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© SUPPLEMENT TO JAPI • february 2012 • VOL. 60
Newer Therapies for Chronic Obstructive Pulmonary
Disease
Rahul Kodgule*, Abhijit Vaidya**, Sundeep Salvi***
Introduction
T
he thick cloud cover over the understanding of
pathophysiology of Chronic Obstructive Pulmonary
Disease (COPD) is unveiling rapidly and this has contributed
significantly to recent drug development and is likely to do so
even in the future. Persistent exposure to an inhaled irritant like
cigarette smoke, biomass smoke or industrial smoke leads to
activation of several inflammatory pathways which contribute
to the pathology of COPD in multiple ways.1-3 These irritants
activate macrophages in the respiratory tract which then release
multiple chemotactic factors to attract neutrophils, monocytes
and T lymphocytes. These cells release a battery of proteins
called as chemokines and cytokines which get involved in the
various complex inflammatory and destructive pathways leading
to chronic bronchitis and emphysema. Moreover, the steroids
which arrest asthmatic inflammation quite effectively are found
to be disappointingly less potent in COPD. As a ray of hope, the
inflammatory process in COPD, has the potential to be inhibited
at different stages of its pathway. Hence, recent drug discovery
has focused on intervention of these pathways by inhibiting one
of the steps. However, real challenge lies in developing such
drugs that are not only effective, but also safe.2-4
Another important mechanism implicated in the pathogenesis
of COPD is oxidative stress. Physiologically, the load of oxidants
Blood
Nicotine
Blood-Brain
Barrier
Nicotine bound to
Nicotine - Receptors
is balanced by the levels of anti-oxidants in the lung. When the
oxidant load exceeds the anti-oxidant response, it is known as
oxidative stress. This oxidative stress fuels the inflammation
in COPD and also contributes to airway remodeling and
emphysema. Oxidative stress is also accused of contributing to
steroid resistance in COPD. This knowledge has stimulated wide
interest in the development of potent anti-oxidants.5-7
Emerging Therapy
In this review article, we discuss the recent advances taken
place in the development of newer drugs for managing Chronic
Obstructive Pulmonary Disease.
Smoking Cessation
Smoking cessation is the only intervention that has been
shown to attenuate the progression of disease (FEV1 decline) in
COPD. However, attempts by smokers to quit smoking end up
more commonly in failures than success. To assist smokers in
smoking cessation, several drugs have recently been developed
successfully. Drugs like Bupropion and Varenicline have been
used as Nicotine replacement therapy (NRT) which has been
shown to double the chances of smoking cessation in those
who attempt it.
Currently, research is focusing on development of antibodies
against the free nicotine circulating in the blood, in order to form
antigen-antibody complexes. These antigen-antibody complexes
being unable to cross the blood-brain barrier would not be able
to stimulate the nicotine receptors and will thus make smoking
non-enjoyable (Figure 1). Preliminary results of early clinical
trials support a beneficial effect of this approach (Figure 2).
Nicotine-Qbeta, CYT002-NicQb and NicVAX are currently three
such vaccines under development. The combination of active and
passive immunization may also be a good strategy.8,9
Newer Bronchodilators
Brain
Fig. 1a : Mechanism of nicotine action
Blood
Antigenantibody
Complex
Bronchodilators are the main stay of COPD management
as they improve symptoms and quality of life significantly
mainly by emptying the trapped air through dilatation of the
distal airways. Thus bronchodilators provide symptomatic relief
only and do not necessarily modify the disease process. Short
Unbound
receptors
Brain
Fig. 1b : Immunization mechanism against nicotine
*
Senior Research Fellow, Chest Research Foundation, Pune; **Project
Manager, Cipla Ltd., Mumbai; ***Director, Chest Research Foundation,
Marigold Complex, Kalyani Nagar, Pune 411014, Maharashtra
Smoking abstainers (%)
Blood-Brain
Barrier
56.6%
60%
P=0.174
50%
40.3%
P=0.004
Ab: Antibody
P=0.920
32.1%
40%
P=0.920
32.1%
31.3%
30%
20%
10%
0%
-10%
Vaccinated
Subjects
High Ab
responders
Medium Ab
responders
Low Ab
responders
Placebo
Fig. 2 : Continuous abstinence rate in smokers after immunization
© SUPPLEMENT TO JAPI • february 2012 • VOL. 60 Novel Combinations
60
40
20
0
-20
Placebo
Roflumilast 250 mcg Roflumilast 500 mcg
-40
-60
9
Prebronchodilator FEV1 in ml
Fig. 3 : Change in lung function parameters after treatment with
roflumilast
acting-bronchodilators have met with serious problems of noncompliance to the treatment because of the discomfort caused
by multiple dosing. This has led to the development of long
acting- and ultra long acting-bronchodilators which produce
sustained bronchodilation lasting for 12-24 hours. This allows
for once-daily or twice-daily dosing which improves patient
compliance.
