www.pharm.monash.edu.au/mips

Asthma & COPD - 13th & 14th April 2011London, 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

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 asa single cause of death after coronary heart disease,cerebrovascular disease and acute respiratory infections

• The primary cause of COPD is smoking

• Other factors include exposure to indoor smoke frombiomass fuel used for cooking, heating and air pollutionfrom fuel exhaust

• 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 riseof dual combination products

COPD

Clinical Diagnosis of COPD

• 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%

Pulmonary function testing 4 components:

Post-bronchodilatorspirometry

Spirometry Diffusion capacityLung volumes

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

Gradation of the severity of airflow obstruction

NICE clinical guideline 12 2004

ATS/ERS 2004 GOLD 2008 NICE clinical guideline 101 2010

FEV1 % predicted

Severity of airflow obstruction

Post-bronchodilator Post-bronchodilator

Post-bronchodilator

≥ 80% Mild Stage 1 – Mild Stage 1 – Mild

50–79% Mild Moderate Stage 2 –Moderate

Stage 2 – Moderate

30–49% Moderate Severe Stage 3 – Severe Stage 3 – Severe

< 30% Severe Very severe Stage 4 – Very severe

Stage 4 – Very severe

• Post-bronchodilator FEV1/FVC < 0.7

Treatment of COPD

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

First line therapy: smoking cessation

Second line therapy: symptoms relief or

prevention

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

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

Does it have a future?

Triple Therapy

• Beta Agonist (formoterol/fluticasone)

• Inhaled Corticosteroid (budesonide)

• Muscarinic Anti Agonist (tiotropium/ipratropium bromide)

• Clinical practice recommends triple therapy, but full clinical evidence is needed

LABA + ICS + L/S AMA

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

Molecules used in the treatment of COPD

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)

SABA - Short 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)

Theophylline (oral) Roflumilast (oral)

slow onset 60 - 500 μg

Nuelin (Meda), Slo-Phyllin (Merck Serono), Uniphyllin (Napp), Daxas (MSD)

LABA - Long Acting Beta 2 Agonist

PDE4I - Phosphodiesterase inhibitor

Molecules used in the treatment of COPD

Ipratropium Bromide; ~ 30 min & 8 Hr; 20 - 40 μgAtrovent (Boehringer Ingelheim), Respontin (GSK), Ipatropium SteriNeb (Teva)

SAMA - Short Acting Muscarinic Anti Agonist

Tiotropium; 1 to 2 Hrs & 24 Hr ; 2.5 μg

Spiriva (Boehringer Ingelheim)

LAMA - Long Acting Muscarinic Anti Agonist

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)

ICS - Inhaled Corticosteroid

New Molecules

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

MABA

VLABA

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.)

Very long acting LABA; bronchodilation for at least 24 hours, once a day

Indacaterol (Novartis, Ombrez®); Carmoterol® (Chiesi Farmaceutici)

Table IV: Drug combinations under clinical investigation

Clinical Trials Data

1991 - 2006

2007

2008-2009

2009 - 2010

Perng et al. (1991)

Tiotropium+LABA/ICS

Improvement in FVC, FEV1, and

perceived lung function and quality of life

Lee et al. (2006)

Tiotropium/ICS/LABA in combination

42,090 patients

Reduced risk of all-cause mortality, COPD

exacerbations, and COPD hospitalisations

Cazzola et al. (2007)

Fluticasone +Salmeterol+Tiotropium

3 months, 90 patients

Significantly improved FEV1 for severe COPD

OPTIMAL trial (2007)

Fluticasone/Salmeterol+Tiotropium

1 year, 449 randomised patients

no reduction in exacerbations. Improved

lung function, quality of life, and

hospitalization. Possibility of a ‘ceiling

effect’Singh et al. (2008)

Ttiotropium + Salmeterol/Fluticasone

2 weeks study

Specific airways conductance (body

plethysmography, sGaw). sGaw and

FEV1 improved

Welte et al. (2009)

Budesonide/Formoterol + Tiotropium

A rapid and sustained lung function

improvement, triple therapy has been well

tolerated

Cazzola and Matera (2009)

VLAMA/VLABA + ICS

triple therapy could be promising

Williamson et al. (2010)

