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New drugs for asthma


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New drugs for asthma

  1. 1. NEW DRUGS FOR ASTHMA* Grerk Sutamtewagul, MD PGY-3 Internal Medicine Resident Texas Tech University Health Sciences Center November 15, 2013 * Semin Respir Crit Care Med 2012;33:685-694
  2. 2. The Need for New Asthma Therapy • Substantial patients burden • 300 million patients worldwide • 7.8% of the US population† • More than half of the patients appear to be poorly controlled. • 80% due to poor compliance • Some due to fear of side effects † MMWR Jan 14, 2011 Vol 60 supplement
  3. 3. The Need for New Asthma Therapy • Inhaled corticosteroid (ICS) does not modify the course of the disease even started early in childhood‡. • 2-year treatment period followed by 1-year observation in preschool children • No difference at the end of 1-year observation in terms of episode- free days, time to first systemic steroid, time to first supplementary asthma treatment ‡ Guilbert, T. et al. N Engl J Med 2006;354:1985-1997
  4. 4. Guilbert, T. et al. N Engl J Med 2006;354:1985-1997
  5. 5. The Need for New Asthma Therapy • 5-10% have uncontrolled asthma despite effective inhaled therapy. • What we need • Drugs with similar mechanism but less side effects • New classes of drug to treat asthma • New classes of drug that modify the course of the disease
  6. 6. The Need for New Asthma Therapy • Improvement in understanding basic pathophysiology of asthma in molecular level • IgE in pathogenesis of asthma • Cytokines and cell signalling • Immunomodulating pathway • Recognition of different phenotypes of asthma • Allergic asthma with elevated IgE – Omalizumab
  7. 7. Allergic mechanism in Asthma
  8. 8. Targets of therapy β2-agonist (short-acting, long-acting, ultra-long acting) Corticosteroid (inhaled, systemic) Omalizumab (anti-IgE mAb) Lumiliximab, IgE peptide-based vaccines Leukotrienes modifiers e.g. montelukast Mast cell stabilizer (Cromones) Phosphodiesterase inhibitor (theophylline) Mast cell receptor/signalling inhibitors (c-Kit antagonist, Stem cell factor antagonist, Syk kinase inhibitors, CD63 inhibitor, K(Ca)3.1 inhibitor) Adhesion molecule blockade Immunotherapy Treg enhancer (vitamin D3)Dendritic cell modulator (sphingosine-1-phosphate, fingolimod) Cytokines/Chemokines antagonists Muscarinic receptor antagonist (tiotropium) TAS2R agonist
  9. 9. NEW BRONCHODILATORS Ultra-long-acting beta-2 agonists Muscarinic receptor agonist Bitter taste receptor agonist
  10. 10. New Bronchodilators • Bronchodilators use • Relieving bronchoconstriction (short-acting) • Preventing bronchoconstriction (long-acting beta-agonist or LABA: formoterol, salmeterol – lasting 12 hrs) • Ultra-LABAs in development (lasting > 24 hrs) for once- daily use • Long-acting muscarinic receptor agonist (LAMA), e.g. tiotropium, can be a useful add-on for severe asthma‡. • Bitter taste receptor (TAS2R) agonist can cause bronchodilation†. ‡ N Engl J Med. 2012 Sep 27;367(13):1198-207. Epub 2012 Sep 2. † Am J Physiol Lung Cell Mol Physiol. 2012 Dec 1;303(11):L953-5
  11. 11. Meta-analysis comparing Tiotropium and Placebo - effect on PEF Respir Care. 2013 Oct 29
  12. 12. Tiotropium as an add-on therapy Kerstjens HA et al. N Engl J Med 2012;367:1198-1207. Two replicate RCTs (n=912) recruited patients with poorly controlled asthma already on LABA and ICS. Tiotriopium vs placebo were given with a follow up at 24th week. The addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation.
  13. 13. Bitter Taste Receptor (TAS2R) Agonist Bitter taste receptor agonist can cause bronchodilator via G-protein-phosphatidylinositol phosphate pathway resulting in activation of Ca- dependent K channel and subsequent hyperpolarization of smooth muscle cell.
