The document discusses future trends in COPD management, including: 1) New long-acting beta agonists (LABAs) and bifunctional bronchodilator drugs that have both beta-agonist and muscarinic receptor activity. 2) Phosphodiesterase (PDE) inhibitors, especially selective PDE3, PDE4, and PDE5 inhibitors, which could reduce inflammation and improve lung function. 3) Other developments like inhaled heparin and L-menthol which may provide relief from COPD symptoms.

1. Future Trends In COPD
Management
Prof. Waheed Shouman
Chest Medicine Department
Zagazig University

2. COPD:

3. Global Causes of Death (WHO 2019-2020) (White 2020, blue
2019)

4.  The 5-year life expectancy for people with COPD ranges from 40% to 70%, depending on
disease severity.
 For men aged 65 who smoke, the drop in life expectancy is:
• Stage 1: 0.3 years
• Stage 2: 2.2 years
• Stage 3: 5.8 years
• Stage 4: 5.8 years
 This is in addition to the 3.5 years of life all smokers, whether they have COPD or not, lose to
the habit.

5. Milestones in Current Management of COPD

6. GOLD 2001 for COPD management (1st)

7. GOLD 2023 for COPD management (Last)

8.  Treatment of COPD benefit from the use of fixed dose combinations of two or more drug
classes.
 Treatment of COPD is dominated by inhaled fixed dose combination.
 Formulations to allow the use of more than one drug in a single inhaler is problematic
 There are differences in duration of action of the mono-components and issues concerning
chemical compatibility and stability as well the different physiochemical properties of the
different drug classes.

9. New LABAs:
 Abediterol is a novel and selective long acting B2-agonist with the potential for once daily
treatment of COPD.
 It has superior bronchodilatory efficacy, and superior selectivity for B2-receptors over current
LABAs (formoterol and indacaterol).
 The duration of abediterol is similar or superior to other LABA compounds, with a reduced
effect on heart rate.

10. Bifunctional Bronchodilator Drugs:
 An alternative approach to delivering complementary pharmacological activities is to develop
molecules having two distinct primary pharmacological actions.
 MABAs, is one of these, which have both β2-agonist activity and muscarinic receptor
antagonism in the same molecule.
 It is not clear the relative contribution of the two different pharmacological activities to the
overall improvement in lung function.

11. Bifunctional Bronchodilator Drugs:
Examples:
 GSK 961081 (batefenterol)
 THR 200495 is comparable to a combination of salmeterol and tiotropium.
 AZD 2115
 LAS 190792
 TEI3252
 PF-3429281
 PF-4348235

12. Bifunctional Bronchodilator Drugs:
 Clinical study showed that treatment with batefenterol is superior in improvements of lung
function in patients with COPD compared with salmeterol
 MABA provides a better treatment than monotherapy with a β2-agonist.

13. Non-steroidal, Selective Glucocorticoid Receptor Modulator
(SGRM):
 They dissociate the anti-inflammatory effects from the adverse effects induced by
corticosteroids
 Valsecorat 200 μg, 400 μg, and 1600 μg via pMDI are under trial for safety and efficacy.
 Valsecorat is a once-daily drug.

14. New Macrolides:
 Treatment with the novel macrolide oral Solithromycin at 400 mg did not significantly
improve FEV1 compared to placebo.
 No SAEs were reported in the study.

15. Phosphodiasterase Inhibitors:
 Withdrawal of theophylline from patients with asthma or COPD leads to worsening of airways
inflammation and symptoms, even in patients taking glucocorticoids and other classes of
bronchodilator drug.
 Xanthines possess other useful pharmacological properties not shared with glucocorticoids and
other classes of bronchodilator.
 The problem with xanthines is the narrow safety profile.

16. Phosphodiasterase Inhibitors:
 Pharmaceutical companies tried to find safer xanthines
 A number of them has been investigated:
 Enprophylline (1985)
 Bamiphylline (1991)
 Isbuphylline (1993)
 Doxophylline (2010) which have been approved for the treatment of asthma and COPD
 Acebrophylline (2014)

17. Phosphodiasterase Inhibitors:
 Another approach to try and improve the therapeutic window of xanthines is to develop more
selective inhibitors of the family of PDEs.
 PDEs, with 11 families (PDE1-PDE11) are a superfamily of enzymes that specifically
hydrolyze the second messengers, cyclic adenosine monophosphate (cAMP) and cyclic
guanosine monophosphate (cGMP).
 Functional disorders of PDE4, PDE7, and PDE8 are associated with developing multiple
neurological and cardiovascular diseases, chronic obstructive pulmonary disease (COPD), and
brain tumorigenesis.