Tiotropium + Budesonide/Formoterol

Additive bronchodilation effect and

improved lung function

Table IV: Drug combinations under clinical investigation

Ongoing Clinical Trials

Phase Compounds Study

Phase II - Completed

Fluticasone Propionate/Salmeterol

+

Tiotropium

Evaluating the Effects of SERETIDE™

150/500μg Twice Daily Plus Tiotropium

Bromide 18 μg Once Daily Compared With

the Individual Treatments in the Treatment

of Subjects With COPD. A Randomised,

Double-Blind, Double Dummy, 3 Way

Cross-Over Study

Phase IV - Completed

Fluticasone Propionate/Salmeterol

+

Tiotropium Bromide

A 24-Week Randomized, Parallel Double-

Blind Study to Evaluate the Safety and

Efficacy of ADVAIR DISKUS 250/50 μg

Plus SPIRIVA HANDIHALER Versus

SPIRIVA HANDIHALER Plus Placebo

DISKUS in Subjects With COPD

Phase IV - Not yet completed Fluticasone Propionate/ Salmeterol

+

Tiotropium Bromide

A Randomized, Parallel, Double-Blind

Study of Fluticasone

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

GS

K

Table IV: Drug combinations under clinical investigation

Ongoing Clinical Trials

Phase Compounds Study

Phase IV

(completed)

Budesonide/Formoterol

+ Tiotropium Bromide

A Double-Blind, Randomised, Parallel

Group, Multi-Centre, Study to Evaluate

Efficacy and Safety of

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

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

Phase IV (not yet completed) Salmeterol + Fluticasone +Tiotropium A Randomized, Parallel, Double-Blind

Inhaled Corticosteroid Withdrawal Study in

Patients With COPDB.I

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ni. D

un

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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

Table IV: Drug combinations under clinical investigation

Triple Formulations

Molecules DPI

Nebulisers

pMDI

Inhalation Delivery

Powder Engineering

Lactose blends

Solutions/suspensions

Triple formulations are no

different from multicomponent

formulations.

Drug dose and loading may be

an issue

Combination Products used in the Treatment of COPD

GSK

AZ

B.I.

Combination Products used in the Treatment of COPD

• Alvesco Combo (Ciclesonide/formoterol; Altana & Sanofi)

• Fostair (Formoterol/beclometasone; Chiesi)

• Flutiform (Fluticasone/formoterol; Skye)

• Allergospasmin (Cromolyn/reproterol; ASTA Medica)

• Triohale (Tiotropium/formoterol/ciclesonide; CIPLA)

pMDI

• Advair (Salmeterol/fluticasone; GSK)

• Symbicort (Formoterol/budesonide, AZ)

• Alvesco Combo (Ciclesonide/formoterol; Altana & Sanofi)

• Bronchodual (Fenoterol/Ipatropium; BI)

• Relovair (Fluticasone/vilanterol; GSK)

• Atmadisc Forte Diskus (Salmeterol/fluticasone; GSK)

DPI

Co

mm

erc

ial D

rive

• Combivent (Salbutamol/Ipatropium; B.I.)

• Duovent (Fenoterol/Ipatropium; B.I.)Nebuliser

• 14 products, 9 manufacturers, 12 molecules, 3 types of formulations

• 1 Triple combination product

Triple therapy on the market

9 mg tiotropium bromide

6 mg formoterol fumarate dihydrate

200 mg ciclesonide

Triohale – CIPLA, HFA pMDI – Not EU, nor USA

IP Landscape

2002 2003 2005 2006 2008

Epigenesis CIPLA Boehringer Ingleheim Schering Plough GSK

WO02085308A2 WO04019985A1 US20060057074A1 WO06105401A2 WO2009036243A1

mRNA, steroid,

upiquinone

Acetylcholinergic,beta2

agonist, corticosteroid

Acetylcholinergic,

corticosteroid,

betamimetic

Acetylcholinergic,

corticosteroid, LABA

Muscarinic AcetylCholine

receptor, beta2 agonist,

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,

corticosteroid,

betamimetic

Acetylcholinergic,

adrenoreceptor agonist,

antileukotrienne, PDE4I

CCR1antagonist,

glucocorticoid agonist,

beta2 agonist (option)

Granted

(ex. De)

Granted

(ex. De & USA)

Not granted in Germany

(national phase for others)

Boehringer Ingleheim Meda Pharma Merck

WO03030939A1 EP2098248A1 WO2009052624A1

Phosphodiesterase,

beta2 agoinist,

corticosteroids

Acetylcholinergic,

glucocorticoid, PDE4I

Montelukast acid, PDE4I,

corticosteroid

Not granted Patent pending Not granted in Germany

(national phase for others)

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 Seretidepatent. 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.”

Opinion

• Size of the market

• Economic benefits of triple therapy

• Cost of clinical trials

• Availability of new molecular entities

For triple therapy to become the standard in the treatment of COPD, a number of questions need to be answered:

Commercial

• Clinical need & benefits

• Nature of optimal combinations

• Dosing frequency, mode of administration

• Improved patient compliance

Clinical