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Newer drugs in Asthma and COPD
- 1. NEW DRUGS IN COPD AND ASTHMA DR. DURGESH HIREKAR
- 2. Contents Newer Drugs for COPD Introduction Traditional management Bronchodilators Anti inflammatory drugs Miscellaneous drugs Smoking cessation Newer drugs in Asthma Introduction Pathophysiology Current management New bronchodilators Corticosteroids Biologicals Other drugs
- 3. NEW DRUGS FOR COPD
- 4. Introduction COPD is a common, treatable and preventable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases. COPD has a global prevalence of 11.7% causing 3 million deaths annually This may increase to 4.5 million deaths per year by 2030, due to increased smoking in developing countries and increased aging population in developed countries Few therapeutic advances in COPD management than asthma Cellular/molecular mechanism understanding increased: Drugs being developed against logical targets
- 5. Traditional Management of COPD
- 8. NEW BRONCHODILATORS New LABA monotherapy New LAMA monotherapy New LABA/LAMA combinations New LABA/ICS combinations Triple combination therapy The MABA approach
- 9. New LAMAs Ach produces inflammation, bronchoconstriction, mucus hypersecretion Aclidinium Glycopyrronium Umeclidinium Greater reduction in exacerbation rate than LABAs Under development: • Darotropium • TD-4208 • CHF5407 • QAT-370 • GSK-573719 • Dexpirronium • RBx343E48F0
- 10. New LABAs
- 11. Indacaterol: better than salmeterol, Formoterol, tiotropium, without tachyphylaxis Vilanterol: safe and effective in both asthma and COPD Olodaterol Abediterol Carmoterol Milveterol: found to be safe in asthma LAS100977 PF610355 JNJ39758979 Saligenin- or indole containing β2- agonists, UK-503590 Compound X
- 12. New LABA LAMA combination therapy LABA/LAMA combination in COPD: a meta-analysis on the duration of treatment Luigino Calzetta, Paola Rogliani, Josuel Ora, Ermanno Puxeddu, Mario Cazzola, Maria Gabriella Matera European Respiratory Review 2017
- 13. LABA/LAMA combination in COPD: a meta-analysis on the duration of treatment Luigino Calzetta, Paola Rogliani, Josuel Ora, Ermanno Puxeddu, Mario Cazzola, Maria Gabriella Matera European Respiratory Review 2017
- 14. Indacaterol/Glycopyrronium Dose: 110 mcg indacaterol, 50 mcg glycopyrronium FLAME: Shown to better at decreasing exacerbations than twice daily salmeterol fluticasone with Lesser adverse effects Most common side effects: nasopharyngitis, hypertension, back pain, oropharyngeal pain
- 15. Umeclidinium and Vilanterol Glycopyrronium and Indacaterol Tiotropium and Olodaterol Aclidinium and Formoterol Glycopyrronium and Formoterol Darotropium and Milveterol/vilanterol Tiotropium and carmoterol Formoterol and Dexpirronium
- 16. New LABA ICS combination therapy
- 17. Increases risk of pneumonia Little role for ICS Maybe useful in ACOS Prominent eosinophilic bronchial inflammation (blood eosinophilia >300 cells/μL) Moderate to very severe COPD and exacerbations Vilanterol and Fluticasone Indacaterol and Mometasone Formoterol and Ciclesonide Formoterol and Fluticasone
- 18. Triple combination therapy Triple therapy versus single and dual long-acting bronchodilator therapy in COPD: a systematic review and meta-analysis Mario Cazzola, Paola Rogliani, Luigi no Calzetta, Maria Gabriella Matera European Respiratory Journal 2018
- 19. India developed the first triple combination: tiotropium, ciclesonide, Formoterol Trelegy Ellipta: US FDA approved Combinations under development Aclidinium, Formoterol, fluticasone/budesonide Tiotropium, Formoterol, fluticasone/budesonide Glycopyrronium, Formoterol, mometasone
- 20. The MABA Approach MABA: Bifunctional (dual pharmacophore) muscarinic anatgonist-Beta 2 agonist agents Disadvantage: inability to adjust the activities as needed, thus limiting dose flexibility GSK961081 (Batafenterol): first one to undergo trial Other drugs under development are: Bicyclohept 7-ylamine derivatives. THRX-200495 THRX-198321 LAS190792 TD-5959
- 23. Theophylline • Low dose (plasma conc of 5-10 mg/dL) markedly potentiates steroid action • Presently not recommended for long term bronchodilation unless other drugs are unavailable
- 25. Roflumilast is indicated when FEV1 <50% predicted and pt has chronic bronchitis phenotype or pt is on triple therapy and is having further exacerbations It decreases exacerbations that require systemic steroids
- 26. Intolerable GI side effects with present PDE4 inhibitors, prompting development of specific PDE4B inhibitors RPL554 (dual PDE3 and PDE4 inhibitors, Phase II) CHF6001 (PDE4 inhibitor) GSK256066 (PDE4B specific inhibitor)
- 27. CXCR2 antagonists CXCR2: receptor on PMN/monocytes for chemotactic agents Anatgonism: decreased chemotaxis, inflammation Danirixin: 75 mg BD, Decreased symptoms and risk of exacerbations in mild- moderate COPD New drugs ADZ8309 MK-7123 SCH 527123 and GSK656933
- 28. TGF-Beta inhibitors Small airway fibrosis= FEV1 decline, reduced exercise capacity SD-280 inhibits TGF receptor tyrosine kinase
- 29. PPAR Activators PPAR α/γ agonism: anti inflammatory, immunomodulatory effects Inhibition of TGF beta Rosiglitazone 8mg/d improves FEV1 and FEF in asthmatic smokers