18. Phosphodiasterase Inhibitors:
 PDE 3 and 4 are found in airway smooth muscle.
 PDE 3, 4 and 7 are found in the majority of inflammatory cellsad are involved in the
pathogenesis of COPD.
 PDE3 isoenzyme is in airway smooth muscle, and inhibition of this enzymeleads to airway
smooth muscle relaxation.
 PDE4 isoenzyme is the predominant isoenzyme in most inflammatory cells, including
neutrophils, which are implicated in the pathogenesis of COPD.
 The nausea and vomiting side effects of PDE4 inhibitors have greatly limited their clinical
usefulness.

19. Phosphodiasterase Inhibitors:
PDE-3 Inhibitors:
 PDE-3 inhibitors have been shown to cause acute bronchodilation in humans.
 The first drug was Zardaverine, which showed bronchodilation in patients with asthma but
unfortunately was halted during clinical development because of gastrointestinal side effects.
 Benzafentrine, which caused bronchodilation but was later discontinued from clinical
development, due to GIT upset
 Dual PDE 3/4 inhibitor, Pumafentrine was discontinued due to GIT side effects.

20. Phosphodiasterase Inhibitors:
PDE-4 Inhibitors:
 Four PDE4 inhibitors have been approved for the treatment of human diseases.
1) Roflumilast for COPD in 2010 and plaque psoriasis by 2022.
2) Apremilast for psoriatic arthritis in 2014.
3) Crisaborole for atopic dermatitis in 2016.
4) Ibudilast for the rare child disease Krabbe in 2016 and for bronchial asthma in1989.
 The side effect profile of this drug still limits the wider use of this agent.
 The clinical benefit of Roflumilast is due to the anti-inflammatory action of this selective
PDE4 inhibitor.

21. Phosphodiasterase Inhibitors:
PDE-4 Inhibitors:
 To improve the therapeutic window of PDE4 inhibitors, several inhaled drugs have been
developed PDE4 inhibitor.
 These drugs have shown little or no efficacy in patients with COPD.
 The exception is CHF6001 which inhaled on top of standard of care for 32 days was well
tolerated and reduced multiple biomarkers of airway inflammation in induced sputum, and
serum surfactant protein D in patients with COPD and chronic bronchitis.
 CHF6001 is currently in clinical trials for COPD.

22. PDE-4 inhibitors (Up to 57 compounds are approved or under trial in 2023)

23. PDE-4 inhibitors

24. PDE-4 inhibitors

25. Phosphodiasterase Inhibitors:
PDE-3/4 Inhibitors:
 In short-term studies, Ensifentrine significantly reduced lung volumes and airway resistance.
 In a four-week study, 4 Ensifentrine significantly improved bronchodilation and symptoms,
and was well tolerated in patients with COPD.
 Ensifentrine has entered Phase III clinical development.
 Ensifentrine administered at 6 mg via jet nebulizer was as effective as ipratropium 40 μg and
salbutamol 200 μg via pressurized MDI (pMDI)

26. Phosphodiasterase Inhibitors:
PDE-5 Inhibitors:
 PDE5 inhibitors such as sildenafil can induce bronchodilation in addition to their well-
documented effects on pulmonary vascular smooth muscle and suppress the pulmonary
inflammation and airway hyperreactivity .
 It has been suggested that a new molecule that inhibits both PDE4 and PDE5 could act at
multiple levels in patients with COPD leading to:
1. Reduced lung inflammation
2. Reduced remodelling
3. Decreased arterial pulmonary hypertension
4. Improved lung function

27. Phosphodiasterase Inhibitors:
PDE-5 Inhibitors:
 One such example is LASSBio596, is a hybrid of thalidomide and aryl sulfonamide
 It has a potent inhibitory effects on both PDE4 and PDE5.
 In a murine model of elastase-induced emphysema, LASSBio596 reduced lung inflammation
and remodelling and improved lung mechanics
 It has been documented that LASSBio596 has the potential to block proliferation of fibroblasts.

