An extensive review of the potential of triple therapy in the treatment of COPD, spanning Clinical Trials, Clinical Practice, Commercial insight and Intellectual Property

1. Asthma & COPD - 13th & 14th April 2011
London, UK
IS THERE A FUTURE FOR TRIPLE THERAPY
IN COPD?
Philippe Rogueda, Rania O Salama, Daniela Traini, Arthur Lallement,
Paul M Young, Ilian Iliev
University of Sydney, University of Alexandria, Cambridge Intellectual
Property Ltd
www.pharm.monash.edu.au/mips

2. Facts
• Every hour COPD kills over 250 people worldwide
• COPD is a major cause of hospital admission
• COPD shares 4th and 5th places with HIV/AIDS worldwide as
a single cause of death after coronary heart disease, C
•
cerebrovascular disease and acute respiratory infections
The primary cause of COPD is smoking
O
• Other factors include exposure to indoor smoke from P
biomass fuel used for cooking, heating and air pollution
from fuel exhaust
D
• COPD drug market in France, Germany, Italy, Japan, Spain,
the UK and the USA was worth nearly $8.4 billion in 2009
• Substantial market growth (2006-2009) driven by the rise
of dual combination products

3. Clinical Diagnosis of COPD
Pulmonary function testing 4 components:
Post-bronchodilator Spirometry Lung volumes Diffusion capacity
spirometry
• Mean FEV1 for COPD patient ~40 %
• FEV1 ≤ 50% determines start of treatment
• Formal COPD diagnosis is defined by FEV1 < 80% predicted, and
FEV1/FVC (forced volume capacity) ratio < 70%
Cf.: NICE (the National Institute for Health and Clinical Excellence), ATS/ERS (American Thoracic
Society and European Respiratory Society) and GOLD (the Global Initiative for Chronic Obstructive Lung
Disease) guidelines

4. Gradation of the severity of airflow obstruction
NICE clinical ATS/ERS 2004 GOLD 2008 NICE clinical guideline
guideline 12 101 2010
2004
FEV1 % Severity of airflow obstruction
predicted
Post-bronchodilator Post- Post-bronchodilator
bronchodilator
≥ 80% Mild Stage 1 – Mild Stage 1 – Mild
50–79% Mild Moderate Stage 2 – Stage 2 – Moderate
Moderate
30–49% Moderate Severe Stage 3 – Severe Stage 3 – Severe
< 30% Severe Very severe Stage 4 – Very Stage 4 – Very severe
severe
• Post-bronchodilator FEV1/FVC < 0.7

5. Treatment of COPD
First line therapy: Second line therapy:
smoking cessation symptoms relief or
prevention
Bronchodilators are the cornerstone
of COPD treatment
Combination therapy has become the Gold Standard
Aims: achieve bronchodilation, reduce hyperinflation, improve emptying of the lung and exercise
performance

6. Treatment of COPD
*offer LAMA in preference to regular SAMA 4 times/day
** Consider LABA+ LAMA if ICS declined or not tolerated
Offer therapy
Consider therapy

7. Triple Therapy
• A LAMA is offered in addition to LABA + ICS to people
with COPD who remain breathless or have exacerbations
despite taking LABA + ICS, irrespective of their FEV1
• If exacerbation or breathlessness persists, triple
inhalation therapy of LABA, LAMA and ICS should be
offered
Triple therapy is a last resort
Use of ICS in COPD is being debated

8. Triple Therapy
LABA + ICS + L/S AMA
• Beta Agonist (formoterol/fluticasone)
• Inhaled Corticosteroid (budesonide)
• Muscarinic Anti Agonist (tiotropium/ipratropium bromide)
• Clinical practice recommends triple therapy, but full clinical
evidence is needed
Does it have a future?