- 30. Broad spectrum anti inflammatory drugs Immunomodulators: cyclosporin, tacrolimus, rapamycin NF-kB inhibitors: IKK2 inhibition by small molecule inhibitors is promising Can cause immunosuppression, mouse models have succumbed to sepsis p38 MAP kinase inhibitors: SB23093: showed anti inflammatory in rat models SB203580 PI-3 γ/δ kinase inhibitors Important for neutrophil migration and activation Wortmannin, LY294002, IC7114
- 31. Adhesion molecule blockers Bimosiomose: mimics Sialyl Lewis X, inhibits neutrophil recruitment Concern over increased susceptibility of infection Potential target: Mac-1, increased expression in COPD JAK STAT inhibitors Cytokines signal through JAK STAT pathway or are produced by it Novel target for COPD therapy Tofacitinib
- 32. Other anti inflammatory agents Macrolides Azithromycin decreases nasopharyngeal colonization, improved QOL. Screen patients before starting. Considered for former smokers Solithromycin: better anti inflammatory than other macrolides Moxifloxacin Prolongs time to next exacerbation. More complete pathogen eradication than other FQ N-Acetyl Cysteine Anti oxidant, reduces bronchial hypersecretion. Slows FEV1 decline, reduces number of exacerbations Others: carbocysteine, erdosteine
- 33. Simvastatin Anti inflammatory action. No evidence of reduction of exacerbations Some positive effect in pts receiving it for cardiovascular indications Anticytokine therapy: TNF alpha, IL-1b, IL-6 (Tocilizumab), IL-8/CXCL8, IL-17, IL-13 Antiproteases Sivelastat: HNE selective inhibitor Silanediol isosters: uncompetitive inhibitors of HNE MMP-9, 12 inhibitors: AZD1236 Broad spectrum MMP Inhibitors: Ilomastat, Marimastat
- 34. Miscellaneous drugs for COPD Mucoregulators EGFR pathway inhibitors: Geftinib, potential target, as of now not effective in COPD CACC inhibitors: niflumic acid, MSI1956 Tachykinin receptor antagonists Potassium channel openers: Senicapoc Drugs to slow aging: Sirtuin 1 activators Drugs to combat cachexia and muscle wasting: GHRH analogue tesamorelin along with exercise training
- 35. Lung regeneration therapy Retinoids (palovarotene) Mesenchymal stem cell therapy: alveolar cell regeneration GHK tripeptide (glycine-histidine-lysine) Respiratory stimulants Decrease chronic hypoxemia especially nocturnal hypoxemia, especially as an adjunct to LTOT and NIV Acetazolamide Medroxy progesterone acetate Almitrine Doxapram
- 36. Advances in Smoking Cessation Nicotine replacement therapy Drugs Nicotine vaccines
- 37. Nicotine replacement therapy Nicotine causes addiction NRT achieves lower blood levels slowly Formulations: transdermal patches, acute dosing products including gums, lozenges, sunlingual tablets, oral inhalers, nasal sprays (ARD-1600) Nicotinic Ach in ventral tegmental area DA release in Nucleus accumbens Decrease in nicotine withdrawal symptoms in smokers
- 38. Nicotine vaccines Forming Ab: IC cannot cross BBB Nicotine becomes a foreign antigen Diasdvantage: pt may compensate, insufficient Ab titers No evidence presently to support use Under development Nicotine-Qbeta NicVAX
- 39. Other approaches to smoking cessation Nicotine partial agonist: Cytisine Cannabanoid receptor 1 antagonist: taranabant Dopamine D3 receptor antagonists : GSK598809 MAO inhibitors: Selegiline Varenicline, Bupropion
- 40. New drugs for asthma
- 41. Introduction Asthma is a heterogenous disease, characterized by chronic airway inflammation, with a history of respiratory symptoms such as wheeze, SOB, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation. Uncontrolled asthma in 5-10% patients despite effective inhaled therapy Need for Newer drugs with similar MOA with less s/e Drugs for severe acute asthma Curative therapy for mild to moderate asthma Drugs to modify course of disease
- 42. Pathophysiology
- 46. Three immunopathological phenotypes Eosinophilic: respond to steroids well Neutrophilic: Th17 predominance, aggressive course, poor responders Paucigranulocytic: poor response to ICS Viral infections: mcc of AE, induce IL-8, CCL-5, added inflammation
- 47. Newer bronchodilators for Asthma LABAs LAMAs Bitter Taste receptor (TAS2R) agonists: Denatonium and chloroquine Magnesium sulfate Reduces intracellular Calcium Add on drug in severe acute asthma Activation of G protein Phosphatidyl inositol pathway Activation of Calcium dependent K channels Hyperpolarization of smooth muscle Smooth muscle relaxation, bronchodilation
- 48. CCBs Reduce stimulus induced bronchoconstriction, doesn’t affect basal caliber Less effective than SABA ANP analogues Activates guanylyl cyclase Add on in severe acute asthma VIP analogues Binds to GPCR, stimulates adenyl cyclase Rapid metabolism and vasodilator s/e RO125-1533: VPAC2 selective
- 49. Corticosteroids: Limitations and Resistance Systemic absorption from lungs producing s/e Cytoplasmic receptors: GR alpha and beta. GR beta implicated in steroid resistance Reduction in glucorticoid receptor affinity: by persistent increased levels of IL-2 & 4 Reduction in numbers of GR Severe asthma Oxidative stress inhibition of HDAC P38 MAP kinase activation Disruption of coupling of GR activation with transcription factor inhibition
- 51. Dissociated steroids/SEGRAs Mapracorat: atopic dermatitis, post cataract surgery Dagrocorat Fosdagrocorat