28. Phosphodiasterase Inhibitors:
PDE-7 Inhibitors:
 The PDE7 family was first reported in 1993.
 The inhibition of PDE7 maybe not cause emetic-like effects.
 The inhibition of PDE7 alone unaffected proinflammatory cells but enhanced the effects of
other cAMP-elevating drugs (such as PDE4 inhibitors).
 Several compounds that exhibit dual inhibition of PDE3/PDE4 or PDE4/PDE7 have been
reported

29. Phosphodiasterase Inhibitors:
PDE-7 Inhibitors:
Types of PDE-7 inhibitors:
1) Pyrimidinones-based PDE7 inhibitors. One of them: Spiro-quinazolinone analogues. The first
Quinazolinone-based PDE7 inhibitor was spiro-quinazolinone 26.
2) Pyridine and pyridinone analogues as PDE7 inhibitors
3) Pyrimidine-based PDE7 inhibitors
4) Benzenesulfonamide-based PDE7 inhibitors
5) Other heterocyclic derivatives as PDE7 inhibitors

30. Phosphodiasterase Inhibitors With Bronchodilator:
 GS-5759 is a bifunctional PDE4 inhibitor/LABA drug that displays PDE4 inhibition and β2
agonism comparable to roflumilast and indacaterol.
 Bifunctional compounds containing a PDE4 inhibitor connected to a antimuscarinic have been
described.

31. Inhaled Heparin in COPD:
 Heparins have anti-inflammatory, antioxidant, mucoregulatory, mucolytic, and tissue repair
properties.
 All studies reported improvements in pulmonary function irrespective of administration via the
subcutaneous, intravenous, or inhaled route, with no effects on systemic coagulation
parameters.
 COPD patients received nebulised inhaled UFH (75,000 or 150,000 IU twice a day) or placebo
for 21 days. All patients also received nebulised salbutamol and beclomethasone twice daily
over the same period.
 UFH significantly increased FVC following 7 days of treatment with both doses. The higher
dose, 150,000 IU b.i.d., significantly increased FEV1 (+249 ± 69 mL compared with placebo)
following 7 days of treatment. With both doses of UFH, a clinically significant improvement.

32. L-Menthol:
 L-Menthol is effective in relieving breathlessness in patients with COPD.
 Augmented inspiratory flow perception by L-menthol is important in relieving breathlessness.
 The application of L-menthol to inspiratory muscle training and exercise is to be expected.
 L-Menthol did not affect the inspiratory neural drive or breathing patterns.
 L-Menthol induced a ‘cognitive illusion’ of inspiratory flow by stimulating nasal afferent
receptors involved in the detection of cooling sensations, and that this led to a rationalization
associated with a favourable reduction in breathlessness.

33. Mitochondria-Targeted Antioxidants in COPD

34. Inhaled A1-AntiTrypsin Replacement Therapy:
 AAT is given twice weekly intravenously.
 Only 2–3% of intravenous AAT reaches the lung.
 Weekly intravenous administration of 60-120 mg/kg of AAT is under trial
 Inhaled AAT to may help by acting directly on the organ of interest.
 However, these come with limitations, including the delivery of AAT to the alveoli via
nebulizers can take up to 100 min, and may be less effective in patients with low FEV1 and the
amount of AAT needed in the interstitium to prevent disease is unclear.

35. Inhaled A1-AntiTrypsin Replacement Therapy:
 Higher local AAT levels in the airway epithelial lining fluid have been achieved with the
inhaled route compared to delivery with the intravenous route.
 In AAT deficiency patients with severe COPD and frequent AECOPDs, AAT inhalation had no
effect on the time to first AECOPD during treatment for 50 weeks.
 Inhaled “Kamada-AAT” is a promising drug, with plasma-derived high purity solution for
inhalation.

36. Selectin Antagonists:
 Selectins are essential for migration of inflammatory cells from the bloodstream into
pulmonary tissue
 They mediate transient adhesive interactions related to inflammation.
 There are three members of the selectin family (E-, L-, P selectin).
 E- and P-selectin are expressed on endothelium, whilst L-selectin is expressed on leukocytes.

37. Selectin Antagonists:
 Inhaled Bimosiamose is a synthetic pan-selectin antagonist that has shown encouraging results
in a phase IIa trial in patients with COPD.
 After its administration for 4 weeks, it induced an attenuation of airway inflammation and
small lung function improvements.
 Uproleselan, a specific inhibitor of E-selectin, and Rivipansel (GMI-1070), a pan-selectin
antagonist, have been tested in humans, but not yet in patients with COPD.

