Early Phase Pharmacodynamic Models For Respiratory Drug Candidates

1 SGS LIFE SCIENCE SERVICES BIOPHARMA DAY – OCTOBER, 29 2015

EARLY PHASE PHARMACODYNAMIC

MODELS FOR RESPIRATORY DRUG

CANDIDATES

Robert Lins, MD, PhD

October 29, 2015

SAFETY & EFFICACY CLINICAL TRIAL SOLUTIONS SGS Life Science Services Biopharm Day Seminar – Antwerp, October 29, 2015


AGENDA

Introduction

Importance and experience

Advanced lung function testing

Bronchial challenging

Lung disposition

Functional respiratory imaging techniques


INTRODUCTION: RESPIRATORY DISEASES

Prevalence (> 500 M pts), + mortality COPD (x 2)

Most common types are asthma and COPD

Enlarged exposure to risk factors and aging population

Majority of treatments by inhalation therapy, often combinations

More insight in mechanism of disease: role inflammation

Need for phenotyping + endotyping, for personalized medicine

Rising cost for development of new drugs and high failure rate


INTRODUCTION: RESPIRATORY R & D

Lack sensitivity PD techniques and surrogate endpoints

Main primary outcome parameters

FEV1: dynamic lung volume after 1 sec of forced expiration

Saint George Respiratory Questionnaire (SGRQ): measuring

impaired health and perceived wellbeing (COPD)

Lack of correlation, at limit of clinical significance

Discrepancy between clinical outcome and survival

Unmet need for more sensitive outcome parameters

Overview of current techniques in early development


RESPIRATORY STUDIES: 843 IN 2014

Oncology; 250

Asthma; 74

COPD; 186

Interstitial; 157

Sleep apnoe; 19

Infection; 157

Clintrials.gov December 2014


EXPERIENCE IN RESPIRATORY TRIALS (N > 50)


WIDE RANGE OF PHARMACODYNAMIC METHODS

Spirometry (Acertys, Cardinal Health)

FeNO (Nioxmino or equivalent)

Whole Body Plethysmography: Airway Resistance,

Arterial blood gases

Continuous monitoring EtCO2, TV, RR, PEF, PIF using CPAP masks

Broncoprovocation: adenosine, histamine, metacholine, allergens, viral

challenge

Sputum induction for mRNA, cytospins, cytokine assays

Inhaled LPS challenge test – see later

Local PK Broncho Alveolar Lavage (BAL) in HV and patients

Functional Respiratory Imaging (FRI)

Access to bioanalytic labs: inflammatory parameters


CASE STUDY

COPD INHALATION DRUG

Design: Phase 2, randomized, placebo-controlled, 5-way

cross-over pharmacological study

Drug: fixed combination beclomethasone, formoterol DPI

Administration: 50 moderate/severe stable COPD (GOLD

guidelines 2013); five 1-day single-dose treatment,

separated by a minimum 7-day wash-out period

Objective: compare heart rate, effect on serum potassium,

glucose, cardiovascular, safety and tolerability

Result:

• Inclusion: IC 106 pt, screen 98, failure 49, included 49 in 2 m

• Challenge: fast inclusion, appropriate technique

• Conclusion: Inclusion completed in less than 2 months

1


BODY PLETHYSMOGRAPHY (“BODY BOX”)


BODY PLETHYSMOGRAPHY

Lung : Volumes and Airway

Resistances

Volumes that are not measures

by ordinary spirometry (RV)

Oscillometry

DLCO : diffusion capacity

(speed of oxygen delivery to the

RBC)

...


BODY PLETHYSMOGRAPHY


MEASUREMENTS

Spirometry (FEV1, VC, IC, ERV)

Flow-Volume (FVC – PEF)

Reversibility after bronchodilatation

Lung volumes (TLC, RV, FRCpleth)

Diffusion capacity fo CO (DLCO)

Airways Resistance (Raw, sGaw)

Maximum Voluntary Ventilation

Thoracic Gas Volume (VTG, IVTG)

PeMax – PiMax mouth pressures

Bronchial Challenge


CHALLENGE METHODS


1. BRONCHOPROVOCATION TESTING


HISTAMINE BRONCHOPROVOCATION TEST

Definition: inhalation of increasing concentrations of histamine

solution with measurement of airway responsiveness

Indication: diagnosis/quantification of bronchial

hyperreactivity:

Diagnosis of asthma

Can replace/adjust reversibility testing, which has a lot of false

negatives in well-controlled mild-to-moderate asthma

Increase recruitment potential and decrease screen failure rate in

studies

Measurement: PC20 =concentration agent producing 20% fall

in FEV1

Adverse events: headache, tachycardia, bronchoconstriction

(shortness of breath)


METACHOLINE/ADENOSINE PROVOCATION

Basically identical to Histamine provocation testing

Metacholine exerts its action by direct stimulation of the bronchial smooth muscle cells

The effect of adenosine (AMP) is rather indirect via mast cell degranulation releasing proinflammatory mediators

PD20/PC20 values: calculated based on the concentration of challenge agent producing a 20% fall in FEV1

All three methods can be used as early POC in asthma using either bronchoprotection or bronchodilation trials


ALLERGEN BRONCHOPROVOCATION

Bergman K et al. EAACI congress Barcelona 2015


2. LPS CHALLENGE


LPS CHALLENGE

Definition:

Inhaled lipopolysacharide (LPS, endotoxin) is a TLR4

agonist which activates cytokine production. It invokes an

acute inflammatory response in the lung.

Indication: study anti-inflammatory drugs asthma, COPD

Methods used in 5 studies:

inhaled LPS via ultrasonic nebulizer, up to 50 mcg LPS/mL

isotonic saline

infused LPS (4 ng/kg ) over a 2-minute (other indications)

Measurements in induced sputum:

granulocyte response

cytokines e.g. TNF-α, IL-1β, IL-6, IL-8, IL-10)


CASE STUDY LPS

MILD ASTHMATICS

Phase I SAD-MAD-POC study

Including mild asthmatic patients

LPS challenge was conducted on 1 cohort healthy male

subjects and 1 cohort of asthmatic patients

LPS (50 µg/mL) was inhaled over a 2-minute period (5 deep

breaths of the nebulized solution)

Sputum induction procedure at preset time points after LPS

inhalation using increasing concentrations of hypertonic

saline (up to 5%)

2


3. VIRAL CHALLENGE TESTING


VIRAL CHALLENGE TESTING - BACKGROUND

The Viral Challenge model (VCM) has proven to be a safe

and effective practice since 1946 (Medical Research Council

(MRC) Common Cold Research Unit (CCRU))

The VCM produces high quality proof of concept, safety and

efficacy data; establishes clear correlates of protection

(CoP); informs Go / No Go decisions and facilitates the Up

or Down selection of study arms

The VCM has been widely adopted by pharma and biotech

companies in early phase studies (2a/b) investigating upper

respiratory tract infections (URTI)

SGS Life Sciences has a dedicated isolation suite (VCU)

within its clinical pharmacology unit (CPU) and experience

with the influenza virus and the VCM


CASE STUDY ASTHMA

DESIGN

mAb (monoclonal antibody) targeting human Toll-like receptor 3

(CRTH2) for the prevention of asthma exacerbations

Phase 1, randomized, double-blind, placebo-controlled study

Study population: 12 healthy normal (part 1) and 60 asthmatic

subjects (part 2)

IV administration of study drug prior to inoculation with human

rhinovirus Type 16

Primary endpoint: safety and tolerability (part 1) – efficacy

(pulmonary function, patient reported outcomes) (part 2)

Secondary endpoint: PK, PD (additional pulmonary function tests in

patients, Cold Symptom Assessment Score, FENO,), biomarkers in

nasal lavage, immunogenicity and pharmacogenomics

3


CASE STUDY ASTHMA: RESULTS

Part 1 finished in 4 months

Challenges:

regulatory approval: novel mechanism + challenge testing

exclusion: positive for AB against rhinovirus (80 %)

160 HV (panel screened) 36 (22% negative for RV

AB) 16 (eligible) 12 (included)

Good tolerance, mild to moderate rhinitis/nasopharyngitis

(10/12 HV), no asthma

Part 2: 79 asthma patients screened, all failures for in-

and exclusion criteria – study stopped in our center


LUNG DISPOSITION


1. SPUTUM INDUCTION


WHAT?