- 52. Soft steroids Improved local/topical selectivity, less effect outside the target area Loteprednol: approved for ophthalmic use Lactone GCS Not metabolized by lung esterases, but rapid metabolism by plasma paraoxonase Butixocort/Tipredane Rofleponide
- 53. Lipid mediator antagonists Presently available: CysLT1 receptor antagonist 5’ LOX and 5’ LOX activating protein antagonists: Zileuton Prostaglandin D2 DP2 receptor (CRTh2): chemotactic. Antagonists include: AMG-853 OC000459, MK-2746 DP1 receptor: Th2 polarization and vasodilation PGD2 synthesis inhibitors: potential for use in asthma
- 55. Proposed benefits of Biologicals It targets the 5-10% patients having severe asthma that put the disproportionately high economic burden on the healthcare system Prevents inflammation rather than reducing or treating it Reduces the long term use of systemic steroids and their myriad side effects
- 56. Potential issues with use of Biologicals Ab formation against the drug itself Cannot be used in pregnancy or lactation Not studied adequately in >65 years Unknown risk of cancer Long term effects are unknown Effect of hepatic/renal impairment on pharamacokinetics are unknown Expensive
- 58. Add-on omalizumab in children with severe allergic asthma: a 1 year real life survey Antoine Deschildre, Christophe Marguet, Julia Salleron, Isabelle Pin, Jean-Luc Rittié, Jocelyne Derelle, Rola Abou Taam, Mickael Fayon, Jacques Brouard, Jean Christophe Dubus, Daniel Siret, Laurence Weiss, Guillaume Pouessel, Laurent Beghin, Jocelyne Just European Respiratory Journal 2013
- 59. Indication: Moderate to severe asthma, >6y, positive skin test or in vitro reactivity to perennial aeroallergen, uncontrolled with ICS Duration No specific guidelines Symptoms, IgE go back to baseline in 18-20 weeks Retrospective study: benefits sustained till 6 m in 50% pts Adverse effects Injection site reactions can occur in upto 45% pts Nasopharyngitis, sinusitis Headache Anaphylaxis in 0.14% Malignancy in 0.5% Transient ischemic attacks, ischemic stroke
- 60. IL-4 and IL-13
- 61. Lebrikizumab IgG4 humanized mab against IL-13 Improves lung function in poorly controlled asthma Higher pretreatment levels of periostin: identify responders
- 62. Tralokinumab IgG4 MAB against IL-13 Improves FEV1 and reduce SABA use Sustained elevation in FEV1 for 12 weeks after cessation
- 63. Pitrakinra Competitive inhibitor of IL4Rα (common receptor) Attenuates late asthmatic response SNP in 3’ UTR of IL4Rα: better response
- 64. Dupilumab Inhibitor of IL4Rα Decreases exacerbations Marked improvement in FEV1, ACQ Reduces Th2 associated biomarkers: FeNO, eotaxin-3, TARC
- 65. IL-5
- 66. Mepolizumab (Nucala) Humanized mab against IL-5, reduces no. of eosinophils in both blood and sputum Steroid sparing effect 100 mg SC dose q4w with much lesser injection site reactions than Omalizumab Cessation: pretreatment levels in 3-6 months No improvement in traditional markers FDA approved for maintenance therapy in >12y Severe headache may occur in 20%
- 67. Reslizumab (Cinqair) Anti IL-5 antibody Used as 3 mg/kg infusion over 20-50 minutes Approved for >18y with severe uncontrolled asthma and baseline eosinophils >400 Most expensive option
- 68. Benralizumab (Fasenra) Humanized afucosylated MAB against IL5Rα Enhances Ab dependent Cell mediated toxicity towards target cells Dose is 30 mg q4w for first 3 doses, then q8w Reduces eosinophilia, exacerbation rates Improves FEV1 and QOL Mc s/e: headache and pharyngitis
- 69. IL-17
- 70. Secukinumab and Brodalumab Secukinumab targets IL-17A is in phase 2 trials for asthma but results are not yet available Brodalumab target IL-17 RA showed change in bronchodilaor reversibillity but no difference in ACQ
- 71. Mast cell inhibitors Mast cell stabilizers Cromones Ketotifen Masitinib: TKI, reduces steroid use in steroid dependent asthma Syk inhibitors R788/fostamatinib R343 (inhalational)
- 72. Future therapeutic options CDK inhibitors: induce inflammatory cell apoptosis R roscovitine induces eosinophil apoptosis Non CDK target inhibition = s/e ATF3: down regulated in severe asthma, repressed by corticosteroids Agonists may be useful in severe steroid resistant asthma MicroRNA inhibition: reduced AHR and airway eosinophilia in mouse models
- 73. Conclusion There is need for newer drugs in both Asthma and COPD for different reasons. With better understanding of the pathogenesis of COPD and asthma at the molecular level, new therapeutic targets have come up. New ultra long acting bronchodilators including MABAs have shown promise in management of COPD SEGRAs and Biological therapy in asthma have overcome many of the limitations of existent therapy options But still a standard non invasive biomarker is yet to be discovered in COPD
- 74. References GOLD 2019 and GINA 2019 guidelines New approaches to COPD P.J. Barnes Eur Respir Rev 2005; 14: 94, 2–11 New treatments for COPD P J Barnes Thorax 2003;58:803–808 Nicotine Replacement Therapy: An Overview Umesh Wadgave, Nagesh L, International Journal of Health Sciences, Qassim University, Vol. 10, No. 3 Theophylline New Perspectives for an Old Drug Peter J. Barnes Chronic respiratory failure in COPD: is there a place for a respiratory stimulant? Thorax 1993;48:781-784 Comparison of acetazolamide and medroxyprogesterone as respiratory stimulants in hypercapnic patients with COPD. Wagenaar M1, Vos P, Heijdra Y, Teppema L, Folgering H. Chest. 2003 May;123(5):1450-9 Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy Lancet. 2015 Mar 7;385(9971):857-66 Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo Stephen J. Galli, ... Gunnar Pejler, in Advances in Immunology, 2015