9. Molecules used in the treatment of COPD
Current therapy in COPD aims to provide bronchodilation
• Most treatments and inhaled and based on 2 agonists or
anticholinergics/muscarinics
• Theophylline (Phosphodiesterase-4 inhibitor, PDE4I) is given orally
• Anti-inflammatory medicines, such as ICS, are also used to treat
secondary symptoms of COPD, but their effectiveness is debated
• LABA, SABA, LAMA and SAMA tend to be used to relieve symptoms,
while ICS and PDE4I could provide a basis of prophylactic therapy
New molecules are being developed with longer or dual action

10. Molecules used in the treatment of COPD
SABA - Short Acting Beta 2 Agonist
Salbutamol sulphate, Terbutaline
~ 5 min & 4-6 Hr; 95 - 500 μg; 1 to 5 mg (nebuliser)
Airomir (Teva), Asmanal Clickhaler (Focus), Easyhaler Salbutamol (Orion), Pulvinal Salbutamol (Chiesi),
Salamol Easi-Breathe (Ivax) , Steri-Neb (Teva), Ventolin (GSK) Bricanyl (AstraZeneca)
LABA - Long Acting Beta 2 Agonist
Indacaterol, Formoterol fumarate dehydrate, Salmeterol Bambuterol (oral)
~ 5 min & > 12 Hr; 6 – 20 mg
Ombrez (Novartis), Oxis (Astrazeneca), Easyhaler formoerol (Orion), Foradil (Novartis), Atimos (Chiesi),
Serevent (GSK), Bambec (AstraZeneca)
PDE4I - Phosphodiesterase inhibitor
Theophylline (oral) Roflumilast (oral)
slow onset 60 - 500 μg
Nuelin (Meda), Slo-Phyllin (Merck Serono), Uniphyllin (Napp), Daxas (MSD)

11. Molecules used in the treatment of COPD
SAMA - Short Acting Muscarinic Anti Agonist
Ipratropium Bromide; ~ 30 min & 8 Hr; 20 - 40 μg
Atrovent (Boehringer Ingelheim), Respontin (GSK), Ipatropium SteriNeb (Teva)
LAMA - Long Acting Muscarinic Anti Agonist
Tiotropium; 1 to 2 Hrs & 24 Hr ; 2.5 μg
Spiriva (Boehringer Ingelheim)
ICS - Inhaled Corticosteroid
Long-term effect, slow onset, typically > 24 Hr; 50- 400 μg
Budesonide, Ciclesonide, Beclomethasone dipropionate, Fluticasone propionate,
Mometasone furoate
Budelin (Meda), Easyhaler budesonide (Orion), Pulmicort (AstraZeneca), Alvesco (Nycomed), Asmabec
(Focus), Becodisks (GSK), Clenil (Chiesi), Easyhaler Beclomethasone (Orion), Pulvinal Beclomethasone
(Chiesi), QVAR (3M), Flixotide (GSK), Asmanex (Merck & Co)

12. New Molecules
MABA
Bifunctional molecules acting both as muscarinic antagonist and 2 agonists
MABAs deliver a fixed ratio into every region of the lung
GSK-961081 is said to have entered Phase III trials in the USA
VLABA
Very long acting LABA; bronchodilation for at least 24 hours, once a day
Indacaterol (Novartis, Ombrez®); Carmoterol® (Chiesi Farmaceutici)
VLAMA
Very long acting LAMA; Long lasting bronchodilation in COPD (>24 hours)
Glycopyrronium bromide (Novartis); Milveterol and vilanterol trifenatate
(GSK); Aclidinium bromide (Almirall S.A.)

13. Table IV: Drug combinations under clinical investigation
Clinical Trials Data
Lee et al. (2006)
Perng et al. (1991)
Tiotropium/ICS/LABA in combination
Tiotropium+LABA/ICS
42,090 patients
Improvement in FVC, FEV1, and 1991 - 2006 Reduced risk of all-cause mortality, COPD
perceived lung function and quality of life
exacerbations, and COPD hospitalisations
OPTIMAL trial (2007)
Cazzola et al. (2007) Fluticasone/Salmeterol+Tiotropium
Fluticasone +Salmeterol+Tiotropium 1 year, 449 randomised patients
3 months, 90 patients 2007 no reduction in exacerbations. Improved
Significantly improved FEV1 for severe COPD lung function, quality of life, and
hospitalization. Possibility of a ‘ceiling
effect’
Singh et al. (2008)
Ttiotropium + Salmeterol/Fluticasone Welte et al. (2009)
2 weeks study Budesonide/Formoterol + Tiotropium
Specific airways conductance (body 2008-2009 A rapid and sustained lung function
plethysmography, sGaw). sGaw and improvement, triple therapy has been well
FEV1 improved tolerated
Williamson et al. (2010)
Cazzola and Matera (2009)
Tiotropium + Budesonide/Formoterol
VLAMA/VLABA + ICS
triple therapy could be promising 2009 - 2010 Additive bronchodilation effect and
improved lung function

