bradykinin target
Product
DX-88
Icatibant
Potential
indications
HAE attack
HAE attack
Administration
SC injections;
required
refrigeration
SC injections;
medicine staff
Mechanism
Recombinant
protein,
Potent inhibitor of
kallikrein
Synthetic
peptidomimetic,
Bradykinin B2
receptor antagonist
Anticipated side
effects
Prolonged partialthromboplastin time;
Development of
antidrug antibodies,
anaphylaxis
Injection site
reactions
Summary
Potential
indications
Modalities
of use
Mechanism
Attack
SC
refrigeration
blocks
production of
bradykinin
Icatibant
Attack
SC
hospital
bradykinin B2
receptor
antagonist
Cinryze
Attack, short-term
and long-term
prophylaxis
IV
inhibit C1 INH
Berinert
Attack
IV
inhibit C1 INH
Rhucin
Attack
IV
inhibit C1 INH
Product
DX-88
The HAE market
A. Why should you focus on ?
An attractive market
 The improvement of the diagnostic


better knowledge
50% probability of passing the condition
on to their child :
family history contributes to the diagnosis
 Medical needs non satisfied



Treatment options for HAE patients in the US have unchanged for over 40
years
Average: 26,9 attacks per year/patient
Individual substantial psychological and financial burden
(missed school, missed educational and career opportunities)
Economic burden of HAE
457 HAE patients / investigators: US HAE Association and Dyax Corp.
Monetizable cost
price ($)
200000
150000
,
170000
100000
81000
50000
45000
0
patient HAE
attack
ttmt hospital
condition
!
Urgent need for effective treatments and impact for reimbursement !!
The HAE market
B. A market in evolution
Pharmaceutical interest
 Jerini bought by Shire in April 2008 : 521 millions $
 Lev pharmaceuticals bought by Viropharma in July 2008 : 442 millions $
Future market
Competition Cinryze/Berinert in terms of Orphan exclusivity
 Both have the same profile but :
 Cinryze applied for acute and prophylactic treatment
 Berinert has not applied for a prevention indication
= FDA approval of Cinryze would assure that Lev would have that market
to itself
 Approval from FDA = seven years of market exclusivity
in the U.S. for the indication
The HAE market
C. Which strategy to adopt to
conquer the market ?
Minimum Acceptable Profile (MAP)
 Drug candidate for HAE treatment
Efficacy
 Fast acting
 Oral route
 Self administation
 Less side effects, well tolerated
 Safety (blood-derived ?)
 Not too expensive

Future market
Approval from FDA & EMEA
 A real work in collaboration with the fundation to launge the
good clinical trials


Rhucin : numbers of patients
Ecallantide : necessity of an other clinical trial
 To propose products more effective than products
already on the market
 To provide a clinical advantage for patients
HAE Market Opportunity : Marketing Mix
environment
company
Drug Candidate
ͯ
HAE Market Opportunity : Marketing Mix
Drug development
research, price of raw material…
environment
company
Drug Candidate
ͯ
HAE Market Opportunity : Marketing Mix
Drug development
research, price of raw material…
environment
company
Regulation
Environment
FDA-EMEA
Orphan
Status
Drug Candidate
ͯ
HAE Market Opportunity : Marketing Mix
Drug development
research, price of raw material…
environment
company
Regulation
Environment
Drug Candidate
ͯ
FDA-EMEA
Orphan
Status
Market
- consummers, patients = 500 millions $
- competitors
HAE Market Opportunity : Marketing Mix
Drug development
research, price of raw material…
environment
company
Regulation
Environment
Drug Candidate
ͯ
FDA-EMEA
Orphan
Status
Drug
Market
countries
for
sales
Market
- consummers, patients = 500 millions $
- competitors
HAE Market Opportunity : Marketing Mix
Drug development
research, price of raw material…
environment
Product
Regulation
Environment
company
efficacy, safety,
administration…
Drug Candidate
ͯ
FDA-EMEA
Orphan
Status
Drug
Market
countries
for
sales
Market
- consummers, patients = 500 millions $
- competitors
HAE Market Opportunity : Marketing Mix
Drug development
research, price of raw material…
environment
Product
Regulation
Environment
FDA-EMEA
Orphan
Status
company
efficacy, safety,
administration…
Advertising
communication,
increase the
diagnosis…
Market
Drug Candidate
ͯ
Drug
Market
countries
for
sales
- consummers, patients = 500 millions $
- competitors
HAE Market Opportunity : Marketing Mix
Drug development
research, price of raw material…
environment
Product
Regulation
Environment
FDA-EMEA
Orphan
Status
company
efficacy, safety,
administration…
Advertising
communication,
increase the
diagnosis…
Drug Candidate
ͯ
countries
for
sales
Sales Forces
medicine or hospital / attack or prophylaxis
Market
Drug
Market
- consummers, patients = 500 millions $
- competitors
HAE Market Opportunity : Marketing Mix
Drug development
research, price of raw material…
environment
Product
Regulation
Environment
FDA-EMEA
Orphan
Status
company
efficacy, safety,
administration…
Advertising
communication,
increase the
diagnosis…
Drug
Market
Drug Candidate
ͯ
Distribution
refrigeration…
Sales Forces
medicine or hospital / attack or prophylaxis
Market
- consummers, patients = 500 millions $
- competitors
countries
for
sales
HAE Market Opportunity : Marketing Mix
Drug development
research, price of raw material…
environment
Product
Regulation
Environment
FDA-EMEA
Orphan
Status
efficacy, safety,
administration…
Advertising
communication,
increase the
diagnosis…
Price
company
reimbursment
Drug
Market
Drug Candidate
ͯ
Distribution
refrigeration…
Sales Forces
medicine or hospital / attack or prophylaxis
Market
- consummers, patients = 500 millions $
- competitors
countries
for
sales
Thank you for your
attention!
Any questions ?