38. CXCR1 and CXCR2 Antagonists:
 Neutrophils have the chemokine receptors CXCR1 and CXCR2, of which CXCR2 is more
responsible for chemotaxis and adhesion.
 Several CXCR2 antagonists, such as SCH5 27123, SB-656933, QBM076, AZD5069 and
Navarixin, have been investigated as potential treatments for COPD, but the Phase II studies
had to be terminated due to adverse events.
 MK-7123 (also known as SCH 527123) is a chemokine receptor antagonist with high affinity
of CXCR2.
 MK-7123 50 mg led to a significant improvement in FEV1.
 There was reduced sputum neutrophil count at 3 and 6 months.
 However, MK-7123 caused a dose-dependent decrease in absolute neutrophil.

39. Interleukin-8/CXCR2
 Several CXC-chemokines, of which interleukin (IL)-8 is the prototype, are potent neutrophil
chemotactic and activating cytokine
 IL-8 is a potent chemoattractant for neutrophils and a member of the CXC family of
chemokines.
 It has been evaluated as a possible target for biologic therapy.
 A monoclonal IgG2 antibody against human IL-8 (ABX-IL8) has been developed and studied
in COPD patients.
 Final results showed a reduced severity of dyspnea in those treated with ABX-IL8, but the
difference was only significant at 2 weeks.

40. CXCR1 and CXCR2 Antagonists:
 Danirixin has been evaluated in 52-week RCT in stable COPD patients.
 It significantly improved symptoms (breathlessness, cough and sputum) and also decreased the
number of days free from AECOPDs compared with placebo.
 However, in a 24-week, Phase II study that enrolled over 600 COPD patients, Danirixin did
not significantly improve AECOPD or change respiratory symptoms.
 Also, a 26-week Phase IIb RCT in patients with COPD at risk for AECOPDs failed to show
any benefit on the incidence and severity of respiratory symptoms but reported a high
incidence of AECOPDs and incidence of pneumonia.
 There was no significant difference in FEV1 between Danirixin administered orally at 75 mg
and placebo.

41. IL-17 Antagonists:
 IL-17 is secreted from T helper 17 (Th17) cells and mediates neutrophilic inflammation by
increasing release of CXCL8 (IL-8) from airway epithelial cells.
 IL-17 in COPD is increased in bronchial biopsy samples and lung and sputum of patients of
COPD.
 Several anti–IL-17 monoclonal antibodies have been developed, including Ixekizumab,
Brodalumab, and Secukinumab, for psoriasis.
 Secukinumab did not attenuate acute ozone-induced airway neutrophilia in healthy subjects.
 CNTO 6785 did not demonstrate in patients with COPD. Furthermore, an increased rate of
AECOPDs was observed.
 Brodalumab did not result in a significant effect in patients with controlled asthma.

42. Neutrophil Elastase Inhibitors:
 NE is the primary enzyme present in azurophil granules in the neutrophil cytoplasm.
 Sivelestat is on the market in Japan and South Korea for the treatment of ARDS.
 There are several NE inhibitors in various stages of development but are not focused on COPD.
 Alvelestat is currently in clinical trials in patients with a1-antitrypsin (AAT) deficiency.
 It did not show clinical benefit and effect on biomarkers of inflammation or tissue degradation
when added to tiotropium in patients with COPD.

43. Eosinophilic Inflammation in COPD:
 Eosinophilic inflammation has been reported in 20% to 40% of induced sputum in patients
with stable COPD.
 Eosinophilic inflammation increases in exacerbations.
 Bronchial biopsies done during acute exacerbations compared with stable COPD had a 30-fold
increase in total number of eosinophils.
 Blood eosinophilia isassociated with increased mortality in COPD exacerbations.
 Several cytokines are involved in eosinophilic inflammation, including IL-5, IL-4, and IL-13.

44. Eosinophilic Inflammation in COPD:
 Benralizumab is a monoclonal antibody that targets the human IL-5 receptor alpha.
 Benralizumab was evaluated in patients with COPD with sputum eosinophil counts of 3% or
more.
 Benralizumab did not reduce the rate of COPD exacerbations. However, there were
improvement in FEV1.