14. Table IV: Drug combinations under clinical investigation
Ongoing Clinical Trials
Phase Compounds Study
Evaluating the Effects of SERETIDE™
150/500μg Twice Daily Plus Tiotropium
Bromide 18 μg Once Daily Compared With
Fluticasone Propionate/Salmeterol
the Individual Treatments in the Treatment
Phase II - Completed +
of Subjects With COPD. A Randomised,
Tiotropium
Double-Blind, Double Dummy, 3 Way
Cross-Over Study
A 24-Week Randomized, Parallel Double-
Blind Study to Evaluate the Safety and
GSK
Fluticasone Propionate/Salmeterol Efficacy of ADVAIR DISKUS 250/50 μg
Phase IV - Completed + Plus SPIRIVA HANDIHALER Versus
Tiotropium Bromide SPIRIVA HANDIHALER Plus Placebo
DISKUS in Subjects With COPD
Phase IV - Not yet completed Fluticasone Propionate/ Salmeterol A Randomized, Parallel, Double-Blind
+ Study of Fluticasone
Tiotropium Bromide Propionate/Salmeterol DISKUS
Combination Product 250/50 μg Twice
Daily Plus Tiotropium 18 μg Daily on
Exercise Time and Physiological
Parameters in Subjects With COPD

15. Table IV: Drug combinations under clinical investigation
Ongoing Clinical Trials
Phase Compounds Study
Phase IV Budesonide/Formoterol A Double-Blind, Randomised, Parallel
(completed) + Tiotropium Bromide Group, Multi-Centre, Study to Evaluate
Efficacy and Safety of
AZ
Budesonide/Formoterol (Symbicort
Turbuhaler) 320/9 µg One Inhalation Twice
Daily on Top of Tiotropium (Spiriva) 18 µg
One Inhalation Once Daily for COPD
patients
Uni. Dundee
Phase IV (completed) Budesonide/ Formoterol + Tiotropium A Proof Of Concept Randomized, Cross-
Over, Double-Blind Study To Evaluate
Tiotropium as Add-on Therapy to Inhaled
Budesonide/Formoterol Combination in
COPD
B.I.
Phase IV (not yet completed) Salmeterol + Fluticasone +Tiotropium A Randomized, Parallel, Double-Blind
Inhaled Corticosteroid Withdrawal Study in
Patients With COPD

16. Table IV: Drug combinations under clinical investigation
Clinical Trials Evidence Needed
• Clinical evidence is lacking to decide whether combination
therapies are less effective than the individual components
given sequentially
• The regulatory approval of triple therapy will need to be based
on multi arm clinical studies. 8 arms needed:
placebo, drug 1, drug 2, drug 3, drug 1+2, drug 1+3, drug 2+3,
drug 1+2+3
• Important advantage of a triple product: compliance

17. Table IV: Drug combinations under clinical investigation
Triple Formulations
Inhalation Delivery
Powder Engineering
Nebulisers Lactose blends
Solutions/suspensions
Triple formulations are no
Molecules DPI
different from multicomponent
formulations.
Drug dose and loading may be
an issue
pMDI

18. Combination Products used in the Treatment of COPD
GSK
B.I.
AZ

19. Combination Products used in the Treatment of COPD
• 14 products, 9 manufacturers, 12 molecules, 3 types of formulations
• 1 Triple combination product
• Alvesco Combo (Ciclesonide/formoterol; Altana & Sanofi)
• Fostair (Formoterol/beclometasone; Chiesi)
pMDI • Flutiform (Fluticasone/formoterol; Skye)
• Allergospasmin (Cromolyn/reproterol; ASTA Medica)
• Triohale (Tiotropium/formoterol/ciclesonide; CIPLA)
Commercial Drive
• Advair (Salmeterol/fluticasone; GSK)
• Symbicort (Formoterol/budesonide, AZ)
DPI • Alvesco Combo (Ciclesonide/formoterol; Altana & Sanofi)
• Bronchodual (Fenoterol/Ipatropium; BI)
• Relovair (Fluticasone/vilanterol; GSK)
• Atmadisc Forte Diskus (Salmeterol/fluticasone; GSK)
Nebuliser • Combivent (Salbutamol/Ipatropium; B.I.)
• Duovent (Fenoterol/Ipatropium; B.I.)

