Newer drugs in management of copd [2018 update]

An overview of the newer drugs for COPD management. A look into the recent trends in research and clinical trials on COPD till 2018.

1. NEWER DRUGS
in management of
COPD

2. CONTENT
◦Introduction and burden
◦Traditional approach to COPD
◦Challenges in newer approach
◦Newer drugs & combinations
◦Newer targets
◦Drugs in the pipeline
◦What lies ahead
◦Conclusion

3. COPD: an introduction
COPD is a debilitating lung disease
characterized by airflow limitation that is usually
progressive and associated with an enhanced
inflammatory response

COPD is a multicomponent disease
characterized by:
Mucus hyper secretion, airway narrowing and loss of
alveoli in the lungs
loss of lean body mass and cardiovascular effects at a
systemic level

4. Bronchodilators are the mainstay of
pharmacological therapies for COPD. Treatment
options include:
Long-acting muscarinic antagonists (LAMAs)
and long-acting β
2 agonists (LABAs), which
could be used as monotherapy or in
combination
Inhaled glucocorticosteroids (ICS)
recommendedonly as add-on therapy in
patients with severe and very severe COPD
and frequent exacerbators that are not
controlled by long-acting bronchodilators
COPD:
traditional approach to management

5. COPD:
traditional approach to management

6. COPD:
traditional approach to management

7. Challenges in developing new
strategies
Clinical studies with new drugs for COPD have
been difficult for several reasons:
The immunopathology of COPD is complex
and variable (cigarette smoke, innate immune
response to oxidants and microbes, effect of co-
morbidities)
Difficulty in starting therapy early in natural
history of the disease (cardiovascular/
metabolic/ malignancies and its treatments)
There is a need to identify and validate
endpoints that can capture the considerable
heterogeneity of pulmonary and systemic
features. (annual rate of change of FEV1

8. Challenges in developing new
strategies
Clinical studies with new drugs for COPD have
been difficult for several reasons:

Phenotypes of COPD needs to be defined
and validated in order to tailor drugs to
individual patients; it is becoming increasing
clear that “one size does not fit all” in COPD.

There is a need to identify and validate
biomarkers that may predict potential
responders for specific therapy.

9. Where we stand
Current therapy is merely palliative.
More focus should be on preventative and
regenerative therapies.

However, these are ambitious targets for
new drugs…

10. So, what’s new?
New pharmacotherapies for COPD


Therapies in development


New strategies/ approaches

11. New
pharmacotherapies
for COPD

12. New pharmacotherapies for COPD
1.New LAMA monotherapy
2.New LABA monotherapy
3.New LABA+LAMA combination therapy
4.New LABA+ICS combination therapy
5.New oral agents

13. New LAMA monotherapy
1.Aclidinium
Faster onset of action to thiotropium
better night-time FEV1
BID dosing

2.Glycopyrronium
Rapid onset
Very good safety profile (antimuscarinic & cardiac side
effects similar to placebo)

3.Umeclidinium
Minimal antimuscarinic side effects
Combined with vilanterol

14. New LABA monotherapy
1.Indacaterol
Improved cardiovascular safety profile & lung function
compared to salmeterol

2.Vilanterol
Ultra-long-acting β₂ adrenoreceptor agonist
Combined with fluticasone furoate

3.Olodaterol
Ultra-long-acting β adrenoreceptor agonist

4.Abediterol
Better lung function impact in comparison to indacaterol

15. New LABA-LAMA combination therapy
1.Umeclidinium & Vilanterol
No increase in adverse events compared to placebo
First LAMA-LABA approved by the US FDA for
maintenance treatment

2.Glycopyrronium & Indacaterol
No increase in adverse events compared to tiotropium
or glycopyrronium alone
Significantly better FEV1 and SGRQ compared to
tiotropium and glycopyrronium alone

16. New LABA-LAMA combination therapy
3.Tiotropium & Olodaterol
Significant improvement in SGRQ score was only
seen in the 5/5 μg dosing
No significant difference in adverse events compared
to monocomponents

4.Aclidinium & Formoterol
Significant improvement in FEV1, 1-hour postdosing
compared to monocomponents

5.Glycopyrrolate & Formoterol
Improvement in FEV1 from 0 hours to12 hours versus
monotherapy with glycopyrrolate, formoterol, or
tiotropium

17. New LABA-ICS combination therapy
1.Vilanterol & Fluticasone
Once-daily FDC of LABA-ICS
Compared to vilanterol alone, FDC leads to an
increased risk of pneumonia

2.Indacaterol & Mometasone
Studied in persistent asthma in adolescents and adults