Ultra Long Acting Muscarinic
Antagonists (ultra-LAMA)
Ultra-LAMAs are presently the best treatment available for
COPD. The action of ultra-LAMAs like Tiotropium is mediated
by good selectivity (for blocking) for and slow dissociation
from M3 receptors in the lungs. They not only have better and
sustained bronchodilatory effect but recently they also have
been shown to have anti-inflammatory properties. It appears
that LAMAs reduce the rate of exacerbation in COPD patients
and hence, have the potential to partially halt progress of the
disease and improve mortality.10,17
Aclidinium, glycopyrronium, darotropium, TD-4208,
CHF5407, QAT-370, GSK-573719, Dexpirronium and RBx
343E48F0 are some of the ultra-LAMAs under development.
Aclidinium is faster acting. Recent clinical trials have casted
doubt on once-daily dosing of aclidinium and trials to investigate
efficacy and safety of twice-daily dosing are underway. The other
bronchodilators are being evaluated in clinical trials.9-16
Ultra long acting β2 agonists (ultraLABA)
Ultra-LABAs have duration of action that lasts for at least 24
hours. Carmoterol, indacaterol, milveterol, vilanterol, olodaterol,
LAS100977, PF610355, JNJ39758979, Saligenin- or indolecontaining β2-agonists, UK-503590 and Compound X are some
of the ultra-LABAs currently under development. Carmoterol,
indacaterol, vilanterol, LAS100977 are faster acting compared
to salmeterol. Indacaterol, a promising ultra-LABA has been
approved in Europe and USA for bronchodilator treatment.
Large clinical trials have shown that indacaterol may be better
than salmeterol, formoterol and tiotropium in increasing trough
FEV1 in COPD patients at doses of 150 and 300 mg and there
was no evidence of tachyphylaxis. In asthma milveterol has been
found to be safe and well-tolerated, with efficacy comparable
to salmeterol. Its role in COPD is yet unexplored. Vilanterol is
another ultra-LABA in clinical trials, and has been found to be
safe and effective in both asthma and COPD patients.9-16
The deposition of inhaled drug into the lungs is usually less
than 30%. However, using a formulation process like Modulite
technology, the drug deposition of carmoterol has been shown
to be improved up to 41%.9
Some COPD patients respond well to LAMAs and some
to LABAs depending on various factors including variable
predominance of beta-adrenergic or muscarinic receptors in
these patients. Using a combination of the two may solve the
problem of such variation in response to bronchodilators.
Furthermore, LAMAs and LABAs have been shown to have
synergistic effects.13,18 Since, these combinations are more likely
to be used in severe or very severe COPD cases, addition of a
steroid or anti-inflammatory drug would make sense, as steroids
are likely to reduce the exacerbations in these patients.19 Various
such triple drug combinations are presently available or would
be available soon in the market.