- 75. BIOLOGIC THERAPY IN THE MANAGEMENT OF ASTHMA Jennifer McCracken, MD*,1, Julia Tripple, MD*,1, and William J Calhoun, MD2 Curr Opin Allergy Clin Immunol. 2016 August ; 16(4): 375–382 Getting Syk: Spleen Tyrosine Kinase as a Therapeutic Target Robert L. Geahlen Trends Pharmacol Sci. 2014 Aug [Anti-inflammatory effects of cromones in asthma]. Braunstein GL Allerg Immunol (Paris). 1995 Feb; Emerging anti-inflammatory strategies for COPD Mario Cazzola, Clive P. Page, Luigino Calzetta, M. Gabriella Matera. European Respiratory Journal 2012 40 The effect of peroxisome proliferator-activated receptor-γ ligands on in vitro and in vivomodels of COPD. Simon Lea, Jonathan Plumb, Hannah Metcalfe, Dianne Spicer, Paul Woodman, J. Craig Fox, Dave Singh European Respiratory Journal 2014 43: 409-420 The nature of the GRE influences the screening for GR-activity enhancing modulators Karen Dendoncker, Steven Timmermans, Kelly Van Looveren LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis Rodrigo GJ, Price D, Anzueto A, Singh D Dove press The Role of Eosinophils in the Pathogenesis of Asthma ProjMed Cytokine modulators as novel therapies for airway disease P.J. Barnes European Respiratory Journal 2001
- 76. THANK YOU Next seminar on Wednesday, 13 March 2019 Lungs in Pregnancy, by Dr. Divya
Editor's Notes
- I will be discussing on the topic in two main parts, newer drugs for COPD and newer drugs for asthma
- GOLD 2019 guidelines define COPD as ….
- This is the initial management protocol according to the ABCD group classification. Group A patients have mMRC grade 0-1 and 0-1 moderate exacerbations per year not leading to admisstion. They should be managed with A short or long acting bronchodilator.
- If the patient does not respond to the intital treatment, most predominant trait should be considered and these pathways should be followed . *To be considered if eosinophilia >300 **de escalation from steroid should be done, if pneumonia occurs, or inappropriate original indication, no response ot ICS
- There is an apparent contradiction between the “poorly reversible” label of the disease in the definition and the indication as “first-line therapy” of drugs whose major action is the reversibility of airflow obstruction through bronchial smooth muscle relaxation. But in fact significant reversibility of the airflow limitation can be detected in about half of patients with moderate-to-severe COPD. In the more recent international documents the expression “poorly reversible” has been replaced by “not completely reversible” and the definition has been reviewed such that now COPD is described as a “treatable and preventable” disease.
- Bronchodilators alter smooth muscle tone and improve expiratory flow. They reduce dynamic hyperinflation at rest and during exercise
- Acetylcholine: binds to M3 muscarinic rec and modulates inflammation, causes smooth muscle contraction, mucus hypersecretion and vasodilation. Muscarinic antagonists can antoagonize all these changes and help in the management of asthma. Aclidinium: Twice daily LAMA with peak plasma time of 10-15 min and half life of 5-8 hrs. Has been shown to reduce frequency of moderate to severe exacerbations and produces marginal improvement in quality of life Glycopyrronium: Once daily LAMA with a peak plasma time of 5 min and elimination half life of 33-53 hrs. It significantly improves lung function and reduces incidence of moderate to severe exacerbations, but did not improve quality of life. It has been shown not to be better than tiotropium in improving FEV1, SOB, exacerbation rates. Umeclidinium: Another once daily LAMA, that causes more FEV1 improvement than tiotropium. No difference compared to tiotropium in SOB, SGRQ, CAT scores The most common side effect is dry mouth, otherwise LAMA appear to be safe over a wide range of doses and clinical settings.
- Beta 2 adrenergic receptor is a GPCR which when stimulated, activates adenyl cyclase, increasing production of cAMP and ultimately producing muscle relaxation All of the drugs that I am about ot mention are ultra LABAs, that is they have a very long duration of action atleast around 24 hours. This is because SABA require multiple doses in a day and this has led to decreased compliance among patients.
- Adverse effects include resting sinus tachycardia, and dysrhythmias in susceptible patients. Metabolic side effects like hypokalemia and increased O2 consumption in CHF decrease over time.
- This is a forest plot of a meta analysis published in europenea respiratory review. We can observe three facts from this. First FDC of LABA/LAMA produce significant improvement in St George respiratory questionnaire and Transition Dyspnea index and FEV1 when compared to monotherapy. Second, This superiority is greatest at 3 months but diminishes at 6-12 months. Third, LAMA LABA combination is more superior to LABA than it is to LAMA, in fact LAMA monotherapy may be better than the combination especially at 12 months.