45. Eosinophilic Inflammation in COPD:
 The data on the role of IL-13 and IL-4 are conflicting in COPD.
 The main evidence for IL-4/IL-13 in COPD is based on a mouse model of COPD.
 Dupilumab, lebrikizumab, and tralokinumab have not been extensively studied in COPD.
 Targeting IL-4 and IL-13 may prove beneficial in a subgroup of Th2-high patients with COPD,
in patients with Asthma/COPD Overlap Syndrome (ACOS), and/or in COPD exacerbations.

46. Eosinophilic Inflammation in COPD:
 As of early 2018, no anti–IL-5 therapies was studied in COPD
 2 Mepolizumab phase studies showed improvements in exacerbation frequency in subjects
treated with Mepolizumab who had an eosinophilic phenotype and a history of COPD
exacerbations, despite triple therapy.
 Patients treated with Mepolizumab 100 mg once monthly had a significantly lower annual
exacerbations compared with subjects treated with placebo.

47. Matrix MetalloPeroxidase Inhibitors:
 The development of drugs inhibiting MMPs is still at an early stage.
 V85546, a selective MMP-12 inhibitor, and AZD1236, a MMP-9 and MMP-12 inhibitor have
been tested in humans.
 V85546 completed phase I clinical testing, whereas AZD1236 showed no clinical efficacy in
the short term after 6-weeks treatment in patients with COPD

48. Phosphoinositide 3-kinase (PI3K) inhibitors:
 PI3K is important in the activation of macrophage and neutrophils.
 PI3K function may be altered in COPD.
 In healthy smokers, Nemiralisib, a potent inhaled PI3Kd inhibitor that is > 1000-fold more
selective at PI3Kd, showed acceptable tolerability with significantly higher levels of the drug in
the lung compared with plasma.

49. p38 MAPK inhibitors:
 Mitogen-activated protein kinases (MAPKs) play a key role in chronic inflammation.
 Inhaled p38 MAPK inhibitors may enhance p38 inhibition in the lung while reducing unwanted
systemic effects.
 The p38 MAPK inhibitors PF-03715455, losmapimod (GW856553) and AZD7624 are tested.
 The effect of PF-03715455 administered at 680 μg via inhalation was not effective in
improving FEV1.
 Oral Losmapimod 15 mg did not change FEV1, SGRQ, and risk of COPD exacerbation.
 AZD7624, a dual p38a/b inhibitor, had a greater effect than budesonide on cytokine production
from bronchial epithelial cells in COPD patients, but failed to provide any benefit in a 3-month
AECOPD Phase IIa RCT.

50. Janus-kinase Inhibitors:
 Janus-kinases (JAKs)-signal transducers and activators of transcription (STATs) signalling
pathways may be involved in the pathogenesis of COPD.
 A pan-JAK inhibitor (PF-06263276) suitable for inhaled administration in COPD patients has
passed the preclinical phase.
 It showed a dose-related inhibition of IL-6-induced increases of pSTAT3 in murine lung .
 Pyridone 34 is an inhaled potent pan-JAK inhibitor with a dose-dependent inhibition of BAL
neutrophils and IL-6.
 No clinical trials have been started

51. Vasoactive Intestinal Peptides (VIP):
 RO 50-24118, a stable analogue of VIP
 It is highly selective for the VPAC2 receptor
 It has dual bronchodilatory and anti-inflammatory effects
 It relaxes airway smooth muscle cell
 It inhibits bronchoconstriction
 It attenuates the influx of neutrophils and CD8+ T cells to the inflamed lung.
 It may have a bronchodilator and anti-inflammatory role in COPD.

52. Club Cell Secretory Protein (CCSP):
 Circulating CCSP is a strong biomarker of lung function.
 CCSP deficits are associated with indices of airflow limitation,
 Replacement therapy with CCSP has proven effective in animal models of various lung
diseases, including BO , ARDS, and lung inflammation.
 In animal models, it did not significantly improve clinical outcomes such as oxygen usage or
ventilator days.

53. Ghrelin:
 Ghrelin is a peptide hormone derived from ghrelinergic cells, was discovered in 1996, which
is reported to be closely associated with appetite.
 Ghrelin is involved in various cellular events, including energy homeostasis, cholinergic–
dopaminergic reward link, and endothelial function and immunomodulation.
 Ghrelin could inhibit the COPD-associated inflammation and autophagy.
 Ghrelin as therapeutic candidates targeting COPD treatment is moving from bench to clinic.