India leads competition in this respect by launching the first
triple inhaler containing tiotropium, formoterol and ciclesonide
is already available in India while such combinations are
presently not there in most of the other countries including
Europe and US.20 Some of the combinations in development
are: aclidinium+formoterol±fluticasone/budesonide, tiotropium
+ formoterol ± Fluticasone /Budesonide, glycopyronium+form
oterol±mometasone, indacaterol+glycopyrronium (QVA-169),
olodaterol + tiotropium, milveterol/vilanterol + darotropium,
carmoterol + tiotropium and formoterol + dexpirronium.9-16
One of the limitations of such approach is delivery of LAMA
and LABA at different locations in the lung which reduces their
synergistic potential. A novel approach of combining these drugs
in a single dimer molecule holds promise to deliver both the
drugs at same locations in order to have maximum synergistic
effect. Such molecules are known as dual-acting muscarinic
antagonist- β2-agonist (MABA) bronchodilators. GSK-961081,
Bicyclohept-7-ylamine derivatives, THRX-200495, THRX-198321,
LAS190792 and TD-5959 are some of the potential MABAs
currently under development.9,13
Anti-Inflammatory Drugs
Drugs that can reduce the lung inflammation in COPD,
safely and effectively, will undoubtedly be the drugs of choice
for managing COPD. Years of research to discover such wonder
drug has given birth to some anti-inflammatory agents or
ideas, which may not be as effective as desired but can be of
pragmatic use in clinical practice. Toiling research to understand
the molecular reasons behind the unresponsiveness of COPD
inflammation to corticosteroids, has led to the understanding
that oxidative stress-mediated reduction in an enzyme known as
Histone Deacetylase (HDAC) might be the culprit. Interestingly,
theophylline has been shown to increase the cellular levels of
HDAC. Hence, it is thought that oral theophylline given in low
doses may augment the anti-inflammatory effect of inhaled
steroids. A study on theophylline with budesonide (ADC4022)
has already been successfully completed.21-23
PDE4 Inhibitors
Phosphodiesterase-4 (PDE4), an isoenzyme of
phosphodiesterase, is specifically expressed in many proinflammatory cells such as neutrophils, macrophages,
eosinophils, mast cells and lymphocytes. As a consequence,
selective PDE4 inhibition may have inhibitory effects
upon various inflammatory and immunomodulatory cells.
Considering the problem of compliance with inhaled drugs
and lack of availability of an effective anti-inflammatory drug,
oral PDE4 inhibitors hold great promise. Roflumilast, a selective
PDE4 inhibitor, has been developed and approved as an anti-
10
© SUPPLEMENT TO JAPI • february 2012 • VOL. 60
Table 1 : Common adverse events recorded in roflumilast trial
Placebo n=280
Roflumilast
250 mcg n=576
500 mcg n=555
382 (66%)
370 (67%)
Patients experiencing ≥ 1 adverse event
174 (62%)
COPD exacerbation
65 (23%)
135 (23%)
113 (20%)
Nasopharyngits
Diarrhea
Upper respiratory tract infection
Nausea
19 (7%)
6 (2%)
14 (5%)
2 (1%)
42 (7%)
28 (5%)
27 (4%)
16 (3%)
46 (8%)
50 (9%)
23 (4%)
27 (5%)
Chemokine antagonists
-Cigarette smoke
-Air pollutants
-Neutrophils
-Macrophages
-mucin
-glutathione
-uric acid
-proteins
-alpha
tocopherol
-ascorbic acid
The chemotactic effects of chemokines CXCL8, CXCL1
and CXCL5 on neutrophils and monocytes are mediated by
a common receptor, CXC receptor (CXCR)-2. ADZ8309, an
oral CXCR1/2 antagonist has shown to inhibit neutrophil
inflammation in humans. Antagonists have also been developed
for other important chemokine receptors like CXCR3 and
CXCR5. SCH-527123 and GSK656933 have already completed
phase I studies.9-16
TGF-β Inhibitors
Fig. 4 : Oxidant-Antioxidant Imbalance
inflammatory agent for COPD. In a multi-centric clinical trial
Roflumilast also improved FEV1 marginally, but significantly in
COPD patients over and above tiotropium (Figure 3).24-27 Recently
it has been suggested that PDE4 inhibitors are the best add-on
therapy over LAMAs and LABAs for COPD.
A combination of the inhaled PDE4 inhibitor GSK256066
(phase II) with a LAMA (potentially darotropium) in addition to,
a LABA (either milveterol or Vilanterol) is also being explored.
However, intolerable gastrointestinal side effects of present PDE4
inhibitors have prompted development of specific PDE4B and
PDE7 inhibitors (Table 1).13
Antiproteases
Proteases like matrix metalloproteinases (MMP), which are
released from macrophages, neutrophils and epithelial cells,
digest elastin to cause emphysema. Selective MMP inhibitors
like AZ11557272, have been shown to prevent emphysema and
airway thickening in guinea pigs. MMP-9 and MMP-12 inhibitors
are being currently investigated in Phase II and Phase III clinical
trials and the results are awaited with interest. Midesteine
and BAY-71-9678 are few other elastase inhibitors that have
completed phase I studies.9-16
Cytokine Inhibitors
TNF-α (Tumour Necrosis Factor-α) is a key mediator of
inflammation including systemic inflammation in COPD.