- Indacaterol and glycopyrronium is a combination that we are using presently at our hospital
- The basis for LAMA LABA synergism: LABAs act on orthosteric and allosteric sites on the β2-adrenergic receptors. In contrast, LAMAs act not only on orthosteric site on the muscarinic receptors, but also allosteric site on the β2-adrenergic receptors, leading to enhancing β2-adrenergic action. Allosteric GPCR modulation is involved in the synergistic effects between LABAs and LAMAs. Various new combinations of LABA and LAMA include:
- This is a meta analysis of two studies comparing LAMA LABA combination with LABA ICS combination in preventing A) moderate and/or severe exacerbation. And in B) severe exacerbations. Both of them favor the use of LABA LAMA combinations
- ICS especially fluticasone increases the risk of pneumonia But overall, LAMA LABA combination and even LAMA alone shows much less side effects than LABA ICS combination Thus there is Little role of ICS in COPD Maybe useful in ACOS to treat the asthma part of the overlap syndrome
- Triple combination therapy with ICS, LAMA and LABA performs better than dual therapy in reducing exacernation rate and improving FEV1, especially in pts with blood eosinophils >300/microL This graph on the left here shows that as eosinophils increases in the blood, the risk of exacerbations increases, and triple combination therapy might be helpful
- India is leading the competition by developing a triple combination inhaler with tiotropium, ciclesonide, formoterol which came to market way back in 2014 Trelegy ellipta is another combination approved by US FDA in September 2018 which is a combination of fluticasone, umeclidinium and vilanterol marketed in a diskus inhaler
- The LABA LAMA approach is associated with delivery of LABA and LAMA at different locations in the lung which reduces their synergistic potential * Combining these drug actions in a single dimer molecule that has both functions, helps in delivering a fixed ratio of the drugs to every region of the lung reducing complexity of combination inhalers, a single pharmacokinetic profile, a uniform ratio of activities at the cellular level and a simplified clinical development programme * GSK961081 (Batafenterol), by Glaxo Smith Kline, is the first such drug that is under trial. It’s been shown to induce sustained bronchodilation similar to salmeterol plus tiotropium, but with more rapid onset of action
- COPD is a chronic inflammatory disease affecting the airways. So treatment for COPD should target inflammation. Steroids are the standard anti inflammatory agents, but they do not work in COPD for certain reasons which I will discuss in the subsequent slides. So many non steroidal anti inflammatory agents have come up.
- Inflammation lies at the heart of pathogenesis of COPD, and thus targeting inflammation at various levels constitute potential treatment for COPD. Smoking induces inflammation by involving chemotactic factors. Recruited neutrophils cause tissue damage by producing protease, and for that we can use protease inhibitors including neutrophil elastase and MMP. Mucus hypersecretion can be countered by mucoregulators and EGFR and CACC inhibitors. The fibrosis pathway can be specifically targeted using TGF beta inhibitors. More broad spectrum anti inflammatory drugs like PDE4….. Can be also used.
- Normally acetylation of histones is a/w unwinding of DNA and increased transcription of inflammatory mediators. Histone deacetylase counters this * Apart from all the different actions of theophylline, increase in Histone deacetylase activity is a recent finding. Corticosteroids recruit HDAC to transcription complex of inflammatory genes, reversing the acetylation induced by Nf-kB. and theophylline activates HDAC, effectively decreasing their trasnscription. So low dose theophylline (plasma conc of 5-10 mg/dL) markedly potentiates anti inflammatory action of corticosteroids. * The oxidative stress in COPD reduces HDAC activity, accounting for decreased response to steroid in COPD patients. Theophylline, in effect, may unlock the resistance to steroids in COPD patients.
- PDE4 inhibitors reduce inflammation by inhibiting the breakdown of intracellular cAMP. PDE3 is responsible for bronchoconstriction.