  14. 14. NEW CORTICOSTEROIDS Designing new corticosteroids to decrease side effects Dissociated steroids Nonsteroidal selective glucocorticoid receptor agonists
  15. 15. New Corticosteroids • ICSs are the most effective anti-inflammatory therapy for asthma. • Currently available ICSs can be absorbed from the lung, leading to potential systemic side effects. • New corticosteroids’ preferred properties • Reduced absorption from the lungs • Inactivated in the circulation • Dissociated steroid (trans-activation vs cis-activation vs trans- repression) • Nonsteroidal selective glucocorticoid receptor agonist (SEGRA)
  16. 16. Transcription Mechanism of Corticosteroid • Most of the anti-inflammatory effects of corticosteroid are due to trans- repression of the pro-inflammatory gene. • Single corticosteroid-GR complex is needed to attach to nuclear factor leading to inhibition of gene expression. • Dimerization of corticosteroid-GR complexes is needed for trans- activation and cis-repression. • Most of the side effects (osteoporosis, HTN, DM) of steroid are from gene trans-activations. Pharmacol Ther. 2002 Oct;96(1):23-43 GRE: glucocorticoid response element
  17. 17. Dissociated Steroid/SEGRA • Dissociated steroid and selective glucocorticoid receptor agonist can bind to glucocorticoid receptor and prevent dimerization. This will prevent trans- activation and cis- repression of metabolic gene products. • However, trans-activation of anti-inflammatory protein will be prevented leading to decreased anti- inflammatory effects. K. De Bosscher et al. Brain, Behavior, and Immunity 24 (2010) 1035–1042
  18. 18. TARGETING ALLERGIC INFLAMMATION Lipid mediators and cytokines modulation
  19. 19. Targeting Lipid Mediators • Problems: More than 100 mediators are involved in the complex inflammatory process in asthma. • The only mediator antagonists available are cysteinyl- Leukotriene CysLT1 receptor antagonists e.g. montelukast. • 5’-lipooxygenase and 5’-lipooxygenase-activating protein inhibitors are in development.
  20. 20. Targeting Lipid Mediators • Prostaglandin D2 is released from mast cells, Th2 cells and dendritic cells. • DP2 receptor (CRTh2)  chemotaxis of Th2 and eosinophil • DP1 receptor  vasodilation, enhancing Th2 polarization • Thromboxane prostanoid receptor  airway smooth muscle constriction • CRTh2 inhibitors: AMG-853 OC000459 and MK-2746 • DP1/DP2 inhibitors: in development • PGD2 synthesis inhibitors: in development
  21. 21. Cytokine Blockade Targets • IL-4 little effects in clinical trials • IL-5 in clinical trial • IL-9 little effects in phase 2 • IL-13 Negative clinical, Preclinical development • IL-17 • IL-25 • IL-33 • Thymic stromal lymphopoietin (TSLP) Preclinical development
  22. 22. Interleukin-4 and Interleukin-13 • Pitrakinra • Mutated IL-4 (recombinant human IL-4 mutein) • Blocking IL-4Rα, the common receptor for IL-4 and IL-13 • Reduces the late response to inhaled allergen in mild asthmatics§ • Clinical studies in severe asthma have been disappointing. • Patients with high eosinophil count and rs8832, rs1029489 GG genotype (compared to AG or GA) have a decrease in asthma exacerbation on pitrakinra.¶ § Lancet. 2007 Oct 20;370(9596):1422-31 ¶ J Allergy Clin Immunol. 2012 Aug;130(2):516-22.e4.
  23. 23. Pitrakinra Lancet. 2007 Oct 20;370(9596):1422-31
  24. 24. Pitrakinra J Allergy Clin Immunol. 2012 Aug;130(2):516-22.e4.
  25. 25. Interleukin-5 • IL-5 is important for eosinophilic inflammation. • Mepolizumab is a blocking antibody to IL-5. • Depletes eosinophil from the circulation and the sputum of asthmatics • No effect on response to inhaled allergen, airway hyperresponsiveness, lung function or exacerbation frequency • Reduces exacerbation in patients with persistent sputum eosinophilia despite high dose ICS but no improvement in lung function.§ • IL-5Rα blocker is currently studied. § PLoS One. 2013;8(3):e59872
  26. 26. Mepolizumab Effects of Mepolizumab on exacerbation rates Effects of Mepolizumab on FEV1 § Efficacy of Anti-Interleukin-5 Therapy with Mepolizumab in Patients with Asthma: A Meta-Analysis of Randomized Placebo-Controlled Trials. PLoS One. 2013;8(3):e59872
  27. 27. Other Interleukins • Anti-TNF-α • No beneficial effect on lung function, symptoms, or exacerbations • Increased reports of pneumonia and cancer • IL-17 • May be a target in severe asthma with neutrophillic inflammation • IL-10 • Broad spectrum of antiinflammatory effects • Efficacy has not been demonstrated in asthma. • IL-12 and Interferons • Not effective and results in unacceptable side effects
  28. 28. NOVELANTIINFLAMMATORY TREATMENTS Phosphodiesterase inhibitors Kinase inhibitors Adhesion molecule blockade PPARγ Agonists
  29. 29. Phosphodiesterase-4 inhibitors • PDE 4 inhibitors have wide spectrum of antiinflammatory effects – inhibiting T cells, eosinophils, mast cells, airway smooth muscle • Reflumilast – inhibitory effect on allergen-induced response similar to low dose ICSs. • Side effects: nausea/vomiting mediated through PDE4D while PDE4B decreases inflammation. • PDE-3 inhibitor can cause bronchodilation.
