Beruflich Dokumente
Kultur Dokumente
firazyr ®
De Blander Hadrien
B1 Receptor B2 Receptor
The Lys118 - attracts the negative charge of the C-ter of B1-selective peptides that
The Ser111 does not repell B2-selective peptide and readily bind
lack the C-terminal Arg
…no counter-ion is available to attract B1-selective peptides
- repels the positive charge of the C-terminal Arg of B2-selective peptides
4
Effects and Pharmacological mechanisms (B2)
Vasodilation
Bk One of the most powerful known vasodilators
Hypotension (particularly marked in capillaries)
Edema
Other actions
BK the most potent stimulator of tissue-type plasminogen activator
(t-PA) release ( Fibrinolysis)
• potent stimulator of prostacyclin synthesis in the endothelial cell
which inhibits platelet function
Bradykinin : autocrine
and paracrine action
(autacoids)
7
Stability
≈15 s
Aminopeptidases (APP) N-ter Arg
H
N OH 95% of bradykinin administered
N O O
H H H intra- venously to humans is
O O O N
H2N N
O OH degraded by pulmonary ACE after a
O O N N
H
H
H H single passage
O N
N
NH H
N NH
H NH2
Bradykinin
HN NH2
HN NH2
OH
NH
How to
H
N OH improve the
O O
N
H H
molecule ?
H H
H2N O N O O N
OH
Hoescht
H2N O O N N O
H
H
H H answer :
O O N Inspired from
S N
NH H
S
the ACE
N NH2
NH inhibitors
H
development
HN NH2
OH
O
O
O N O O
O O
O O O
HN NH
NH
O
NH O
O
H
H
O N N O
N O
O OH
OH
O OH H
H
Jochen Knolle
1978 Hoescht
11
Structure evolution of B2 Antagonists : From Bradykinin to Icatibant
Duration of action in
Icatibant
Vavrek 19911988
and Stewart (Hoe-140)
(NPC-349) vivo and potency
1st Generation antagonist D-Arg Arg Pro Hyp Gly Thi Ser D-Phe Thi Arg
(NPC-349) Stewart
2nd Generation antagonist D-Arg Arg Pro Hyp Gly Thi Ser D-Tic Oic Arg
(HOE-140/Icatibant) Hoescht
Next ? Icatibant is still cleaved by NEP ( BK[1–4] product in urin ) 3rd generation…
12
Conformation
• The C-terminal region plays an important role for its binding interaction to the B2 receptor
• Bulky hydrophobic unnatural amino acids force the resulting peptide in a β-turn motif
D-Tic7-Oic8 is crucial for antagonist activity
• Pseudocyclic conformation involving a βII-turn (positions 2–5) and a βII′-turn (positions 6–9)
+ hydrogen bond between the amide hydrogen of Gly 4 and the carbonyl oxygen of D-Tic 7
• Substitution of the D-Tic7-Oic8 dipeptide in HOE 140 with constrained mimetics induced a potent B2
receptor agonist activity and even a potent and selective B1 antagonist activity
Potency
Selectivity
14
Chemical Synthesis
• Laboratory
• Industrial
Solid
Phase
Peptide synthetiser (500L)
Peptide
Synthesis
15
After 1991 … until 2001
HOE 140 has been used extensively in animals to block exogenous bradykinin.
It has also been used in various pathological states to evaluate the role of kinins in pain and
hyperalgesia and in inflammatory states (rhinitis, asthma, cystitis, pancreatitis, etc..)
Peptides having a
bradykinine
inhibiting
Activity
(new molecule Suspension of development in
Allergy, Asthma, Rhinitis and Pain
= icatibant)
• BK administration to airways
– Bronchoconstriction only in asthmatics (enhanced B2 receptor expression in this sensitized patient
population ?)
– Sore throat and rhinitis blocked by Icatibant
– Inactive on nasal obstruction and albumin extravasation (Akbary & Bender,1993) (Turner et al., 2001 )
• In moderately severe asthma (double-blind, placebo controlled, 4-week clinical trial, 264 patients (Hoechst-1996) )
B1
B2
Analgesic profile of B1 receptor antagonist :
(in the periphery and the CNS ):
• Longer term inflammation and pain
(sometimes in the absence of inflammation)
• Hoe 140 was completely ineffective against the abdominal constriction response induced by Zymosan, kaolin and
acetic acid
In contrast, morphine, ibuprofen and indomethacin had similar potencies (John S. Shaw & Susannah C. Farmer 1993)
18
After 1991 … until 2001
HOE 140 has been used extensively in animals to block exogenous bradykinin.
