Futuristic strategies for asthma management Jaideep A Gogtay MD Cipla 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 receptorAntagonist Inhibitor mRNA Antisense oligonucleotide Kinase inhibitorSignal transduction Soluble cytokine receptor

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 elastase Cathepsins Matrix metalloproteinases CD8 + lymphocyte IL-8, LTB 4 PDE4 PDE 4 INHIBITORS (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 Ciclesonide Inactive compound Lungs Activated by esterases to Desisobutyrl ciclesonide Systemic circulation Inactive

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 CH C NH OH HO C* CH C NH 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

Mean effect of inhaled (R)-salbutamol, (S)- salbutamol, (R,S)-salbutamol and placebo on FEV Pre Dose (R)-/(S)-Salbutamol: (R,S)-Salbutamol: Dose (R)-Salbutamol (R,S)-Salbutamol (S)-Salbutamol Placebo FEV (L) 1

Airway hyperresponsiveness Change in PD 20 of methacholine * * *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:

Effect of R and S salbutamol on various inflammatory mediators JACI, 2002;109: R10 -8 ControlR S R S 10 -6

Effect of enantiomers with steroid on GM-CSF production by human airway smooth muscle cells 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.h r C max ng.mL –

Repeated Inhalations lead to accumulation of (S)-isomer Time after inhalation (hrs.) hours6 hours9 hours (S)-salbutamol (R)-salbutamol Plasma concentration ng. mL * *p<0.001

55 0 Pre0123 Time (hrs) 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 FEV 1 after the first dose in a subgroup of patients with pretreatment FEV 1 of < 60% of predicted Day 0 (Week 0) Nelson et al, R-salbutamol 1.25 – 52% Racemic salbutamol 2.5 – 37% JACI,1998 Mean changes in FEV 1 (%)

Change in mean glucose Change in mean K + Change in mean heart rate

Superior therapeutic index

Am J Emerg Med 2004; 22 (1): Changes in FEV 1 in the emergency department

Levosalbutamol Vs Salbutamol nebulization J Allergy Clin Immunol 2001; 108: N=338, 4-11 years

Mean change in heart rate 30 mins after dosing *#+ *# * 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:

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

Treating asthma according to its phenotype Randomized CO study of Fluticasone and Montelukast FP M Either None Change in FEV1 6.8% 1.9% > 7.5% in FEV1 23% 5% 17% 55% FP response associated with low FEV1, FEV1/FVC ratio, high eNO, AHR Montelukast associated with lower age and high urinary LTE 4 JACI, 2005

Asthma control depends on correct inhaler usage Eur Resp J 2002;19:246-51

Conclusion Future management Novel compounds Improve on current steroids and bronchodilators Easier to use devices Compliance Understanding asthma phenotypes