54. Autoantibodies in COPD:
 Autoantibodies make a significant contribution to COPD in some patients.
 The serum levels of autoantibodies against alveolar type II cells was elevated in human COPD
patients compared with healthy control subjects.
 This suggests that anti-autoantibody disease therapies may be useful in patients with elevated
levels of autoantibodies.

55. Gene Therapy for COPD:
 Gene therapy is one of the most promising strategies for the treatment of chronic lung diseases
such as COPD that is progressive in nature.
 The first step in the treatment of COPD involves identification of the defective gene.
 Once it is identified, the next step would be the vector design and delivery.
 Adenoviral vector-based gene therapy has been regarded as best strategy for lung diseases.
 Viral liposome complexes carrying the AAT (α1 anti-trypsin) gene in mice produced detectable
levels of AAT in the serum for up to 30 days on intravenous administration.

56. Cystic Fibrosis Transmembrane Conductance Regulator
(CFTR) Modulators:
 CFTR modulators have the potential to be useful in COPD because dysfunction of CFTR
induced by smoking-related oxidative stress.
 Two CFTR potentiators, Ivacaftor and Icenticaftor, were evaluated in patients with COPD.
 Ivacaftor did not improve FEV1, but improved symptoms, and caused a 20% improvement in
CFTR activity, with no real safety concerns.
 Icenticaftor produced small improvement over placebo in FEV1. It also improved
inflammatory markers (fibrinogen), and decreased sputum colonization.

57. New Anti-Fibrotics in COPD:
 Few studies addressed the role of small airway fibrosis in COPD.
 Signals that activate fibroblasts may include miRNAs released in extracellular vesicles from
airway epithelial cells that are taken up by local fibroblasts promoting cellular senescence.
 Inhaled delivery of antagomirs of these mirNas to the small airways and peripheral lung of
COPD patients may be effective clinically.

58. Transient Receptor Potential Channels (TRP)
 Transient receptor potential channels are a superfamily of 28 transmembrane cation permeable
channels
 It is subdivided into seven families – on the basis of sequence homology
1. Ankyrin (TRPA)
2. Canonical (TRPC)
3. Melastatin (TRPM)
4. Mucolipin (TRPML)
5. NOMPC (TRPN)
6. Polycystin (TRPP)
7. Vanilloid (TRPV)
 TRP channels have been heavily implicated with roles in COPD, namely, TRPA1, TRPV1,
TRPV4 and TRPM8.

59. Transient Receptor Potential Channels (TRP)
 TRPV1 is well known as the receptor responsible for the perception of heat, particularly so for
mediating the ‘spicy hot’ effects of capsaicin, the active constituent of chilli peppers which
activates TRPV1 n sensory nerves (Role in cough)
 TRPV1-expressing C-fibers have been demonstrated to release pro-inflammatory
neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) which
mediate neurogenic inflammation (Role in inflammation)
 Of all the TRP channels, antagonists for TRPV1 are the most advanced in terms of drug
development and clinical trials.

60. Transient Receptor Potential Channels (TRP)
 The main difficulties with TRPV1 antagonist development is dueto its function as a
thermosensor for hot temperatures.
 Its adverse effects such as increased body temperature and latent withdrawal to noxious hot
stimuli have dogged development.
 The TRPV1 antagonist AMG 517 caused significant and long-lasting increases in body
temperature to above 40C.
 MK-2295 (or NGD-8243), caused an increase in body temperature and altering noxious heat
sensation threshold.

61. Transient Receptor Potential Channels (TRP)
 The compound PHE377 was ‘well tolerated’, has ‘on-target activity’ and ‘does not increase
body temperature’.
 The GSK SB-705498 for chronic refractory cough and was reported to be well tolerated, with
no significant increases in tympanic temperature.
 This was the first TRPV1 antagonist to be examined clinically as an antitussive, but
disappointingly, SB-705498 lacked efficacy in improving 24 h cough counts.
 XEN-D0501 was approximately 1,000 times more potent than SB-705498 at inhibiting
capsaicin depolarization of human in vitro, and 100 times more potent at inhibiting capsaicin-
evoked cough in conscious guinea.

62. Trials of targeting microbiome in COPD:

63. Extracellular Vesicles (EVs) in COPD:
 Extracellular vesicles (EVs) are a general term for nanoscale lipid bilayer vesicles released
upon activation, injury or apoptosis of almost all kinds of cells.
 Based on particle diameter size, EVs can be classified into three categories, namely exosomes
(~ 40–100 nm in diameter), microvesicles (~100–1000 nm in diameter) and apoptotic vesicles
(~1000–5000 nm in diameter).
 Research on COPD suggest that EVs have the potential to be a new therapeutic direction.
 There are two general approaches to treatment through EVs: (1) removal of EVs containing
nucleic acids or proteins involved in disease pathogenesis, (2) use of EVs as a source of
pulmonary immunomodulator.

