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Through a CME Grant sponsored by

Session on COPD: Novel Concepts

and Promising New Drugs

Topic: New Treatment = Better Outcome?

New Treatment = Better Outcome ?

Tim S. Trinidad, MD

Disclosure

Present: COPD Advisory Board Member & Lecturer

– Novartis

– Astra Zeneca

– UAP

Past: COPD Lecturer

– Nycomed Takeda

– Boehringer Ingelheim

– Glaxo Smith Kline

Scope of the Discussion


Pharmacologic

Non-pharmacologic

– Risk reduction

– Vaccination

– Rehab or Physical Activity

– Invasive (surgical or non-bronchoscopic LVRS)

Reference Point for “New”

LABA/ ICS Tiotropium

PDE4I

(2001) (2004) (2011) (2014)

“Old” “New”

Pharmacologic Agents: Recently approved in some countries or Undergoing clinical development (Not listed in GOLD 2014)

TNF-a inhibitors: Infliximab, PKF242-484,

PKF241-466

IL-6 inhibitors: Tocilizumab

Chemokine antagonists: ADZ8309, SCH-527123, SB-656933

NF-kB inhibitors: IMD-0354, IMD-0650,

BMS-345541, SC-514, AS602868

p38 MAPK inhibitors: SB681323, PH797804,

PF03715455, GSK681323

PI3K inhibitors: PI3K-g inhibitors, TG100-115

JAK/STAT inhibitors: Tofacitinib

Ngkelo, A. et al. New treatments for COPD. Current Opinion in Pharmacology 2013, 13:362–369

Pharmacologic Agents: Recently approved in some countries or Undergoing clinical development (Not listed in GOLD 2014))

LABA/ICS combination:

Mometasone/ Indacaterol (QMF149)

LAMA/LABA/ICS ‘‘triple combination inhalers’’:

Ciclesonide/ Tiotropium/ Formoterol

Beclomethasone/ Formoterol/ Glycopyrronium

QMF149/Glycopyrronium

Umeclidinium/ Vilanterol/ Fluticasone furoate

GSK961081/ Fluticasone


LABAs:

Olodaterol, Vilanterol, Abediterol

LAMAs:

Umeclidinium

LAMA/LABA combinations:

Glycopyrronium/ Indacaterol (QVA149),

Umeclidinium/ Vilanterol

Tiotropium/ Olodaterol

Aclidinium/ Formoterol

Glycopyrronium bromide/ Formoterol (PT001)

MABAs:

GSK-961081, AZD2115


“New” Pharmacologic Treatment

LABA/ ICS Tiotropium

PDE4I LABA/LAMA

(2001) (2004) (2011) (2014) (2015)

(UPDATE 2015)

Reference Point for Better Outcome (GOLD Treatment Goals)

Reduce symptoms

– Relieve symptoms

– Improve exercise tolerance

– Improve health status

Prevent future risks

– Prevent and treat exacerbations

– Prevent disease progression

– Reduce mortality

GOLD 2014. Available from: http://www.goldcopd.com.

LABA/ ICS & Treatment Goals

• Calverley, P et al. Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary Disease. N Engl J Med 2007;356:775-89.

• Cochrane Database of Systematic Reviews, Issue 4, 2008

Relieve symptoms

Improve exercise tolerance

Improve health status Prevent and treat exacerbations

X Reduce mortality ? Prevent disease progression

Tiotropium & Treatment Goals

• Tashkin, D et al. A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease. N Engl J Med 2008;359: 1543-54.

• The Cochrane Library 2012, Issue 7

Relieve symptoms

Improve exercise tolerance

Improve health status Prevent and treat exacerbations

? Reduce mortality X Prevent disease progression

Unmet needs in COPD management

Rennard SI, et al. The safety and efficacy of infliximab in moderate-to-severe COPD. Am J Respir Crit Care Med 2007; 175: 926–34.

Infliximab (TNF-A Inhibitor)X CRQX Pre-FEV1X 6-MWTX SF-36 X TDI(?) Cancer(?) Pneumonia

Mahler DA et al. Efficacy and safety of a monoclonal antibody recognizing interleukin-8 in COPD: a pilot study. Chest 2004; 126: 926–34.

ABX vs IL-8 TDIX FEV1X SGRQX 6MWT

PDE4I: Roflumilast Achieved GOLD guidelines

recommendations and FDA approval in several countries

Anti-inflammatory drug: used for ECOPD prevention

In comparison to other (old) drugs (NNT)

– LAMA: 16

– LABA/ ICS: 20

– Roflumilast: 3-4 • Cochrane Database Syst Rev. 2012 Jul 11; 7:CD009285.

• Nannini LJ, et al. Cochrane Database of Systematic Reviews 2012, Issue 9

• Bateman, E et al. Roflumilast with long-acting β2-agonists for COPD: influence of exacerbation history. ERJ September 1, 2011 vol. 38 no. 3 553-560

“General COPD”

http://www.ncbi.nlm.nih.gov/pubmed/22786525

We continue to know more

Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points(ECLIPSE)