18. New LABA-ICS combination therapy
3.Formoterol & Ciclesonide
Noninferiority comparison to combined fluticasone
propionate/ salmeterol in asthma

4.Formoterol & Fluticasone
More rapid bronchodilator effect than fluticasone
propionate/salmeterol
Approved for asthma, but in Phase III clinical trials for
moderate to severe COPD

19. New oral agents
1.Azithromycin
Careful risk–benefit assessment given the side-effect profile
QT interval prolongation, ototoxicity, and drug–drug
interactions

2.Moxifloxacin
Intermittent pulsed therapy with 5 days of moxifloxacin every
8 weeks for six courses
Significant GI side effects compared to the placebo group

4.Simvastatin
No significant difference in exacerbations in one
randomized, placebo-controlled trial
No significant difference in fatal or nonfatal adverse events

20. Pathology, targets,
and new drugs for
COPD

21. Pathology, targets, and new drugs
for COPD
Potential therapy approaches

22. Overview of some of the pathophysiologic
processes involved in COPD

Cigarette smoke contains reactive oxygen
species, particulates, and chemicals, which lead
to a range of inflammatory effects:

Macrophage, epithelial cell, and CD81 T cell
activation → These cells in turn release
neutrophil chemotactic factors → Numerous
local inflammatory mediators are then
released, along with proteases, which break
down connective tissue in the lung, causing
emphysema.

23. Proteases are also important in stimulating
mucus hypersecretion, which may manifest as
chronic bronchitis.
Profibrotic mediators are also released by
epithelial cells, contributing to fibroblast
proliferation and small airway fibrosis.
Novel therapies include those aimed at local
as well as systemic inflammation.
The most ambitious target is to regenerate
lung tissue in response to emphysema.
Overview of some of the pathophysiologic
processes involved in COPD

24. New Therapies in
Development

25. New therapies in development
1.Novel inhaled dual PDE3 & PDE4 inhibitors
2.Novel macrolide / fluroketolide
3.NAC
4.CXCR2 antagonists
5.Emerging anticytokine therapies

26. Novel inhaled dual PDE3 & PDE4
inhibitors
Novel inhaled dual PDE3 and PDE4 inhibitors,
such as RPL554 and the PDE4 inhibitor
CHF6001, are being investigated for their
potential bronchodilator and anti-inflammatory
effects in asthma and COPD.
In multiple functional assays, CHF6001 – more
potent than roflumilast and cilomilast.
In 4 exploratory studies, inhaled RPL554 was
proven to be an effective and well-tolerated
bronchodilator and anti-inflammatory drug.
Safety profiles and bronchodilator response of
these compounds with comparable efficacy to
salbutamol

27. Novel macrolide / fluroketolide

Solithromycin:

currently being investigated in the treatment of
community-acquired pneumonia
has shown better anti-inflammatory profiles
compared with the currently available
macrolides
may be a promising anti-inflammatory and
antimicrobial drug for the treatment of COPD
in the future.

28. N-acetylcysteine (NAC)
One of the most widely used and tested
antioxidants.
This drug has been shown to reduce bronchial
hypersecretion and has been used as a
mucolytic for many years.
Only recently have studies addressed its
effects more scientifically; it has reportedly
slowed the decline in FEV1 and led to a
reduction in the number of COPD
exacerbations

29. CXCR2 antagonists
Antagonists of the human CXCR2 receptors
may affect neutrophil trafficking
have been investigated in COPD
One of the CXCR2 antagonists, MK-7123,
showed improved FEV1 in comparison to
placebo in patients with COPD, and it has also
been investigated in Phase II clinical trials

30. Emerging anticytokine therapies
Benralizumab and mepolizumab are
humanized monoclonal antibodies directed at
the alpha subunit of the interleukin (IL)-5
receptor (IL-5Rα).
Both drugs are currently in Phase III
development for both COPD and severe
asthma.
Benralizumab was shown to reduce COPD
exacerbations and improve other symptoms of
COPD in certain patient groups.

31. New strategies &
approaches

32. New therapies in development
1.Drugs to aid smoking cessation
2.Anti-infective and anti-inflammatory agents
3.Miscellaneous class of drugs

33. Smoking cessation
Smoking cessation is the first priority in the
management of a COPD patient who smokes.
To date, it is the only intervention shown to
convincingly reduce the accelerated decline in
pulmonary function and improve long-term
prognosis
Success in quitting is increased by behavioral
support in addition to a range of
pharmacotherapies.