Infliximab, an inhibitor of TNF-α, has been clinically tested
and was however, not been found to be of any clinical benefit
in COPD. Other cytokines that are being targeted presently for
inhibition include interleukin (IL)-1β, IL-6 and IL-7. Tocilizumab,
a potent inhibitor of IL-6, is yet to be tested in COPD patients.
These drugs are still in the development phase.9-16
Transforming growth factor (TGF)-β plays a key role in
fibrosis of small airways, which is a major cause of progressive
FEV1 decline and reduced exercise capacity in COPD patients.
SD-280, a TGF-β inhibitor has been developed. However, there
are long-term concerns about inhibition of TGF-β.9-16
Nuclear factor-kB inhibitors
Nuclear factor-kB is a transcription factor that plays a key
role in COPD inflammation by regulating the expression of
CXCL8 and other chemokines, TNF-α and other inflammatory
cytokines, as well as MMP9. Therefore, inhibition of NF-kB by
inhibition of the inhibitor of NF-kBkinase (IKK)-2 seems to be
a promising therapeutic option. Several (IKK)-2 inhibitors are
currently under development.9-16
p38 MAP Kinase inhibitors:
p38 mitogen-activated protein kinase (p38 MAP kinase)
is activated by cellular stress and regulates the expression of
IL-8, TNF-α and MMPs, proteins involved in driving COPD
airway inflammation. Inhaled formulations of p38 MAP kinase
inhibitors, currently in the development phase, are GSK681323
and GSK856553.9-16
PI3K Inhibitors
Phosphoinositol 3-kinases (PI3Ks) are involved in the
inflammatory process, specifically in neutrophil recruitment
and activation. PI3K-γ and PI3K-δ have been targeted for
inhibition and several such inhibitors are currently in early drug
development phase.9-16
PPAR Agonists
Peroxisome Proliferator-activated Receptors (PPARs) are a
family of ligand-activated nuclear hormone receptors belonging
to the steroid receptor super-family. Recently, PPAR-α and
PPAR-γ have demonstrated immunomodulatory properties.
PPAR-γ agonists also inhibit TGF-β and hence may be helpful in
preventing fibrosis. The PPAR agonists currently being studied
for therapeutic use in COPD are rosiglitazone and SB 219994.9-16
© SUPPLEMENT TO JAPI • february 2012 • VOL. 60 11
Mean change in eCO from baseline
Mean change in FEV1 from baseline
Mitochondria
N-Acetyl
Superoxide
dismutase
Endoplasmic
Reticulum
NADH/NADPH Oxidase
Xanthine oxidase
Lipooxygenase
Cyclooxygenase
P450 monooxygenase
Mitochondrial oxidation
phosphorylation
H2O2
.Oxidative Stress
- DNA damage
-Oxidize proteins
(enzymes, histones)
-Oxidize lipids
-Apoptosis
-Neutrophil
sequestration
-Inactivation of antiproteases
- Steroid
unresponsiveness
-Transcription of
proinflammatory
cytokines
Fenton
Reaction/
Haber Weiss
Reaction
OH
-
Generation of oxidant radicals
and effects of oxidative stress
Fig. 5 : Reactive oxygen species generation and its effects
Antioxidants
Oxidative stress arising out of oxidant-antioxidant imbalance,
contributes quite significantly to the pathophysiology of COPD
in multiple ways (Figures 4 and 5). N-Acetyl-Cysteine (NAC) is
one of the most widely used and tested anti-oxidants. NAC has
been shown to reduce both local as well as systemic oxidative
stress. Some studies have demonstrated that NAC reduces
bronchial hypersecretion, prevents the decline in FEV1 and helps
reduce the numbers of COPD exacerbations.5,28
In our own study (unpublished data) comparing high dose
NAC (1200 mg OD) with inhaled fluticasone in a randomized,
double blind study in 23 subjects with moderate-to-severe COPD,
we found a significant reduction of exhaled carbon monoxide
(which is a biomarker for oxidative stress) by 1.09 ppm in NAC
group against 0.43 ppm decrease in the fluticasone group after
a 4 weeks treatment. Intriguingly, this was accompanied by
an increase in FEV1 by 112ml in NAC group against a 30ml
reduction in the fluticasone group (Figure 6). This suggests that
in higher doses NAC reduces oxidative stress and may lead to
mild bronchodilation, an added advantage over corticosteroids.