  30. 30. Roflumilast • Roflumilast can inhibit both the early and late phase response in patients with mild allergic asthma. Respir Res. 2011; 12(1): 140
  31. 31. Kinase inhibitors • Inhibitor of κB kinase (IKK2/IKKβ) inhibits inflammation induced by NF-κB • p38 mitogen-activated protein kinase (MAPK) inhibitor • Phosphoinositide-3 kinase (PI3K)-γ and -δ inhibitor • All are in pre-clinical phase/clinical development.
  32. 32. Other novel antiinflammatory drugs • Adhesion molecule blockade • Adhesion molecules play important role in recruitment of inflammatory cells from the circulation to the airways. • PPAR (peroxisome proliferator-activated receptor)-γ agonist • Wide spectrum of anti-inflammatory effects • Polymorphism of PPARγ gene is linked to increased risk of asthma • Rosiglitazone marginally improves lung function in smoking asthmatics.
  33. 33. Rosiglitazone Clin Pharmacol Ther. 2009 Jul;86(1):49-53 Rosiglitazone 8 mg/day helps improve FEV1 and FEF in smokers with asthma.
  34. 34. ANTI-ALLERGY TREATMENTS Anti-IgE therapy Mast cell inhibitors Syk Kinase inhibitors
  35. 35. Anti-IgE therapy • Omalizumab, monoclonal antibody that blocks IgE, is now used in treatment of selected patients with severe asthma. • More potent anti-IgE antibodies are in development. • Low-affinity IgE receptor (FcεRII or CD23) antagonist seems to be well tolerated and reduces IgE concentrations in patient with mild asthma in a phase I study.§ § J Allergy Clin Immunol. 2003 Sep;112(3):563-70.
  36. 36. Mast cell Inhibitors • Mast cell stabilizers • Cromones (Sodium cromoglycate, nedocromil sodium) • Furosemide • Short-acting, not effective as long-term controllers • Stem cell factor (SCF) • Key regulator of mast cell survival • Acts via c-Kit, effective in animal model • c-Kit antagonist (masitinib) • A potent tyrosine kinase inhibitor that block c-Kit and PDGFR • Reduction in steroid use and symptoms in patients with severe steroid-dependent asthma¶ ¶ Allergy. 2009 Aug;64(8):1194-201
  37. 37. Signaling pathway for mast-cell activation Nature Reviews Immunology 6, 218-230 (March 2006)
  38. 38. Masitinib • A c-kit/PDGF receptor tyrosine kinase inhibitor is shown to reduce symptoms (ACQ = asthma control questionnaire). ¶ Allergy. 2009 Aug;64(8):1194-201
  39. 39. Syk kinase Inhibitors • Spleen tyrosine kinase is involved in activation of mast cells and other immune cells. • Still in pre-clinical studies for asthma
  40. 40. IMPROVED IMMUNOTHERAPY Specific Immunotherapy Targeting Treg Targeting Dendritic Cells
  41. 41. Specific Immunotherapy • Sublingual immunotherapy • Well tolerated • Effective in reducing symptoms and medication use for allergic asthma§ • Need long-term study and comparison with ICS § Clin Respir J. 2013 Oct 4 Epub ahead of print
  42. 42. Specific immunotherapy • Injection Allergen Immunotherapy • Cochrane Database 2010 has included 88 trials§ • Significant reduction in asthma symptoms and medication • Improvement in bronchial hyperreactivity • NNT = 3 to avoid one deterioration in asthma symptoms • NNT = 4 to avoid one requiring increased medication • The effect size is comparable to ICS. • Local and systemic reactions are common. • Limitation: significant heterogeneity § Cochrane Database Syst Rev. 2010 Aug 4;(8):CD001186
  43. 43. Targeting Tregs • Specific immunotherapy increases Treg numbers and their expression of IL-10  suppressed Th2 responses  decrease IgE synthesis
  44. 44. Clin Exp Allergy. 2011 Sep;41(9):1235-46
  45. 45. Targeting Tregs • Tregs from patients with corticosteroid resistant produce less IL-10. • This can be restored in vitro and in vivo by vitamin D3. J Clin Invest. 2006 Jan;116(1):146-55
  46. 46. Vitamin D as an adjunct to IT Allergy. 2013 Nov 4 Epub ahead of print
  47. 47. Targeting Dendritic Cells • Several classes of drug have been shown to suppress myeloid dendritic cell activation • Prostacyclin (PGI2) e.g. iloprost • Sphingosine-1-phosphate and analogues (fingolimod) • In preclinical development
  48. 48. Bronchial thermoplasty • Controlled thermal energy to airway wall • Aim to reduce hyperresponsiveness and smooth muscle mass • Found to be effective in long-term (5-year) and relatively safe in severe persistent asthma¶ ¶ J Allergy Clin Immunol. 2013 Aug 30.
  49. 49. Bronchial thermoplasty J Allergy Clin Immunol. 2013 Aug 30.