- Roflumilast is a oral PDE4 inhibitor Adverse effects include: diarrhea, nausea, LOA and LOW, abdominal pain, sleep disturbances and headache. It should be used with caution in underweight patients and depression
- Present PDE4 inhibitors like roflumilast have intolerable GI side effects, prompting development of specific PDE4B and PDE7 inhibitors. GI side effects are mediated by PDE4D, while anti inflammatory action is mediated by PDE4B, so it makes sense to use PDE4B specific inhibitors PDE3 inhibition can lead to bronchodilation. RPL554 (dual PDE3 and PDE4 inhibitors, Verona pharma, Phase II): being studied as add on to LAMA/LABA therapy and has so far shown favourable outcomes. CHF6001 (PDE4 inhibitor): better efficacy than roflumilast, cilomilast GSK256066 is a PDE4B specific inhibitor that decreases LPS induced TNF alpha production by monocytes, and is under investigation as Rx for COPD
- Chemotactic effects of chemokines CXCL8, CXCL1, CXCL5 on neutrophils and monocytes are mediated by a common receptor: CXCR2 New drugs include ADZ8309 an oral CXCR1/2 antagonist has been shown to reduce neutrophil inflammation MK-7123 has improved FEV1 in one trial SCH 527123 and GSK656933 have completed phase 1 trials
- Small airway fibrosis is a major cause of progressive FEV1 decline and reduced exercise capacity in COPD, and TGF beta is the main culprit SD-280 inhibits TGF receptor tyrosine kinase
- Peroxisome proliferator-activated receptors alpha and gamma activation may have anti inflammatory and immunomodulatory effects PPAR gamma agonists also inhibit TGF beta, thus help preventing fibrosis The graph on the left shows that they inhibit cytokine release in response to LPS. Especially TNF alpha and CCL5 but not so much with CXCL8. We can also see COPD patients produce more cytokines in response to LPS than smokers without COPD and never smokers Troglitazone and Rosiglitazone (approved for use in DM2): inhibit cytokines release and induce T cell apoptosis. Trials are underway for use in COPD
- NF kB is a transcription regulator responsible for expression of IL-8 and other chemokines, TNF alpha and some MMPs. IKK-2 inhibition seems to be most promising. IKK2 is a NF-kB kinase inhibitor. P38 MAP kinase pathway is activated by cellular stress and regulates expression of inflammatory cytokines. SB23093 reduces neutrophil infiltration and BAL IL-6 and MMP-9 levels in rats after inhaled endotoxin. This potentially have some toxic effects, it is better to develop inhalational route for this drug. PI 3K gamma is an enzyme that leads to generation of lipid second messengers like leukotrienes and ultimately neutrophil migration and activation. Knock out mice show decreased neutrophil as well as macrophage and T cell mediated inflammation
- Adhesion molecule inhibitors * Recruitment of inflammatory cells is mediated by adhesion molecules on these cells and on the respiratory epithelium, for example E selectin on endothelium interacts Sialyl Lewis X on neutrophils. Bimosiomose, mimics Sialyl Lewis X and inhibits adhesion and recruitment of neutrophils. * concerns about this therapeutic approach for a chronic disease, as an impaired neutrophilic response may increase the susceptibility to infection * The expression of macrophage associated antigen-1 (Mac-1) (CD11b/CD18) is increased on neutrophils, monocytes and macrophages of patients with COPD, suggesting that targeting this adhesion molecule, might be beneficial
- Azithromycin: 250 mg daily dose of azithromycin leads to decreased rate of nasopharyngeal colonisation and improved quality of life; but may lead to increased colonisation with macrolide resistant organisms. Patients should be screened for hearing loss, resting tachycardia, risk of QTc prolongation before initiating Azithromycin Moxifloxacin: A respiratory flouroquinolone that can also prolong the time to next exacerbation, better than other FQ This is due to immunomodulatory action, more complete eradication of pathogens, preventing epithelial damage and restores local defence mechanisms and a longer time for bacteria to increase in sufficient numbers to induce a new exacerbation NAC: Most widely used and tested anti oxidant and mucolytic, reduces bronchial hypersecretion. Even at high doses it has a favourable risk-benefit ratio Recent studies have shown it can slow FEV1 decline and reduce no. Of exacerbations in especially chronic bronchitis and frequent exacerbator phenotype
- Simvastatin: Have anti inflammatory effects in addition to lipid lowering actions. Some retrospective studies have shown benefit in COPD exacerbation prevention. A recent prospective multicenter trial has not confirmed this Some of anti cytokine therapies will be discussed under biologicals in asthma Antiproteases: HNE plays an important role in pathogenesis of ARDS. Sivelestat reduces ICU stay significantly in patients with ARDS silanediol isosters (Uncompetitive inhibitor of HNE) (Uncompetitive inhibition, also known as anti-competitive inhibition, takes place when an enzyme inhibitor binds only to the complex formed between the enzyme and the substrate (the E-S complex). AZD 9688, being studied for use in AAT patients MMP-9 and 12 inhibitors: AZD1236 Broad spectrum MMP inhibitors ike ilomastat, marimastat
- Mucus hypersecretion is a/w frequent exacerbations and accelerated FEV1 decline. It is driven by neutrophilic inflammation. EGF is responsible for goblet cell hyperplasia and mucus secretory response: geftinib. Presently effective only in lung cancer, further studies required for efficacy in COPD Calcium activation chloride channels are also important for mucus secretion. Muscle wasting is one of the systemic manifestation of COPD, and is associated with decreased exercise tolerance, quality of life and even survival in COPD patients.
- Retinoids (palovarotene) Mesenchymal stem cell therapy: can help regenerate alveolar cells by themselves or by stimulating the secretion of growth hormones, especially VEGF. But they can lodge in pulmonary blood vessels and lead to a potentially fatal outcome GHK tripeptide (glycine-histidine-lysine): a natural peptide involved in wound healing. In expiremental studies it has been shown to partially reverse emphysema related phenotypes in fibroblasts of COPD patients
- As we all know, Smoking cessation is the only intervention that can attenuate the progression of FEV1 decline in COPD. Nicotine replacement therapy can double the rate of smoking cessation in those who are attempting it. Other novel approaches in smoking cessation include: electronic cigarettes
- Tobacco containing products contains nicotine that is mainly responsible for addiction behaviour, while other components are responsible for the toxicity of tobacco smoking Pharmacological interventions for smoking cessation thus target nicotine addiction primarily * NRT acheives lower blood levels over minutes to hours in the brain, rather than seconds-minutes as with cigarette smoke. This reduces the nicotine withdrawal symptoms and thus the craving. Various forms include transdermal patches, acute dosing products like gum, lozenge, sublingual tablet, oral inhaler, nasal sprays.