20. Triple therapy on the market
Triohale – CIPLA, HFA pMDI – Not EU, nor USA
9 mg tiotropium bromide
6 mg formoterol fumarate dihydrate
200 mg ciclesonide

21. IP Landscape
2002 2003 2005 2006 2008
Epigenesis CIPLA Boehringer Ingleheim Schering Plough GSK
WO02085308A2 WO04019985A1 US20060057074A1 WO06105401A2 WO2009036243A1
mRNA, steroid, Acetylcholinergic,beta2 Acetylcholinergic, Acetylcholinergic, Muscarinic AcetylCholine
upiquinone agonist, corticosteroid corticosteroid, corticosteroid, LABA receptor, beta2 agonist,
betamimetic corticosteroid (option)
Not granted Patent pending Not granted Not granted Not granted in Germany
(national phase for others)
Boehringer Ingleheim Meda Pharma AstraZeneca
WO03000241A2 WO2007071313A2 WO2008103126A1
Acetylcholinergic, Acetylcholinergic, CCR1antagonist,
corticosteroid, adrenoreceptor agonist,glucocorticoid agonist,
betamimetic antileukotrienne, PDE4I beta2 agonist (option)
Granted Granted Not granted in Germany
(ex. De) (ex. De & USA) (national phase for others)
Boehringer Ingleheim Meda Pharma Merck
WO03030939A1 EP2098248A1 WO2009052624A1
Phosphodiesterase, Acetylcholinergic, Montelukast acid, PDE4I,
beta2 agoinist, glucocorticoid, PDE4I corticosteroid
corticosteroids
Not granted Patent pending Not granted in Germany
(national phase for others)

22. IP landscape – GSK 2010 Annual Report
“A number of companies have challenged the Group’s patents covering Advair/Seretide in certain
European jurisdictions, including in the UK, Belgium, France, Germany, Ireland and the Netherlands.
As reported previously, the Group’s Seretide combination patent covering the product in the UK was
revoked in 2004.
On 23rd February 2010, in actions brought by Mylan, Hexal, Neolab and Ivax, the Federal Court in
Munich revoked the Group’s German Seretide combination patent for lack of inventive step. The
Group has appealed this decision.
In the Netherlands, in an action brought by Sandoz and Hexal, the District Court of The Hague on
26th January 2011 revoked the Supplementary Protection Certificate (SPC) which extends
protection for the product until September 2013. The Group is determining whether to appeal this
decision.
A revocation action against the basic patent covering the Seretide combination in Ireland was filed
in the High Court in Dublin on behalf of Ivax in July 2008. The High Court handed down a decision
on 26th June 2009 finding the patent invalid for obviousness. The Group filed an appeal of this
decision in October 2009. No trial date has been set for the appeal.
An action for revocation of the French Seretide combination patent was filed by Sandoz with the
Tribunal de Grande Instance of Paris. Trial has been scheduled for June 2011. The basic patent
covering the combination product in Seretide expired in September 2010 but is subject to a SPC
which extends protection until September 2013.
In January 2011, Sandoz initiated a revocation action against the Group’s Belgian Seretide
patent. To date, no generic Seretide product has been approved in any major European market
despite the revocation of certain Group patents covering Seretide in some countries.”

23. Opinion
For triple therapy to become the standard in the treatment of
COPD, a number of questions need to be answered:
• Size of the market
• Economic benefits of triple therapy
Commercial • Cost of clinical trials
• Availability of new molecular entities
• Clinical need & benefits
• Nature of optimal combinations
Clinical • Dosing frequency, mode of administration
• Improved patient compliance