It has also been used in various pathological states to evaluate the role of kinins in pain and
hyperalgesia and in inflammatory states (rhinitis, asthma, cystitis, pancreatitis, etc..)
Peptides having a
bradykinine
inhibiting
Activity
(new molecule Suspension of development in
Allergy, Asthma, Rhinitis and Pain
= icatibant)
Pubmed entries
Jerini licensed
exclusive worldwide
development and
commercialization
rights to icatibant
from Aventis
Phase I trials in
liver cirrhosis
Refractory ascites in liver cirrhosis and 20
Hepato-Renal Syndrome
Cirrhosis : significant abnormalities in their fluid and electrolyte balance
ascites and edema
5–10%
Refractory ascites
liver transplantation
Phase IIa (randomized, crossover, placebo-controlled) Icatibant met all the primary endpoints :
- improved sodium and potassium excretion
- urine flow
- body weight
21
Icatibant indications in :
- edema with severe burns
- ascites in liver cirrhosis
…no longer listed on the
Jerini’s pipeline
still capillary leak syndrome
22
• no evident etiology
Icatibant indications in
edema with severe
burns, as well
as ascites in liver
cirrhosis were no longer
listed on the Company’s
pipeline still capillary
leak syndrome
24
Efficacy and Safety Study of Intra-Articular Multiple Doses of Icatibant
in Patients With Painful Knee Osteoarthritis
Phase IIa :
Icatibant quick and sustained pain relief in a phase II study in patients with osteoarthritis of the knee
Phase IIb :
o To compare icatibant treatment with steroid treatment and placebo
The symptoms of HAE are caused by the extravasation of plasma into the deeper cutaneous
or mucosal layers as a result of one or more locally released vasoactive peptides.
27
2 types (possibly X-linked “type III” HAE primarly women and exacerbated by estrogens)
C1 Inhibitor (C1-INH)
• Hepatic Glycoprotein
• Serpin family = 20% of all plasma proteins
• Serine Protease Inhibitors
• Suicide substrate
More than 200 different mutations of the C1INH reported in HAE patients
29
Trauma
General pattern
FXII
FXIIf
FXIIa
Plasminogen
Plasmin
Prékallikrein Kallikrein
HMWK
Bradykinin
• Increased Capillary
• Vasodilation Permeability, Fluid
• Nonvascular Smooth Extravasation, and
Muscle Contraction Edema
MAC : Membrane attack complex
30
Treatments
Acute Long term Short term prophylaxis
treatment
Antifibrinolytic agents prophylaxis
Antifibrinolytic agents C1-inh concentrate
(ex :Tranexamic acid) (ex :Tranexamic acid)
Proof-of-concept study
• 20 acute HAE attacks (10 cutaneous, 3 abdominal, 7 combined) were treated with Icatibant as follows (n=4 each group) :
• A 59-year-old patient
• 4 episodes laryngeal (particularly)
significant relief of symptoms
complete recovery
Laryngeal oedema
(endoscopic finding)
36
Advantages Inconvenients
• Active in all types of attacks (cutaneous, abdominal, laryngeal) • Not for oral administration
• Excellent systemic safety demonstrated to date • Access
• Ease of use: subcutaneous administration
• Pre-filled syringe (stable in solution at room temperature >1 year)
• Synthetic product (not plasma-derived, not recombinant)
« …Because the protocol developed by Jerini pooled numerical data from multiple types of attacks, the data analysis
may have led to difficulties with adequate comparisons »
37
Avis
29 octobre 2008
• D'après les résultats des essais cliniques il n’est pas attendu d'impact pour la spécialité
FIRAZYR en termes populationnel sur la morbi-mortalité et la qualité de vie des patients.
• En conséquence, en l’état actuel des connaissances, il n’est pas attendu d’intérêt de santé
publique pour la spécialité FIRAZYR dans cette indication.
• SMR
important
•Amélioration du SMR
mineure (ASMR IV) dans la prise en charge des crises d’angio-oedème
héréditaire.