However, the results are needed to be confirmed by large scale
multi-centric clinical trial.29
Several anti-oxidants like N-acestelyn (NAL), N-isobutyrylcysteine (NIC), erdosteine, procysteine and carbocysteine are
currently under development. As against NAC, effective inhaled
preparation of these anti-oxidants can be developed making it
possible to deliver them in higher doses locally. NAL has been
tested in clinical trials and was well tolerated. Erdosteine has
additional property of reducing bacterial adhesiveness suggesting potential use to prevent bacterial exacerbations. NIC is less
effective and procysteine more toxic.5,28
NRF-2 Activators
Nuclear factor erythroid-2 related factor 2 (NRF2), a
transcription factor, induces antioxidant expression, thus
inhibiting oxidative stress. Plant products 6-methylsulfinylhexyl
isothiocyanate (6-HITC) found in Japanese horseradish,
sulforaphane isolated from broccoli and wasabi are the NRF-2
activators currently being studied.30,31
-0.2
-0.4
-0.4347
-0.6
-0.8
-1
-1.2
Fluticasome
120
-1.087
p=0.017
Mean change in FEV1
(in Mililiters)
O2
Mean change in eCO (in ppm)
Superoxide
anion
O2
N-Acetyl
Fluticasome
0
Hydrogen
peroxide
100
80
60
113
40
20
0
-20
-31
-40
Fig. 6: Outcomes of clinical trial using higher dose NAC
Statins
Statins or 3-hydroxy-3-methylglutaryl coenzyme-A
(HMG-CoA) are used widely as lipid lowering agents. However,
recently statins have been found to have anti-inflammatory,
antioxidant, anti-thrombogenic and vascular function-restoring
actions. Retrospective studies indicate that statins might improve
all-cause mortality, deaths from COPD, respiratory-related
urgent care, COPD exacerbations, intubations for exacerbations
of COPD, exercise capacity and lung function decline in COPD
patients. Lipophilic statins such as atorvastatin and simvastatin
are thought to be more effective than the hydrophilic pravastatin.
However, statins have been inadequately studied and need
further evaluation in objective clinical trials before they can be
used in the management of COPD.32-34
Regenerative Therapies
Presently COPD is managed only symptomatically and
is a progressive disease. Any drug/therapy that restores the
destroyed alveolar tissue may actually reverse the disease.
Stem Cells
Infusion with allogenic mesenchymal stem cells offer
hope, as they have the potential to regenerate alveolar tissue
by themselves or by secreting growth hormones, specifically,
vasculo-endothelial growth factor (VEGF). However, lodging
of the pulmonary blood vessels with the infused stem cells
(arborization) leading to fatal outcome is an undeniable
possibility. Trials investigating the efficacy and safety of stem
cells in COPD patients are underway.
Retinoic Acid
Retinoic acid is known to increase alveolar septation during
lung development. All-trans-retinoic acid has been shown
to induce regeneration of the terminal respiratory tract and
reverse elastase induced emphysema. However, this was not
substantiated by a clinical trial evaluating health status on CT
density.9-16
Anti-ageing Therapy
Accumulating DNA damage caused by oxidative stress is
a hallmark of accelerated ageing. Accelerated aging has been
implicated in the pathogenesis of COPD and is mediated
by inactivation of Silent Information Regulator Two (SIR2)
protein-1 or sirtuin1 (SIRT1). Resveratrol, found in grape
skin, seeds and nuts, activates SIRT1, and is being studied as
a possible therapeutic agent for COPD. New SIRT1 activators
under development are SRT1720, SRT501 and SRT2104. These
molecules are many times more potent than resveratrol.5,28,35
Apart from new drug discoveries, a lot of research is taking
place to discover new devices, formulation strategies and drug
12
© SUPPLEMENT TO JAPI • february 2012 • VOL. 60
Table 2: Summary of newer therapies for COPD
a. Smoking Cessation
b.Bronchodilators
c. Novel combinations:
d. PDE4 Inhibitors
e. Anti-Inflammatory
drugs:
1.
