il bisogno di nuove terapie in bpco
TRANSCRIPT
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THE NEED FOR NEW
TREATMENTS FOR COPDCLIVE PAGE
The Sackler Institute of Pulmonary Pharmacology
Institute of Pharmaceutical Science
King’s College London
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Current Bronchodilator Options
Bronchodilators
Short-acting Long-acting
β-agonists:Salbutamol
Levalbuterol
Terbutaline
Pirbuterol
Antimuscarinics:
Ipratropium
Oxitropium
β-agonists:
Salmeterol
Formoterol
Indacaterol
Antimuscarinics
TiotropiumAcladinium
Glycopyrollate
Xanthines:Theophylline
Doxophylline
Fixed Combinations
Salbutamol + ipratropium
Budesonide + formoterol
Fluticasone + salmeterol
Mometasone + Formoterol
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NEW BRONCHODILATORS
• Ultra-LABAs eg indacaterol, vilanterol, olodaterol
• Ultra-LAMAs eg Acladinium, glycopyrollate,
daratropium
• New pharmacological classes eg Rho kinase inhibitors,
PDE3 inhibitors, Bitter taste receptors (quinine
analogues)
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All compounds reported to date follow a “linked or conjugated pharmacophore”
approach to achieve dual pharmacology in a single molecule:
HN
O
HO
NH2
OH
HO
NH2
OH
HO
HO
NH2
OHHNO
Based on b2 adrenergic heads Based on M3 antagonists’moieties
N
O
O
OH
Ar Ar
N
O
O
N
O
O
N
R
OH
Ar
indacaterol
like
salbutamol,
salmeterol like
formoterol like
solifenacin
like
glycopyrrolate
like
aclidinium
like
Introduces diversity
Modulates physical
properties
Modulates potency,
selectivity, metabolism,
…
linker
Structural Novelty
The Design of MABA molecules
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TD-5959 confers potent 24 h bronchoprotection in guinea pigs through a dual
mechanism involving antagonism of muscarinic receptors and agonism of β2-
adrenoceptors
Pulido-Rios et al, Am J Respir Crit Care Med 2009;179:A6195
The MABA effect of TD-5959 was observed for up to 24 h after inhalation
0
5
10
15
20
25
30
35
40
I D 5 0 , µ g / m L
TD-5959
ipratropium
salbutamol
HAMCh ±
propranolol
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Lack of effect of GCS on decline in lung function
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NeutrophilMacrophageCD8+ T-Cell Eosinophil EpitheliumMast cell
PDE4Endothelium
Bronchoconstriction
Airway
Smooth
Muscle
The profile of biological activity suggests that PDE4
inhibition has good therapeutic potential for inflammation
Mediator
Release
From
Pro-inflammatory
Cells Influx of Inflammatory Cells
Fibroblasts
Mucus Hypersecretion
Mucus Gland
Edema andAdhesion
Airway Remodelling
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Compound Company Status
Roflumilast(Daxas/
Daliresp)
Nycomed/Mitsubishi/TanabePharma
corp/Forestlaboratories)
ApprovedbyEuropeanMedicines
AgencyandFDA2010/11
Oglemilast Glenmark/Forest Phase2 –asthmaPhase2b-COPD
OX914 Orexo/Inflazyme Phase2b –asthma,COPD
MEM1414 MemoryPharmaceuticals/Roche Phase2a-asthma
ELB353 Biotietherapies/Elbion Phase1 –inflammatorydiseases
Apremilast Celgene Phase2 –psoriaticarthritis,RA?
GRC4039 Glenmark Phase2 –RA,asthma
Tetomilast Otsuka Phase3-Crohnsdisease,
Ulcerativecolitis,COPD
PDE4 inhibitors developed for oral administration in late
stage development
Discontinued:
Cilomilast (GSK) , CDP840 (Celltech/Merck ), SCH 351391 (Schering Plough ), YM-976 –(Yamanouchi) ,Arofylline (Almirall), V11294A (Napp ), CI1018 –(Parke-Davis), Lirimilast (Bayer), Filaminast (Wyeth-Ayerst ),
C-3885 (Merck-Frosst), D-4418 (Celltech / Schering Plough) , IC-485 (ICOS), L826,141 (Merck), ONO 6126
(Ono), IPL-512602 (Inflazyme/Aventis).