34. Drugs to aid smoking cessation
Current treatments
First line
Nicotine replacement
therapy
 Bupropion
 Varenicline (partial agonist for a4b2 nicotinic
acetylcholine receptors)

Second-line
 Nortriptyline
 Clonidine

35. Drugs to aid smoking cessation
New approaches
Anti-nicotine vaccines: NicVAX, SEL-068
Electronic cigarettes
Novel nicotine formulations: inhaled
aerosolized nicotine (ARD-1600)
Nicotine partial agonist: cytisine
Cannabinoid receptor 1 antagonists:
taranabant
Dopamine D3 receptor antagonists:
GSK598809
Monoamine oxidase inhibitors: selegiline

36. Anti-infective and anti-inflammatory
agents
There is growing evidence that exacerbations
accelerate the progressive decline in lung
function in COPD patients.
Several studies now implicate bacteria as an
important cause of exacerbations and bacterial
colonization is frequently found in patients with
COPD.
There seems to be a correlation between
bacterial colonization of lower airways and
elevated levels of inflammatory mediators

37. Anti-infective and anti-inflammatory
agents
There is growing evidence that exacerbations
accelerate the progressive decline in lung
function in COPD patients.
Several studies now implicate bacteria as an
important cause of exacerbations and bacterial
colonization is frequently found in patients with
COPD.
There seems to be a correlation between
bacterial colonization of lower airways and
elevated levels of inflammatory mediators

38. Miscellaneous class of new drugs
for COPD
1.Antioxidants
2.Mucolytics
3.Protease inhibitors
4.Antifibrotics
5.Drugs to combat cachexia & muscle wasting
6.Monoclonal antibodies
7.Drugs to slow aging
8.Lung regeneration

39. Antioxidants
Dietary antioxidants
N-acetyl-cysteine, N-acystelyn, N-isobutyryl-
cysteine, erdosteine, procysteine,
carbocysteine
Thiols, spin traps
Enzyme mimetics: superoxide dismutase,
catalase and glutathione peroxidase
Polyphenols

40. Mucolytics
N-acetyl-cysteine and carbocysteine
Epidermal growth factor receptor tyrosine
kinase inhibitors

41. Protease inhibitors
Neutrophil elastase inhibitors: sivelestat
(ONO-5046), silanediol isosteres, AZD 9688
MMP-9 & MMP-12 inhibitors
Broad-spectrum MMP inhibitors: ilomastat,
marimastat

42. Antifibrotics
Agents used in idiopathic pulmonary fibrosis:

Pirfenidone
Endothelin antagonists
PDE5 inhibitor: sildenafil
MoABs: anti-TGF-b, anti-FGF, anti-IL-13, anti-
avb6 integrin (STX-100), anti-CCL2 (CNTO
888)

43. Drugs to combat cachexia &
muscle wasting
Growth hormone releasing factor analogue
(tesamorelin)

44. Monoclonal antibodies
Anti-TNFa
Anti-IL-1b
Anti-IL-6 (tocilizumab)
Anti-CXCL8 (IL-8)
Anti-IL-17, anti-IL-13, anti-IgE
Anti-TGF-b

45. Drugs to slow aging
Sirtuin 1 activator (GSK2245840)

46. Lung regeneration
Retinoids (g-selective retinoid agonist,
palovarotene)
Mesenchymal stem cell therapy
Gly-his-lys (GHK) tripeptide

47. To summarize,
anti-infective
and
antioxidant
therapy
improved
current drugs
novel
approaches
directed
against innate
immune
system
For the future treatment of COPD, it should be
possible to have

48. To summarize,
In terms of the processes involved in COPD, there is
rapid advancement of knowledge of viral responses
and fibrosis, steroid-insensitive inflammation,
autoimmunity, aberrant repair, accelerated aging, and
appreciation of systemic disease and comorbidities.

There is the need to develop validated noninvasive
biomarkers for COPD and to have novel challenge
models in animals and humans

49. Conclusion
The availability of increasing numbers of
therapeutic agents brings new optimism in
the management of patients with COPD.

51. References
Ross, C.L. and Hansel, T.T., 2014. New drug therapies for
COPD. Clinics in chest medicine, 35(1), pp.219-239.

Compton, C., McBryan, D., Bucchioni, E. and Patalano, F., 2013.
The Novartis view on emerging drugs and novel targets for the
treatment of chronic obstructive pulmonary disease. Pulmonary
pharmacology & therapeutics, 26(5), pp.562-573.

Barjaktarevic, I.Z., Arredondo, A.F. and Cooper, C.B., 2015.
Positioning new pharmacotherapies for COPD. International
journal of chronic obstructive pulmonary disease, 10, p.1427.