1.
Vaccines:
a.Nicotine-Qbeta
b.CYT002-NicQb
c. NicVAX
Ultra long acting β-2 agonists:
a.Carmoterol
b.Indacaterol
c.Milveterol
d. GSK-642444
e. BI-1744-CL
f. Saligenin or indole containing β-2
agonists
g. UK-503590
h. Compound X
2.Ultra long acting anti-muscarinic agents:
a.Aclidinium bromide
b. Glycopyrronium bromide
c.TD-4208
d.QAT-370
e. CHF 5407
f. Darotropium bromide
g.dexpirronium
1. MABA (Muscarinic-antagonist- β-2agonist):
a. GSK-91081
b.Bicyclohept-7-ylamine derivatives
2. LABA and ICS:
a. Carmoterol and budesonide
b.Formoterol and mometasone
(MFF258)
c.Formoterol and ciclesonide
d. Indacaterol and mometasone
(QMF-149)
e. Indacaterol and QAE-397 (a novel
corticosteroid)
f. Fluticasone furoate and GSK-642444
3. LABA, LAMA and anti-inflammatory
compounds:
a. Tiotropium, salmeterol and
fluticasone/ciclesonide
b. Indacaterol, glycopyrronium and
mometasone
c. Milveterol, darotropium and
fluticasone furoate
d. GSK-642444, dartropium and
fluticasone furoate
1. Roflumilast
2.Cilomilast
1. Cytokine Inhibitors :
a. Infliximab (Anti-TNFα)
b.Tocilizumab
delivery agents as present devices and drug delivery systems
are able to deliver only a marginal amount of the drug to the
desired portion of the lung.12
Although the exciting novel therapies may take some time
to reach practicing physicians, it is encouraging to realize that
our COPD patients will be receiving more effective and safe
treatment in near future (Table 2). We may soon make the
inflammation in COPD respond to therapy. By then, smoking
cessation remains the most important intervention and long
acting-bronchodilators the most effective symptom-relievers.
2. Chemokine antagonists:
a. ADZ8309: CXCR1/2 antagonist
b. Anti-CXCR3
c. Anti-CXCR5
3. TGF-β Inhibitors:
a.SD-280
4.Antiproteases:
a. Marimastat: Non-selective MMP
Inhibitor
b. AZ11557272: Dual MMP-9/MMP-12
Inhibitor
5. Drugs for improving steroid resistance:
a. Low dose theophylline
b.Anti-oxidants
6. Nuclear factor-kB inhibitors
7. p38 MAP Kinase inhibitors
8. PI3K Inhibitors
9. PPAR Agonists:
a.Rosiglitazone
b. SB 219994
f.Anti-oxidants
1. N-acetyl cysteine (NAC) derivatives:
a. N-acestelyn (NAL)
b. N-isobutyrylcysteine (NIC)
c.Erdosteine
d.Procysteine
e.Carbocysteine
2. NRF-2 Activators:
a. 6-methylsulfinylhexyl isothiocyanate
(6-HITC)
b.Sulforaphane
g.Statins
Statins being studied for effects on COPD:
a.Simvastatin
b.Atorvastatin
c.Pravastatin
h.Regenerative therapies 1.Retinoic acid:
a.All-trans-retinoic acid
b. 9-cis-retinoic acid
2. Stem cells
i.Anti-ageing therapy
1. SIRT1 Activators:
a.Resveratrol
b.SRT1720
c.SRT501
d.SRT2104
j. Inhalation devices
New carrier systems:
1. Matrix particle carrier formulations
(using chitosan)
2. Liposomes: Poly-lactide-co-glycolide
(PLGA)
3. Polymeric Nano-particles
4. Absorption enhancers: surfactant,
fatty acid, taurochlorate, saturated
polyglycolysed glyceride, trihydroxy bile
salt and hyaluronic acid
5. Cyclodextrins: Cyclosporine A
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