3 yearsFollow-up

Vestbo J, et al. Am J of Resp & Crit Care Med Vol. 189 Num. 9 | May 1 2014

Pulmonary function

Whole body impedance/fat-free mass

Chest computed tomography

Exercise capacity

Resting oxygen saturation

Biomarkers

– Blood samples

– Induced sputum

– Exhaled breath condensate

– Blood and urine metabolomics

Health outcomes

Blood samples for genetic markers


COPD is very heterogeneous clinical presentation

Some patients are frequent exacerbator others are not

Some patients have severe inflammation others have

less inflammation

Some patients are rapid FEV1 decliners others are not

For those rapid decliners, the greatest decline occurs in

the moderate to severe stage

A single or combination of disease attributes

that describe differences between individuals with COPD

as they relate to clinically meaningful outcomes :– Symptoms

– Exacerbations

– Response to therapy

– Rate of disease progression

– Death

COPD phenotype

COPD Phenotype Application

Roflumilast Story

Design OPUS ( 111) / RATIO (112) Study

N: 2,686

FEV1: <50%

Meds:

SABA & SAMA

ICSRoflumilast: 500

Placebo

52 Weeks

Rate Ratio of Exacerbation (moderate & severe)

0.75 1.00 1.25

Rate Ratio

0.50 1.50

Favors Roflumilast Favors PlaceboStudy iExacerb. Rate (%)

M2-111 -14.0

M2-112 -15.2

Why?

Post-hoc Analysis: Who are the responders?

Identification of Patient Target Population

Confirmatory 1-yr pivotal studiesM2-124, M2-125

Severe/very severe COPD

Hx chronic cough & sputum

Hx of exacerbations

Hx chronic cough & sputum

Subgroup analyses ofearly phase III studies

M2-111, M2-112

Severe/very severe COPD

N: 3,091

FEV1: <50%

IC:

(+) C. Bronchitis

(+) Sputum

(+) Exacerbations

Meds:

No ICS

(+) LABA

(+) SAMA

Pivotal Study M2-124/ M2-125

Roflumilast: 500

Placebo

52 Weeks

Calverley PMA, Rabe, KF et al. Lancet 2009;374:685–694.

Rate Ratio of Exacerbation (moderate & severe)

0.75 1.00 1.25

Rate Ratio

0.50 1.50

Favors Roflumilast Favors Placebo

M2-124 -14.9

M2-125 -18.5

Study iExacerb. Rate (%)

M2-111 -14.0

M2-112 -15.2

Calverley PMA, Rabe, KF et al. Lancet 2009;374:685–694.

The phosphodiesterase 4 inhibitor (Roflumilast)

may also be used to reduce exacerbations

for patients with

chronic bronchitis,

severe and very severe airflow limitation,

and frequent exacerbations

that are not adequately controlled by long- acting

bronchodilators.

GOLD: Statements on Roflumilast

GOLD 2014. Available from: http://www.goldcopd.com.

Decline in Lung Function of COPD Patients Fletcher-Peto Curve vs ECLIPSE Curve

FE

V1

(% o

f va

lue

at

ag

e 2

5)

25 50 75

Age (years)

100

80

50

30

0

Smoked

regularly and

susceptible to

its effects

Never smoked

or not susceptible

to smoke

Most Rapid

Decline(Fletcher)

Most Rapid

Decline(ECLIPSE)


Do we have a better response if we give the drugs during the early stage?

Tiotropium UPLIFT Story

UPLIFT Study

N: 4,383

FEV1: <70%

Meds allowed:

SABA, LABA

ICS, XanthineTiotropium 18 ug OD

Placebo

4 Years

Yearly decline in Pre FEV1Post FEV1

UPLIFT Decline in FEV1

N: All Subjects N: Subjects with moderate Obstruction

Tiotropium : 40±1 ml per yearPlacebo: 42±1 ml per yearP = 0.21

Tiotropium : 43±2 ml per yearPlacebo: 49±2 ml per yearP = 0.024

• Tashkin, D et al. A 4-Year Trial of Tiotropium in COPD. N Engl J Med 2008;359: 1543-54.• Decramer, M. et al. Effect of tiotropium on outcomes in patients with moderate chronic

obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet 2009; 374: 1171–78

Study FEV1 % predicted inclusion criteria

TORCH (2003-06) < 60% UPLIFT (2004-08) < 70%Glycopyronium/ Indacaterol < 80% and ≥ 30%Umeclidinium/ Vilanterol ≤70% Glycopyrrolate/ Formoterol < 80% and ≥ 30%Tiotropium/ Olodaterol < 80%

http://www.clinicaltrials.gov

Clinical Trials in COPD FEV1 Inclusion Criteria

Banerji, D. et al. Dual bronchodilation for the treatment of chronic obstructive pulmonary disease: a review of the latest clinical data. Clin. Invest. (2014) 4(6), 511–533

LAMA/ LABA FDC for COPD: Approved or Under Investigation

Banerji, D. et al. Dual bronchodilation for the treatment of chronic obstructive pulmonary disease: a review of the latest clinical data. Clin. Invest. (2014) 4(6), 511–533


Yes, but there is room for improvement.

Medicines in Development COPD: 2012 Report America’s biopharmaceutical research companies

New Treatment = Better Outcome ?(part 2)

PCCP Mid-year 2018 Version


We know more about COPD.

Beginning to know: Who and when to give the drug.

Yes, new treatment = better outcome but we need more.

More drugs in development.

New Treatment Better Outcome

RCT

Morbidity Mortality

Real World

Health providers

General population

Patient

• Diagnose early COPD• Spirometry facility• Increase awareness• How to recognize • How to treat• Why & how to use inhalers

Thank you very much for your attention

Through a CME Grant sponsored by

Session on COPD: Novel Concepts

and Promising New Drugs

Topic: New Treatment = Better Outcome?

topic: new treatment = better outcome? · pdf filetopic: new treatment = better outcome? ......

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