64. Inhaled Anti-Viral Agents in COPD:
 Respiratory viruses together with opportunistic bacterial infections are the major causes of
COPD exacerbations.
 Antiviral agents must be given at the earliest possible time after the viral infection to reduce the
severity or prevent COPD exacerbations.
 Ribavirin is effective against respiratory viruses associated with COPD exacerbations
including human rhinovirus (HrV), respiratory syncytial virus (RSV), and influenza virus.
 Ribavirin (cci15106, GlaxoSmithKline) by inhalation has been investigated in 2 clinical trials.
 It was well tolerated in healthy subjects and moderate COPD patients

65. Targeted Lung Denervation (TLD):
 Bronchoconstriction and airway inflammation are mediated by the parasympathetic airway
nerve fibres.
 TLD aims to disrupt the peri-bronchial vagal lung innervation via radiofrequency ablation
under fluoroscopic guidance.
 It is suitable for symptomatic patients with advanced COPD (FEV1 30–60%.
 TLD caused reduction in COPD respiratory adverse events, in particular severe COPD
exacerbations, over a year.
 The main concern would be the development of increased gastrointestinal events due to
damage to the vagal esophageal plexus in the process of conducting TLD.

66. Senotherapy in COPD (Senolytics)

67. Senotherapy in COPD (Senolytics)

68. Senotherapy in COPD (Senolytics)

69. Senotherapy in COPD (Senolytics)

70. Drugs Stimulating Lung Regeneration:
 Many potential stem cell therapies already exist, but most of them are at the preclinical stages.
 A new potential approach to regenerative medicine is laser therapy.
 Lasers typically generate electromagnetic radiation which is relatively uniform in wavelength,
phase and polarisation.
 Low Level Lasers (LLL) induce their effects through non-thermal means and may activate
endogenous pulmonary stem cells and neoangiogenesis, which is optimal for stem cell growth.
 LLLs been proposed as regenerative photoceutical treatment for COPD.
 This is called Photobiomodulation (PBM).
 An in vivo study showed that both lasers could modulate VEGF secretion and MMP-2 activity
in a dose-dependent manner.

71. Drugs Stimulating Lung Regeneration:
 In animal models of COPD intravenous, intratracheal and endobronchial injections of MSCs
significantly attenuated emphysematous changes and significantly improved lung function.
 Studies have demonstrated that MSC-derived EVs, such as bone marrow, cord blood, and
adipose-derived MSCs, may have a protective effect on COPD etiology.

72. Regenerative Therapies in COPD:
 Therapeutic attempts to stimulate lung regeneration in COPD are limited to 4 relatively short-
term clinical trials with retinoids.
 Retioic Acid was well tolerated but no differences were observed in CT, lung function, or
quality of life scores between treatment groups.
 Serum level decreased rapidly attributed to auto- induced catabolism, so it is unclear whether
RA reached cell types necessary for repair.
 The findings that an RAR-γ agonist may reduce the rate of decline in a subset of patients,
particularly during exacerbations, may warrant further investigation.

73. Morphologic treatments of emphysema
1. Bullectomy
2. Lung volume reduction surgery
3. Bronchoscopic lung volume reduction (BLVR)
4. Foam sealant
5. Thermal vapor ablation
6. Airway bypass stents
7. Self-activating coils
8. Endobronchial valves (EBV)
9. Lung transplantation

74. Morphologic Treatments of COPD
Airway Bypass Stents
 (Expandable silicone coated, paclitaxel eluting stents are placed endobronchially from
emphysematous tissue into airways to promote emptying of trapped air and hence achieve
reduction in lung volumes)

75. Morphologic Treatments of COPD
Self-activating coils (PneumoRx coils)
 They are self-activating nitinol coils that work by compressing lung parenchyma once they are
deployed leading to volume reduction with atelectasis.