- * Nicotine is an incomplete antigen, it is linked to a carrier protein in order to stimulate the immune system so as to identify nicotine as foreign and to mount an immune response to it. * When the patient smokes the nicotine forms an antigen-antibody complex that cannot cross the blood brain barrier and cannot stimulate nicotine receptors in the brain, making smoking non enjoyable * Disadvantage with this is that, the patient may compensate by increasing tobacco consumption to overcome this effect. Also the vaccine may not lead to sufficiently high antibody titers * Presently there is no evidence to support nicotine vaccine for long term smoking cessation * Nicotine-Qbeta or CYT002-NicQB, NicVAX are the vaccines under development
- The present problem in asthma management is….uncontrolled asthma is seen in 5-10% patients despite maximal tolerated inhaler therapy
- When there is inhalational exposure to an allergen in a susceptible individual, it will be processed by APCS and presented to Naive T cells that then differentiate into Th2 lymphocyte under the influence of IL-4. Th2 cells produce IL-4,5,13 and eotaxin and recruit eosinophils and stimulate B cells to produce allergen specific IgE IgE will bind to mast cells. When there is reexposure to the same allergen, Mast cell bound IgE can bind to it resulting in degranulation and release of chemical mediators resulting in bronchoconstriction etc.
- Various mediators released are responsible for recruitment of eosinophils.
- There are different categories of asthma medications as proposed by GINA Controller medications are for regular maintenance, they decrease inflammation, symptoms, risk of exacerbations and further FEV1 decline Relievers are used as and when needed for the management of break through symptoms and for exercise induced bronchospasm Add on therapies for pts with severe asthma are used when pts have persistent symptoms despite optimized Rx with high dose controller medications
- It is better to start a controller medication as soon as asthma is diagnosed (ie a low dose ICS even for Step 1) because this leads to
- Three immunopathological phenotypes exist based on the composition of cellular infiltrates: • eosinophilic: pts tend to be atopic, triggered by allergens, respond well to corticosteroids • neutrophilic: There is predominance of Th17 cells with high levels of IL-17. pts tend to have more severe, aggressive, poorly controlled asthma. They dont respond to corticosteroids as well as eosinophilic • paucigranulocytic: have low number of neutrophils and eosinophils in bronchi. These pts also do not respond to ICS • Viral infections are mcc of AE in children and adults, inducing airway epithelial cells to secrete IL-8 and CCL-5, causing cell recruitment and adding on to the already existing allergic inflammation
- Bitter tase receptors (TAS2R) are present on airway smooth muscles. Agonism also leads to inhibition of mitogen induced smooth muscle cell proliferation. Magnesium sulfate • Reduces intracellular Ca in SMC causing relaxation and bronchodilation • Given IV or nebs • Add on drug in severe acute asthma, not used alone • Cheap and well tolerated
- CCB: Nifedipine, verapamil. Reduce Ca entry into SMC, decrease stimulus induced bronchoconstricition, but no effect on basal airway calibre. Less effective than SABA ANP: Activates guanylyl cyclase, increases cGMP, SMC relaxation. Comparable to SABA. Add on in severe acute asthma VIP analogues: VIP binds to its receptors VPAC1 and 2, which are GPCRs, stimulating adenyl cyclase and inducing SMC relaxation. In vitro studies are promising, but in patients it is rapidly metabolised and has vasodilator ADR. RO25-1533: selective to VPAC2, produces rapid bronchodilation
- Steroid resistance is defined as failure to improve baseline FEV1 by more than 15% after RX with prednisolone 30-40 mg/d for 2 weeks Cytoplasmic glucocorticoid rec include GR-alpha that binds to steroids, and GR beta an alternatively spliced form (present in low levels) that binds to DNA but cannot be activated by corticosteroids. GR beta isoform is implicated in steroid resistant asthma Persisitently elevated IL2 and 4 levels are associated with decreased GR affinity and increased levels of GR beta isoform Other mechanisms of steroid resistance severe asthma can be a/w increased oxidative stress as in COPD, and inhibition of HDAC activity p38 MAP kinase activation disruption of coupling of GR receptor activation to transcription factor inhibition
- There are two types of new drugs that have been developed that can overcome the problem of systemic side effects: the first one is dissociated steroids. GC bind to GC receptors that then bind to GC response elements, leading to activation or inhibition of transcription of genes by affecting other transcription factors like AP-1 or Nf-kB (transrepression) Transrepression is responsible for anti inflammatory action while cis repression of certain metabolic genes leads to ADR New steroids that can dissociate transactivation from transrepression are being developed. This function is lost in vivo though SEGRA: Selective glucorticoid receptor agonist
- There are two types of new drugs that have been developed that can overcome the problem of systemic side effects: the first one is dissociated steroids. GC bind to GC receptors that then bind to GC response elements, leading to activation or inhibition of transcription of genes by affecting other transcription factors like AP-1 or Nf-kB (transrepression) Transrepression is responsible for anti inflammatory action while cis repression of certain metabolic genes leads to ADR New steroids that can dissociate transactivation from transrepression are being developed. This function is lost in vivo though SEGRA: Selective glucorticoid receptor agonist
- Biologicals are high molecular wt products derived from live cells or living organisms that are used to treat a disease. Common examples include monoclonal antibodies and fusion proteins. Used in Inflammatory bowel disease, psoriasis, RA and many other autoimmune diseases. They are often immunogenic. The degree of immunogenicity depends on their structure.
