Personalized Medicine in Asthma & Allergy

Canonica G.W.Personalized Medicine Clinic

Asthma & Allergy

PresidentPresident

Milano Italy

GWC reports having received research grants as well as lecture or advisory board fees from:

Canonica G.W. Disclosure of Interests

•A.Menarini•Alk-Abello’•Allergy Therapeutics•Anallergo•AstraZeneca•Boehringer Ingelheim•Chiesi Farmaceutici•Circassia•Danone•Faes•Genentech•Guidotti-Malesci•Glaxo Smith Kline•Hal Allergy•Lofarma•Meda

•Merck•Merck Sharp & Dome•Mundipharma•Novartis•Phadia•Recordati-InnuvaPharma•Roche•Sanofi-Aventis•Schering Plough•Stallergenes•UCB Pharma•Uriach Pharma•Teva•Thermo Fisher•Valeas

Ferrando et al . AAIR 2016

Ferrando et al . AAIR 2016

Clinical phenotypes

in relation to sputum eosinophils

Haldar et al AJRCCM 2008; 178: 218-224

6

Drazen J.M. NEJM 2011

Asthma phenotypes

»Type 2 »Non-type 2

Wenzel SE. Nat Med 2012;18(5):716–25.AERD = aspirin exacerbated respiratory disease;

EIA = exercise-induced asthma

Clinico-functional Phenotypes

Molecular phenotypes

Endotypes

Clinical physiologic biologic hereditary characteristics

Add pathobiologic processes at molecular level to clinical phenotype

Identifiable molecular pathway contributes to/causing clinical characteristics associated with

molecular phenotypes

Transition from

Phenotype to Endotype

Wenzel S., Nature Med.2012

Auffray et al. Genome Med 2009;1:2

Patient reported

Clinical

Functional

Cellular

Molecular

Future of phenotyping: ‘Systems Medicine’

Phenotyping……….

Chung et al ERJ 2014

Staton et al. Biomarkers in Medicine

2015

DeFerrari et al. Exp.Rev.Resp.Med. 2015

CLINICAL CHARACTERISTICS

• sympthoms

• QoL

• comorbidity

LUNG FUNCTION

• bronchialhyperreactivity

• airflowobstruction

• RV, FRC

• small airwaysobstruction

INFLAMMATORY BIOMARKERS

• bloodeosinophilia

• sputumeosinophilia

• sputumneutrophilia

• airwaysremodelling

MOLECULAR BIOMARKERS

• Th2-cytokines

• serum IgE

• FeNO levels

• CCL-11

• periostin

• Gal-3

GENOMICS

BIOMARKERS

• unknown

reactivemedicine

personalizedmedicine

hypothesisbased

approach

unbiasedmolecularapproach

biomarkers development

phenotyping evolution

Figure 1: Biomarkers discovery and phenotyping in severe asthma: actuality and perspectives

DeFerrari et al. Exp.Rev.Resp.Med. 2015

Ferrando et al . AAIR 2016

Bunyavanich & Schadt JACI 2015

Bunyavanich & Schadt JACI 2015

From Bench to Bedside

Medicel Oy - Keilaniemi 12, FIN-02150 Espoo, Finland - phone: +358-9-3867092 - info@medicel.com

24

Epigenomics

Genomics

Transcriptomics

Proteomics

Metabolomics

Biologicaldata

Modeling in basic research

Science observes phenomena and objects on multiple layers in a biological system:

ChromosomeChr. scaffoldChromatin fiberNucleosomesGenesRNAPrimary amino acid chainProtein foldingPost-translational modificationsTransport, storageProtein functionDegradation

Medicel Oy - Keilaniemi 12, FIN-02150 Espoo, Finland - phone: +358-9-3867092 - info@medicel.com

25

Epidemiology

Etiology

Diagnosis

Treatment

Response

Clinical observations on population samples and patient cohorts on multiple layers:

Risk factors, markers, e.g.Chemical / molecularAlimentaryFamily history, socialBehavioral, physical activity

Biomarkers of disease, e.g.PhenotypicMolecular

Pharmacokinetics, ADMEPharmacodynamics, MOABiomarkers of response

Biologicaldata

Clinicaldata

Biological attributes of:

Modeling in translational and clinical research

AGUSTI A., Thorax 2014

ASTHMOSOME

Innate Immune Response

Th2 Immune Response

Inflammation

Remodeling

AIT-Allergen ImmunoTherapy

Predisposition

Breastfeeding

Tobacco Smoke

InfectionsEnviroments

LifestylePhenotype

Endotype

Pharma Treatment

Metabolomics

Breathomics

Genomics

Transcriptomics

Proteomics

Interactome

Biomarkers

Biological Treatment

Microbiome

28

NEJM 2012

Mirnezami et al.NEJM 2012

Teran et a J.Prot.Res. 2014

Teran et a J.Prot.Res. 2014

Carraro……Baraldi, Allergy 2013

BREATHOMICS

Rossi et al Proteomics Clin Appl. 2014

ASTHMA

Rossi et al Proteomics Clin Appl. 2014

Rossi et al Proteomics Clin Appl. 2014

ASTHMA 2

Ferrando et al . AAIR 2016

Bagnasco et al. Exp Rev Resp Med 2016

Bagnasco et al. Exp Rev Resp Med 2016

THERE IS URGENT NEED

of well trained specialists to lead

the process of

PRECISION MEDICINE

in ASTHMA

in Clinical Practice

1975

1980

1985

1990

1995

LABA/ICS

for mx and

relief(SMART)

Combination

LAßA+ICS

Bronchospasm Inflammation Remodelling

50 years of asthma pharmacotherapy

Montelukast(1998)

Once-daily

LABA/ICS

LAMA

Inhaled

corticosteroid

1972

Long-

acting ß2-

agonists

2000 2005 2010 2015

Omalizumab

(2003)

Short-acting

ß2-agonists

[Chromone]

theophylline

[Nedocromil]

Anti-IL5

MAB

Varricchi et al COAI 2016

Varricchi et al COAI 2016

Bagnasco et al. Int.Arch.All.Imm. 2016

Bagnasco et al. Int.Arch.All.Imm. 2016

Bagnasco et al. Int.Arch.All.Imm. 2016

AIT as PERSONALIZED THERAPY

Identification of MolecularMechanism of disease

Diagnostic Toolfor the Molecular Mechanism

Treatment Blockingthe Molecular Mechanism

Molecular mechanism:IgE, arming effector cells, binds

allergen/component :mediator release & symptoms

Diagnostic Tool:IgE to causal allergen/component detection

Treatment Blockingthe Molecular Mechanism

AIT- Allergen Immunotherapy

(SCIT-SLIT)

Hamburg & Collins, NEJM 2010 [22]Canonica et al. WAO J.2015 [18]

Passalacqua & Canonica, CMA 2015 [23]

Canonica et al. Curr..Opin.Pulm.Med. 2015

(Mosbech et al.,J Allergy Clin Immunol 2014;134:568-75.)

Der p 1

Der p 2 Der f 1

Der f 2

Composition of a new HDM SLIT-tabletGroup 2

Group 1

50/50

MOSBECH ET AL., J.A.C.I 2014

PRIMARY ENDPOINT

ICS Sparing

Virchow et al. JAMA 2016

Virchow et al. JAMA April 26, 2016

1975

1980

1985

1990

1995

LABA/ICS

for mx and

relief(SMART)

Combination

LAßA+ICS

Bronchospasm Inflammation Remodelling

50 years of asthma pharmacotherapy

Montelukast(1998)

Once-daily

LABA/ICS

LAMA

Anti-IL5

MAB

Inhaled

corticosteroid

1972

Long-

acting ß2-

agonists

2000 2005 2010 2015

Omalizumab

(2003)

Short-acting

ß2-agonists

[Chromone]

theophylline[Nedocromil]

AIT

The most important

PLAYER

PATIENT

So…we should

not forget the

starting point

Canonica et al WAO J. 2015

Precision / Personalized Medicine

In this context my perception is :

PRECISION MEDICINEis focused on the ENDOTYPE (or on the

Mechanisms of patient’s disease)

PERSONALIZED MEDICINE

is focused on the PATIENT/PERSON not just on

the mechanism

P4 Medicine

• Predictive

• Preventive

• Personalized

• Partecipatory

Case Report, Ideas

Editorials, Expert Opinion

Cohort Studies

Case series

Meta-analysis and

Systematic reviews

Randomized

DBPC

EBM Hierarchy

D

A

Shekelle BMJ 1999; 318; 593-596

EBM

From EBM to Clnical Recommendation

Evidence-based medicine

Clinical recommendationson efficacy for an intervention

E.B.M

A general process in guidelines evolution

Factors that influence the strengths of a recommendation

• Balance betweendesirable and undesirable effects

• Quality of evidence

• Patients’values and preferences

• Costs

Two Examples

DRUG A:Effective

Safe

Cheap

DRUG B:Effective

Safe

Fast Dissolving Tablet with a good taste

Administration : 18 shots a day

Cost: 300.000 € /year

Third Example

DRUG C:Effective

Cheap

Fast Dissolving Tablet with a good tasteMake the patient sleeping all day long

DIFFICULT to POSITIONING THOSE PRODUCT in CLINICAL RECCOMENDATIONS

although there is Scientific Evidence of Efficacy

From EBM to recommendation

Evidence-based medicine

Clinical recommendationson efficacy for an intervention

recommendationsfor an intervention

Safety

including

post-marketing

surveillance

Health

economics

Patient’s views& Preference

PERSONALIZED TREATMENTASTHMA

Personalized Medicine is

notjust related

to the new biologics

PERSONALIZED TREATMENTASTHMA

A Step by Step approach….......