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Evolution of PDE4 Inhibitors
cilomilast
roflumilast
theophylline
non-selective
PDE inhibition rolipramselective PDE4
2nd gen oral
PDE4s; lower
affinity for
HARBS
piclamilast
inhaled PDE4
inhibition;
decreased
systemic
exposure
apremilast
oglemilast
3rd gen oral
PDE4s
less CNS-
penetrant?
PDE4B- or
PDE4D-
selective?
inhibitionAWD12-281
UK500001
tofimilast
2nd gen inhaled
PDE4s
GSK256066
ultra-potentinhaled PDE4
Dose-limited by nausea ,
emesis, diarrhoea
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Trend towards drug combinations or drugs with mixed
activities
• MABAs – single drug combining muscarinic receptor
antagonism and B2 agonist activity
• Mixed PDE3/4 inhibitors eg RPL 554
• Mixed PDE4/7 inhibitors
• Fixed dose combination Inhalers containing multiple
drugs
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• Derivative of trequinsin (a cardiovascular drug originally discovered byHoechst). Discovered by Sir David Jack and Alex Oxford at Vanguard
Medica
• Molecular Weight: 478
• Stable as solid or solution
• Crystalline; feasibility studies demonstrate that it is possible to formulate
for nebulizer, dry powder or pMDI
RPL554 – A novel Inhaled dual PDE3/4 inhibitor
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Effect of increasing dose of RPL554 on contractile effect of
histamine in passively sensitized isolated human bronchi.
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Bronchial relaxation iduced by RPL554, salbutamol and atropine
on sub-maximal contraction of isolated human bronchi by ACh.
Cazzola, unpublished data
S f
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Synergic interaction surfaces analysis by Bliss
Independence method.The volume above the 0-plane represents synergistic (positive ΔE)
interaction for bronchial relaxation. n=3
RPL554 plus
salbutamol
RPL554 plusatropine
Low doses synergisticinteraction
Cazzola, unpublished data
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Synergic interaction analysis by Berenbaum method.bars below the 0-line (additively line) indicate synergistic interaction for bronchial
relaxation. n=3;
RPL554 plus salbutamol RPL554 plus atroipine
data expressed as mean±SEM. *P
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RPL554 by inhalation in COPDFEV1(Δ ml vs pre administration)
Data normalized for predicted FEV1 (age, weight, eight)Cazzola, unpublished data
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Potent anti-inflammatory activity in cell models
20
-9 -8 -7 -6 -5 -4
0
25
50
75
100
RPL554
Log10 PDE inhibitor (M)
% C
o n t r o l
IC50 = 0.46 m M (0.24 - 0.90) IC50 = 7.5 nM (3.9 - 14.2)
-9 -8 -7 -6 -5 -4
-25
0
25
50
75
100
125
Log10 PDE inhibitor (M)
% C
o n t r o l
RPL554
Inhibition of LPS-induced TNFa production
from human monocytes in vitro
Inhibition of mitogen-induced proliferation
of human mononuclear cells in vitro
DATA: C P Page Lab; Sackler Institute of Pulmonary Pharmacology, King’s College London
Cazzola, unpublished data
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Anti-inflammatory effects in vivo
21
Inhibition of plasma extravasation in trachea Inhibition of eosinophils in lavage fluid
Inhibition of EPO
in lavage fluid
Boswell-Smith et al 2006
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RPL554, but not a PDE3 inhibitor (siguazodan), es
22Boswell-Smith et al 2006
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The inflammation in the lung ‘spills over’ into the systemic
circulation to produce systemic effects, such as muscle
weakness or cardiovascular complications
Cazzola et al, Trends Pharmacol Sci 2007
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Treating systemic effects of COPD
• Traditional treatment and its potential to modify systemic
effects of COPD• Smoking cessation
• Bronchodilators
• Inhaled corticosteroids
•Combination therapy
• Potential more specific anti-inflammatory therapies