- * As already discussed B cells are stimulated by sensitized Th2 cells to produce allergen specific IgE. This IgE is bound to mast cells. When there is repeat exposure with the same allergen, it binds to this IgE on mast cells and leads to mast cell degranulation and an asthmatic attack Humanized anti IgE antibody that binds to Fc portion of unbound IgE: reducing free IgE levels and preventing it from binding to FCeRIs (high affinity receptor for heavy chain of IgE, present on mast cells), so mast cell degranulation does not occur. * Low free IgE also downregulates the expression of FCeRI
- The graph on the left shows the effect of omalizumab on asthma control. In the study, 80% were having poor control at baseline, and by 20 weeks only 20% were still having poor control The second graph on the right shows the effect of omalizumab on rate of exacerbations per year. At baseline, the exacerbation rate was more than 4 per year, it decreased to 1-2 after 1 year and less than 0.5 after 2 years of omalizumab
- malignancy in 0.5%, compared to 0.2% in the placebo arm. including breast, skin, prostate, parotid. The results of EXCELS trial did not show any increased risk of primary malignancy with long term omalizumab Transient ischemic attack and Ischemic stroke: as shown by EXCELS. But pooled data from FDA did not support this
- Mainly produced by CD4+ Th2 cells and type 2 innate lymphoid cells (ILC2). These two cytokines induce B lymphocytes to synthesize large amounts of immunoglobulin E (IgE) antibodies, and also promote the recruitment of eosinophils. Moreover, IL-13 elicits airway epithelial cell expression of iNOS, mucus production and goblet cell hyperplasia, stimulates ASM contraction and proliferation, and also enhances extracellular deposition of collagen and fibroblast to myofibroblast phenotypic transition. All these effects of IL-4 and IL-13 significantly contribute to airway inflammation and remodelling in asthma
- IgG4 humanized mab against IL-13 improved lung function in poorly controlled asthma, especially in pts with higher pre treatment levels of periostin (a protein secreted by bronchial epithelial cells in response to IL-13) serum periostin levels may identify pts who will respond to anti-IL13 therapy
- IgG4 MAB against IL-13, shown to inhibit AHR and airway eosinophilia Shown to improve FEV1 and reduce SABA use, especially in patients with elevated sputum IL-13 levels One advantage is that FEV1 remained elevated for 12 weeks after cessation of therapy
- recombinant human IL-4 variant that competitively inhibits IL-4 receptor alpha, decreasing down stream signalling of both IL-4 and IL-13. So blocking this receptor can negate the effects of both IL4 and IL13 it attenuates the late asthmatic repsonse Pts with specific SNP in the 3' untranslated region of IL4 R-alpha had more reduction in exacerbations than pts who did not
- inhibits IL-4 receptor alpha decreased exacerbations in moderate to severe asthma patients with eosinophilia produces marked improvement in FEV1, Asthma control questionnare scores, decreased symptoms, reduces Th2 associated biomarkers FeNO, eotaxin-3 and TARC (thymus and activation-regulated chemokine)
- pro inflammatory cytokine produced by T cells, mast cells and eosinophils It enhances the production and maturatioin of eosinophils in bone marrow, and priming and activation and increases their survival in tissues
- *humanized mab against IL-5, reduces no. of eosinophils in both blood and sputum *produces a steroid sparing effect and improved outcomes in pts with severe eosinophilic asthma phenotype and also decreased the incidence of exacerbations *cessation of mepolizumab leads to pretreatment blood and sputum eosinophilia within 3 months and loss of asthma control in 3-6 months *But many studies have failed to show significant effect on traditional markers like FEV1, PEF, AHR, ACQ, AQLQ Recently FDA approved under trade name Nucala for add on maintenance treatment for >12 y old patients
- another anti IL-5 antibody that improves airway function and asthma control, decreases exacerbation rate FDA approved under trade name CINQAIR for >18 yr old patients with severe uncontrolled asthma
- Humanized afucosylated MAB against IL5 receptor alpha lack of fucose moiety improves binding affinity of benralizumab and enhances antibody dependent cell mediated cytotoxicity leading to target cell apoptosis (the target cell we are talking about here is eosinophil) It decreases blood eosinophil numbers, exacerbation rates and improved FEV1 and QOL
- Th17 cells are subset of T cells associated with predominant neutrophilic inflammation and an asthma phenotype that is less responsive to steroids In fact they may play a role in any patient who has severe uncontrolled asthma. They produce IL-17A, IL-17F, IL-21, Il-22. Increased BAL levels of these mediators is a/w increased airway neutrophilic inflamation, mucous cell metaplasia and smooth muscle proliferation
- We know that Mast cell degranulation initiates an asthmatic attack, so inhibition of this process is one treatment option Mast cell stabilizers include cromones like sodium cromoglycate and nedocromil, that act by phosphorylation of a cell membrane protein resulting in termination of secretion, inhibiting Ca influx preventing membrane changes, and by reducing pre secretion membrane fluidity Masitinib is a TKI that has direct anti proliferative action on mast cells by inhibiting c-Kit pathway. It also intereferes with mast cell survival, migration, cytokine production and degranulation Syk (spleen trysrosine kinase) couples the FCeR1 (the high affinity receptor for IgE) on the mast cell to degranulation of mast cells
- CDK inhibitors may induce inflammatory cell apoptosis R-roscovitine can induce eosinophil apoptosis, but no significant reduction in eosinophilic inflammation was found in animal models non CDK targets of these inhibitors may produce side effects ATF3 (activating transcription factor 3) is down regulated in sever asthma, steroids enhanced repression of ATF3. ATF3 agonists may be useful in severe and steroid resistant asthma Off target effects of many of these compounds is a limitation Inhibition of microRNAs can provide specific anti inflammatory therapy without many side effects. MiR145 blockade using a specific antagomir leads to reduction in AHR and airway eosinophilia in mouse models of allergic asthma