Sputum induction is relatively “simple”

Repeatable (?) and noninvasive method

Goal = collecting lower airway secretions for

Inflammatory cells

Cytokines (IL5, ECP, …)

NO species

Since the 1990s it serves as alternative to bronchoalveolar lavage

CAVE

Lack of “gold standard”

Only few methodological studies have examined the influence of

various technical factors on the repeatability of sputum induction

and collection


GOOD TO KNOW: LIMITATIONS

Effective collection of sputum samples:

Non-smoking healthy volunteers : 10% success

Smoking volunteers : 10-20% success

Asthma : 70% success rate

COPD : 80% success rate

Procedure:

Quite elaborate and time-consuming

2h per sample

Need for trained technicians for both the induction

procedure and the sample handling/cell counting


RESULTS CPU

Type number inductions success (%)

Healthy volunteers: 64 175 61 (29%)

Asthma: 12 35 26 (74%)

Smokers 4 7 3 (75%)


2. LOCAL BRONCHIAL PHARMACOKINETICS


WHAT?

Definition: Determination of the time-concentration profile of drugs in

bronchoalveolar lavage fluid (BALF) for prediction of therapeutic

efficacy.

Indications for the technique

assessment of local and systemic pharmacokinetics of single

and repeated doses

oral inhalation drugs for bronchodilatation, antimicrobial, or

antiviral treatment

foreseen in European guideline for orally inhaled products

potential application in systematically administered drugs

local + systemic T1/2,disposition,bioavailability,accumulation

determination of urea + red blood cells (RBCs) in blood and

in BALF for determination of the dilution factor


CASE STUDY RSV: BRONCHIAL PK IN HV

Design: Phase 1, single center, open label study in male

HV to evaluate local and systemic pharmacokinetics

Drug: nanobody against RSV

Administration: 41 healthy male volunteers, oral inhalation

of single or multiple dose or IV infusion of single dose

Objective: local (BALF) and systemic PK after single and

repeated administration, urinary PK, safety,

immunogenicity

Result:

• 44 volunteers included (3 drop outs) in 5 months

• Challenge: 138 screened, 74 failures for in/exclusion criteria

• Adverse events due to BALF: 4 moderate (3 fever, 1 dyspnoe)

• Completed successfully, robust data for PK/PD modeling


FUNCTIONAL RESPIRATORY IMAGING


FUNCTIONAL RESPIRATORY IMAGING (FRI)

3D segmented computer models of human organs scanned

by imaging techniques: CT, MRI, US

Fluidda FRI technology combines High Resolution

Computed Tomography with 2 advanced computational

fluid dynamics tools – Computational Fluid Dynamics (CFD)

and Finite Element Analysis (FEA)

Support early phase clinical trials in respiratory therapeutic

area: asthma, COPD, idiopathic pulmonary fibrosis, cystic

fibrosis, sleep disorders



De Backer L. et al. Int J. COPD 2011;6:637-646


FRC lobes reduce significantly in volume for the responders (-4.88 %p) as

compared to the non-responders (+3.47 %p) and placebo (+8.28 %p)

p=0.025

p=0.001

p=0.16

ROFLUMILAST RESPONDERS IN TERMS OF

HYPERINFLATION


FRI can determine aerosol deposition patterns:

ROFLUMILAST RESPONDERS IN TERMS OF

BRONCHODILATION


OTHER IMAGING TECHNIQUES

Ultrasound (US)

Magnetic Resonance Imaging (MRI)

Positron Emission Tomography (PET)

Inhaled radiolabelled studies


CONCLUSION

Low performance of classical primary respiratory endpoints

in exploratory and confirmatory studies

High need for more sensitive PD markers in respiratory R&D

Great number of emerging new and existing techniques

Most value demonstrated in translational and exploratory

development

Some are useful for confirmatory trials too


Life Science Services Dr. Robert Lins

Senior Clinical Adviser - Clinical Research

SGS Belgium NV Phone: + +32 (0)15 40 50 82

Generaal De Wittelaan 19A Bus 5,

B - 2800 Mechelen E-mail : [email protected]

Belgium

Web : www.sgs.com/lifescience

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Early Phase Pharmacodynamic Models For Respiratory Drug Candidates