76. Morphologic Treatments of COPD
Airway predominant treatments
 (No specific medical intervention has been shown to alleviate chronic bronchitis in any
clinically meaningful way.
 New interventions have been proposed to address this clinical void by using either metered
dose nitrogen cryospray or rheoplasty to eliminate airway epithelium goblet cell hyperplasia
and reduced mucous hypersecretio)

77. Morphologic Treatments of COPD
Lung Sealants:
 Application of biological adhesives within the targeted airways to deactivate surfactant and
promote local atelectasis, induce local inflammatory response and form fibrotic tissue, thus
shrinking the hyperinflated lung.
 Autologous blood and AeriSeal are candidate potential bio-adhesives.

78. Morphologic Treatments of COPD
Bronchial Rheoplasty:
 RheOx® bronchial rheoplasty (Gala Therapeutics, San Carlos, CA, USA).
 It delivers short bursts of high-frequency electrical energy to the airway epithelium and
submucosal tissue layers in order to target goblet cells.
 The procedure is performed in two separate treatments (one lung per treatment) with one
month in between.
 Treatment is delivered from second- to seventh-generation airways.
 A multicenter clinical trial demonstrated significant improvements in CAT and SGRQ scores
with no change in lung function parameters at 3 and 12 months.

79. Morphologic Treatments of COPD
Metered Cryospray and Balloon Deobstruction:
 Metered Cryospray (RejuvenAir, CSA Medical, Lexington, MA, USA) and balloon
deobstruction (Rezektor Balon, Istanbul, Turkey).
 They are two additional bronchoscopic treatment modalities specific to chronic bronchitis.
 Both are intended to destroy hyperplastic goblet cells via freezing and mechanical disruption,
respectively.
 All three of these modalities are in the very early phase of research and development, having
demonstrated quality-of-life improvements but little effect on cough or sputum production.

80. Lung Assist Devices:
 This is to build on the idea of ECMO which is not a feasible long-term assist as regard
complications and bleeding.

81. Lung Bioengineering:
 There is interest in approaches for growing functional lung tissue ex vivo for potential use in
transplantation and for the study of lung biology.

82. Lung Bioengineering:
Lung Organoids
 Organoid technology is a powerful tool for studying lung developmental biology, cell–cell
interactions, and cell–matrix interactions, and further serves as a pharmaceutical platform for
screening and evaluating small molecules and other potential new therapeutic agents.
 Organoid technology has not been utilized to study defective epithelial cell biology in COPD.
 Classic methods for generating organoids involve the use of either pluripotent or tissue-derived
stem cells.
 The generation of organoids from pluripotent stem cells requires a first step for the
determination of the germ-layer (endoderm, mesoderm or ectoderm), followed by the
sequential addition of specific signalling factors to differentiate into the tissue of interest.

83. Lung Bioengineering:
Three-Dimensional Bioprinting and Lung-on-a-Chip
 This includes increasing ability to include live cells in the printing processes and creation of
complex multilayered printed tissues.
 A growing number of studies are using these approaches for clinical management of diseases of
the larger airways (trachea/ mainstem bronchi), usually in the setting of congenital defects,
cancer, or trauma.
 Three-dimensional printing has had less progress in lung parenchymal applications as yet, in
large part due to the current limitations on the printing resolution of current 3D bioprinters.
 Neither 3D bioprinting nor lung-on-a-chip has yet been extensively utilized to study lung
epithelial or progenitor cells and/or matrix obtained from patients with COPD.
 The first lung-on-a-chip device was fabricated by Hugh and coauthors (2010), who recreated
the blood–air barrier.

84. Lung Bioengineering:
Organ Decellularization/Recellularization
 Organ decellularization has been one of the preferred strategies for the development of
biomimetic lung 3D models.
 Lung donor cells are removed while the acellular 3D scaffold retaining the biochemical
components, mechanical properties and the structural integrity of the native lungs (including
the original vasculature) prevails. (simulating lung ECM)

85. Paolo Macchiarini

86. Lung Bioengineering:
 Paolo Macchiarini is a Swiss-born Italian thoracic surgeon and former regenerative medicine
researcher who became known for research fraud and manipulative behavior.
 He has been convicted of research-related crimes in Italy and Sweden.
 He was considered a pioneer for using both biological and synthetic scaffolds seeded with
patients' own stem cells as trachea transplants,
 Macchiarini has been accused of unethically performing experimental surgeries, even on
relatively healthy patients, resulting in fatalities for seven of the eight patients who received
one of his synthetic trachea transplants.

87. Thank You

88. This lecture was built on and copied from many review articles and books