Il Bisogno Di Nuove Terapie in BPCO

8/18/2019 Il Bisogno Di Nuove Terapie in BPCO

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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


8/35Barnes (2000)


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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


15/35Cazzola, unpublished data

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



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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



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Anti-inflammatory effects in vivo

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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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Il Bisogno Di Nuove Terapie in BPCO

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