PERSONALIZED TREATMENTASTHMA

Nowadays this concept is including

also the right choice of

the DEVICE…........Patient’s Preference and Value

Low intrinsic airflow resistance

Cost, reimbursementInsurance coverage

Liked by patients

Ease of UseDeliver wide range of therapies

Clinical Efficacy

Type of prescribed medication: ICS vs. bronchodilators

Patient’s disease severity

Accurate and consistent drug delivery

Robust

the “ perfect inhaler ”

The “least imperfect” inhalerThe inhaler which the patient

can and will use effectively

The poorer the device technique,

the poorer the outcome

Giraud V, Roche N.Eur Respir J 2002;19:246–51

Good users

Misuser, poor coordinators

n= 3709

Misusers good coordinators

Asthma Instability Score AIS (0-best; 9-worst)

Improved inhalation technique

affects outcome

Outpatient management in children with severe asthma improves inhalation technique from 65% to 95% with correct inhaler technique

Kamps AW, et al. Thorax 2003;58:968–73

-Lower corticosteroid dose

-Improved asthma control

Laube et al.ERJ 2011

Laube et al.ERJ 2011

Laube et al.ERJ 2011

Laube et al.ERJ 2011

Laube et al.ERJ 2011

Laube et al.ERJ 2011

Laube et al.ERJ 2011

CHILDREN & ELDERLY

>250 inhaler devices and medications1

Inhalers

for

COPD & Asthma

SABAs

LABAs

LAMAsICS

Combination medications

COPD, chronic obstructive pulmonary disease; HCPs, healthcare professionals; ICS, inhaled corticosteroid; LABA. long-acting ß-agonist; SABA, short-acting ß-agonist;

1. Bonini M, et al. COPD Research and Practice. 2015;1:9. 2. Haughney J, et a;.Resp Med CME. 2010;3:125–131.

Given the huge array of available devices:-HCPs may not know all the inhaler key features and the way to use them

-Patients often make mistakes when using their inhalers2

• 41 different brands

• 13 different inhalers

HUNDREDSPOTENTIAL SWITCHES !

To Switch or Not To Switch

Assessment of inhalertechnique iscrucial !

The device is

“intrinsic” part

of each inhaled product

KEY MESSAGE

DEVICE FEATURES

in

REAL LIFE

Norderud Laerum et al.Mult.Pulm.Med.2016

SHELF LIFE and STORAGE ( opened )

Norderud Laerum et al.Mult.Pulm.Med.2016

Patient reported device

control frequencies

Norderud Laerum et al.Mult.Pulm.Med.2016

Canonica et al. J.Aerosol Med.Pulm.Drug.Del. 2015

Canonica et al. J.Aerosol Med.Pulm.Drug.Del. 2015

Canonica et al. J.Aerosol Med.Pulm.Drug.Del. 2015

Canonica et al.J.Aerosol Med.Pulm.Drug.Del. 2015

Canonica et al.J.Aerosol Med.Pulm.Drug.Del. 2015

Canonica et al. J.Aerosol Med.Pulm.Drug.Del. 2015

Canonica et al. J.Aerosol Med.Pulm.Drug.Del. 2015

1

Canonica et al. J.Aerosol Med.Pulm.Drug.Del. 2015

2

Canonica et al. J.Aerosol Med.Pulm.Drug.Del. 2015

KEY MESSAGES

TAKE HOMEMESSAGE

AGUSTI A., Thorax 2014

Gustaffson et al Genome Medicine 2015

Gustaffson et al Genome Medicine 2015

WC

GWC 2016

BLOOD BIOMARKERS URINE BIOMARKERS

BAL BIOMARKERS EXHALED BIOMARKERS INFLAMM BIOMARKERS

OUTDOOR BIOMARKERS INDOOR BIOMARKERS

THANKS• RICCIO AnnaMaria

• DE FERRARI Laura

• CHIAPPORI Alessandra

Consiglio Nazionale delle Ricerche

Istituto di Tecnologie Biomediche

Unità di Proteomica e Metabolomica

• Diego BAGNASCO

• Matteo FERRANDO

• Alice BRAGANTINI

• Stefano BERNARDI

• Marcello MINCARINI

• Filippo TARCHINO

• Anthi ROGKAKOU

• Ilaria BAIARDINI

• Fulvio BRAIDO

• Giovanni PASSALACQUA

MAURI Pierluigi

ROSSI Rossana

DI SILVESTRE Dario

BENAZZI Louise

VARRICCHI Gilda

HEFFLER Enrico

PUGGIONI Francesca

THANK YOU