Jerini licensed Phase IIa Phase I trials in Phase III trial the FDA issued a
exclusive worldwide proof-of- edema with FAST-2 non-approvable
development and concept trial severe burns letter
commercialization was initiated ………………
rights to the drug in HAE the FDA granted
Dec : Jerini and The drug was
from Aventis Orphan Drug
Abbott, following approved by the
status for the
Jerini received its acquisition of EMEA for HAE
treatment of
European Kos were also under the
edema in severe
Phase I trials in Orphan Drug developing an
burn patients trademark Firazyr
liver cirrhosis designation inhaled
for icatibant formulation of
(FDA for Sept : Phase III HAE icatibant for the
angioedema trials designated potential
FAST-1 Icatibant indications in
treatment of
edema with severe
asthma
burns, as well
as ascites in liver
cirrhosis were no longer
listed on the Company’s
pipeline still capillary
leak syndrome
39
Ki = 64 nM
Ki ~ µM
not specific for BK
(1997)
(1997)
= Anatibant
Ki = 20 nM Ki = 0.67 nM
BK important growth factor for small-cell lung cancer and prostate cancer
B-9870
Suim = suberimidyl moiety
1997 -C(=NH)-(CH2)6-C(=NH)-
J. Stewart
- Blocked the proliferation of tumour-derived cell lines (activation of c-Jun kinase, caspase 3 ( apoptosis) and
antagonizes BK-induced calcium signalling )
- Dual B1R and B2R antagonist / partial agonist in lung cancer cell lines + "biased agonist" action
- Icatibant lower efficacy (minor activation of endocytosis and ERK kinase activation)
- Idem for Hoe 140 dimer (B-9872)
2008 : Phase I Clinical : small cell and non small cell lung cancer
Bibliography
• Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies
• Hoe 140 a new potent and long acting bradykinin-antagonist: in vivo studies
• Inhibition of the response to nasal provocation with bradykinin by HOE-140: efficacy and duration of action
• Nonpeptide antagonists for kinin receptors
• A non-peptide antagonist unusually selective for the human form of the bradykinin B2 receptor
• Review : Kallikrein–kinin in infection and cancer
• The design of non peptide human bradykinin B2 receptor antagonists employing the Benzodiazepine peptidomimetic scaffold
• Knee osteoarthritis: a role for bradykinin?
• Hereditary Angioedema by the New england journal
• C1inhibitor deficiency: consensus document
• Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond
• Hereditary angioedema: Optimal therapy
• Current and future therapy for hereditary angioedema
• What future for the new therapies?
• Bradyzide, a potent non-peptide B2 bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia
• Synthesis and Structure-Activity Relationships of Potent New AngiotensinConverting Enzyme Inhibitors Containing Saturated Bicyclic Amino Acids’
• The Kallikrein-Kinin System: Current and Future Pharmacological Targets
• The kallikrein-kininogen-kinin system: lessons from the quantification of endogenous kinins
• International Union of Pharmacology. XLV.Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological
Consequences
• La bradykinine par M/S
• The Role of Plasma High Molecular Weight Kininogen in Experimental Intestinal and Systemic Inflammation
• Bradykinin receptors and their antagonists
• Antagonist, partial agonist and antiproliferative actions of B-9870 (CU201) as a function of the expression and density of the bradykinin B1 and B2
receptors
• CHMP ASSESSMENT REPORT FOR Firazyr
• The Kallikrein-Kinin System: Current and Future Pharmacological Targets
• Role of kinins in seasonal allergic rhinitis: Icatibant, a bradykinin B2 receptor antagonist, abolishes the hyperresponsiveness and nasal eosinophilia
induced by antigen
• Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist
• Reduction by Hoe 140, the B2 kinin receptor antagonist, of antigen-induced nasal blockage
• Efficacy and tolerability of Icatibant (Hoe 140) in patients with moderately severe chronic bronchial asthma
• Novel pharmacotherapy of acute hereditary angioedema with bradykinin B2-receptor antagonist icatibant
• Bradykinin antagonists modified with dipeptide mimetic b-turn inducers
• Bradykinin receptor ligands: therapeutic perspectives
• Bradykinin antagonists as new drugs for prostate cancer
• Combination cancer chemotherapy with one compound: Pluripotent bradykinin antagonists
• …………………………..
• …………………………………and more