• Selective phosphodiesterase inhibitors
• Glycosaminoglycans
• Antioxidant therapy
• Statins• Angiotensin-converting enzyme inhibitors and angiotensin II
type 1 receptor blockers
• Peroxisome proliferator-activated receptor agonists
Cazzola et al. Trends Pharmacol Sci 2007
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Anti-inflammatory effects of heparin relevant to COPD
• Heparin neutralises elastase (Walsh et al, 1991) and cathepsin G(Ledoux et al, 2003)
• Heparin inhibits release of elastase from human neutrophils(Brown et al, 2003)
• Heparin inhibits function of various adhesion molecules onleukocytes and vascular endothelium (Lever et al, 2000)
• Systemic heparin inhibits leukocyte trafficking into lung tissues(Lever and Page, 2002)
• Addition of enoxaparin to the combination of
salmeterol/fluticasone improves symptoms in patients withCOPD (Brown et al, 2006)
• Heparin reduces inflammation in patients with COPD (Shute,,2012)
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Beneficial effects of statins in COPD
Barnes and Celli, Eur Respir J 2009
Patients with COPD and taking statins have reduced
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Patients with COPD and taking statins have reduced
hospitalisation for COPD exacerbations, lower mortality from
COPD exacerbations (or chest infections) and lower cardiovascular
mortality compared to those not taking statins
Young et al. Eur Respir Rev 2009
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PMNs, platelets and Endothelium
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The adhesion cascade
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LEUKOCYTES ROLLING ON ENDOTHELIUM
ARE STAINED FOR PLATELETS
(red fluorescence, CD41 positive)
INDIVIDUAL PLATELETS
(red, CD41 positive) CAN BESEEN ATTACHED TO EOSINOPHILS
(green MBP positive)
Pitchford et al., (2005) Blood 105; 2074-2081
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Neutrophil attachment to
Endothelium is greatly
enhanced by thepresence of platelets:
PMNs PMNs + Platelets
Platelet depletion
inhibits PMN
recruitment todifferent anatomical
sites:
Lungs: Peritoneum:
Effects of platelets on neutrophil recruitment and diapedesis
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Increased neutrophil rolling and adhesion to
endotheliumThis can occur by platelets acting as a ‘bridge’ for PNC via various
adhesion interactions with the endothelium:
Platelet --------------- EndotheliumPSGL-1 P-selectin
GPIbα vWF
GPIbα P-selectin
GPIIb/IIIa ICAM-1-Fibrin
Platelets can also increase direct neutrophil adhesion to
endothelium by inducing surface expression of neutrophil integrins:
Neutrophil -------------- Endothelium
CD11a/CD18 ICAM-1 +2
CD11b/CD18 ICAM-1
Effects of platelets on neutrophil recruitment and diapedesis
Neutrophil
Platelet
Endothelium
Increased neutrophil trapping and transmigrationRelease of platelet derived CXCL4, CXCL-7, CCL5
CXCL-1, CXCL-8 release from endothelium activated by
platelets.
Neutrophil chemotaxis enhanced by the
presence of platelets in vitro.
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Anti-platelet drugs effective in COPD
• Anti-platelet drugs improve survival in patients withoxygen-dependent COPD (trends also observed with
statins and ACEI and ARBs)
• Beta blockers and oral steroids not associated with such
protection
• Ekstrom et al, Am J Respir Crit Care Med, January 17th,
2013
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Sackler Institute of Pulmonary Pharmacology
• Dr Dom Spina
• Dr Victoria Boswell-
Smith
• Dr Simon Pitchford• Dr Yanira Bravo
• Dr Luigi Calzetta
• Dr James Moffatt• Dr Sandra Rudman
• Dr Tanya Holand
• Dr Rachel Brown
• Dr N Jones
• Professor Mario Cazzola(University Tor Vergata,
Rome)• Sir David Jack (deceased)
• Dr Alex Oxford
• Dr Gabriella Matera (Visiting
Professor)• Professor Michael Walker
(Verona Pharma)
• Dr Lui Franciosi (VeronaPharma
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