Futuristic strategies for asthma management Jaideep A Gogtay MD Cipla Ltd Mumbai, India.

Futuristic strategies for asthma management

Jaideep A Gogtay MDCipla Ltd Mumbai, India

Why do we need new weapons?

• No cure• Current therapy effective, but asthma control is

inadequate in majority of patients• Compliance poor with inhaled therapy• Fear about inhaled steroids• In 5% of patients current therapies do not work• Different asthma phenotypes ??

Strategies for new therapies

• Improved understanding of the disease process – Development of novel compounds

• Improvement of existing classes of drugs

• Enhancing outcomes with current therapies

Novel compounds

Transcription factor NFkB

CytokineMonoclonal antibody

Cytokine receptor Antagonist

Inhibitor

mRNA

Antisenseoligonucleotide

Kinase inhibitor Signal transduction

Soluble cytokinereceptor

Inhibition of pro-inflammatory cytokines

• IL-5 antibody – Mepolizumab reduces circulating and sputum eosinophils, but no effect on AHR

• Soluble IL-4 receptors – improved asrhma control;no further effects seen

• TNF inhibitors – etanercept, infliximab produce remarkable responses in patients unresponsive to steroids

IgE - Omalizumab

• Recombinant Humanised Monoclonal anti-IgE antibody

• Decreases response to both early and late allergen challenge

• Reduces exacerbations and improved quality of life

• Indicated in allergic asthma and allergic rhinitis• Steroid sparing• 10,000 $/year

PHOSPHODIESTERASE 4 INHIBITORS

Alveolar macrophage

PROTEASES

Alveolar wall destruction

(Emphysema)

Mucus hypersecretion

(Chronic bronchitis)

Neutrophil elastaseCathepsins

Matrix metalloproteinases

CD8+

lymphocyte

IL-8, LTB4PDE4

PDE4

PDE4

PDEPDE44 INHIBITORS INHIBITORS

(eg cilomilast, roflumilast(eg cilomilast, roflumilast))

?

Neutrophil

Improvement of existing classes of drugs

New Steroids

New bronchodilators

Inhaled steroids

• Beclomethasone/Triamcinolone

• Budesonide

• Fluticasone

• Mometasone

• Ciclesonide

Improvements in steroids

CiclesonideInactive compound

LungsActivated by esterases toDesisobutyrl ciclesonide

Systemic circulationInactive

Dissociated steroids

Steroids

Transactivation Transrepression

The different effects of steroids have been attributed to binding at different domains of the receptor

New bonchodilators

• New long acting bronchodilators used once daily – under development

• Chiral separation of isomers of bronchodilators viz. levosalbutamol, R,R-formoterol

Salbutamol isomers are enantiomers

Mirror images that are non-superimposable upon one another

Salbutamol exhibits chirality

S-Salbutamol Levosalbutamol

CH3

CH3

CH3

C NH

OH

OH

HO

C*

CH3

CH3

CH3

CNH

OH

OH

*Chiral carbon atom

HO

C*

Fundamental Biochemistry and chiral science

 • The biological messenger molecules and cell

surface receptors that medicinal chemists try to target are chiral, so drug molecules must match their stereochemistry.

• The building blocks of nucleic acids, proteins and carbohydrates are single isomers

Thalidomide tragedy was due to the presence of the R isomer

Epinephrine – Natural bronchodilator

• However all beta- agonist drugs including salbutamol, developed on the basis of epinephrine are racemates

Endogenous epinephrine produced by the adrenal glands responsible for bronchodilation is a single isomer – (R)-epinephrine

Mode of action of ß2-agonist

Activates Proteinkinase A

Decreases intracellular Ca2+

Smooth muscle cell relaxation

2-agonist

2-receptor

Smooth muscle cell

AC

Mean effect of inhaled (R)-salbutamol , (S)-salbutamol , (R,S)-salbutamol and placebo

on FEV1

3.4

3.2

3.0

2.8

2.6

2.4

Pre 6.25 12.5 2.5 50 100 200 400 800 1600Dose 12.5 25 50 100 200 400 800 1600 3200

(R)-/(S)-Salbutamol:(R,S)-Salbutamol:

Dose

(R)-Salbutamol

(R,S)-Salbutamol

(S)-Salbutamol

Placebo

FEV (L)1

Airway hyperresponsivenessChange in PD20 of methacholine

310243320225

850

1100

313340 392

158

906

400

0

200

400

600

800

1000

1200

Racemic R-salbutamol S-salbutamol Placebo

Baseline 20 mins 180 mins

*

*

*p<0.05 Vs placebo & (S)

Effect of S and R salbutamol on intracellular calcium in bovine tracheal

smooth muscle cells

Mol Pharmacol 1998; 53: 347- 54

200

150

100

50

0

-50

-100

-150

-200

-12 -11 -10 -9 -8 -7 -6 -5 -4 -3

Concentration, M

(S)-salbutamol

Dec

reas

e in

Ca

, nM

Inc

reas

e in

Ca

, nM

2+2+

(R)-salbutamol

Effect of R and S salbutamol on various inflammatory mediators

0

50

100

150

200

250

300

IL-13 IL-5 IFN-Gamma

JACI, 2002;109:449-54

R10-8Control R10-8 +S 10-8

R10-8 +S 10-6

Effect of enantiomers with steroid on GM-CSF production by human airway smooth muscle cells

-25

-37

-9

-46-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

Dex Dex + Rsalbutamol

Dex + Ssalbutamol

Dex + R,R-Formoterol

JACI 2004; 113 (2): 159

Recognized by US FDA

“S-salbutamol not only fails to relax

airway smooth muscle but under certain

circumstances (absence of R

isomer;activated cells) may augment

bronchial constriction…increased

intracellular calcium and BHR….”

FDA Medical Reviewer, 1999

Pharmacokinetic data obtained in plasma after administration of a 4 mg tablet to healthy volunteers

S-salbutamol R-salbutamol

AUC 0-6 h ng.mL–1.hr 26.5 3.2

Cmax ng.mL–1 7.2 1.0

Repeated Inhalations lead to accumulation of (S)-isomer

Time after inhalation (hrs.)

2.5

1.5

0.5

2

1

03 hours 6 hours 9 hours

(S)-salbutamol

(R)-salbutamol **p<0.001

55

0

Pre 0 1 2 3

Time (hrs)4 5 6 7 8

5101520253035404550

Lev 1.25 (n=36)Lev 0.63 (n=32)Rac 2.5 (n=38)Rac 1.25 (n=26)PBO (n=37)

Mean % change in FEV1 after the first dose in a subgroup of patients with pretreatment FEV1 of < 60% of predicted

Day 0 (Week 0)

Nelson et al,

R-salbutamol 1.25 – 52%Racemic salbutamol 2.5 – 37%

JACI,1998

Me

an

ch

ang

es in

FE

V1 (

%)

-2

0

2

4

6

8

Placebo Lev 0.63 Racemic2.5

Day 0 Day 28

-0.3

-0.25

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1

Placebo Lev 0.63 Racemic2.5

Day 0 Day 28

-4

-2

0

2

4

6

Placebo Lev 0.63 Racemic2.5

Day 0

Day 28

Change in mean glucose Change in mean K+

Change in mean heart rate

Superior therapeutic index

350

300

250

200

150

100

50

0

The

rape

utic

Inde

xLevosalbutam ol

0.63 m g

Salbutam ol2.50 m g

13

45

56

82

34

78

56

95

6

43

14

46

0

10

20

30

40

50

60

70

80

90

100

LEV 0.63 LEV 1.25 LEV 2.5 LEV 5.0 RAC 2.5 RAC 5.0

Ist nebulization 60mins post doseAm J Emerg Med 2004; 22 (1): 29-36

Changes in FEV1 in the emergency department

Levosalbutamol Vs Salbutamol nebulization

41.8

62.9

0

10

20

30

40

50

60

70

Racemicsalbutamol 1.25

mg

Levosalbutamol0.31mg

% of patients with > 15% change in FEV1

J Allergy Clin Immunol 2001; 108: 938-45N=338, 4-11 years

Mean change in heart rate 30 mins after dosing

-2

0

2

4

6

8

10

12

Placebo Lev 0.31 Lev 0.63 Rac 1.25 Rac 2.5

Day 0

Day 21

*#+ *#+

*#

*#

*#*#

* p<0.001 vs plac; #p< 0.02 vs lev 0.31;+p<0.002 vs rac 2.5 J Allergy Clin Immunol 2001; 108: 938-45

Enhancing outcomes with current therapies

•Inhaled steroids + LABAs

•Montelukast

•Treatment must be taken regularly even if there are no symptoms

•Inhaler technique must be correct

Conclusion

Future management

Novel compounds

Improve on current steroids and bronchodilators

Easier to use devicesCompliance

Understanding asthmaphenotypes