Sandy MunroVP, Pharmaceutical Development

MATCHING DELIVERY DEVICE TO A PATIENT'S CONDITION: USE OF LUNG

DEPOSITION MODELLING TOOPTIMISE DELIVERY IN IDIOPATHIC

PULMONARY FIBROSIS

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Content

Vectura Group

Idiopathic pulmonary fibrosis (IPF)

Devices available and device selection for IPF

IPF lung deposition modelling study

• Data gathering

• IPF lung models and conduct of modelling experiments

Results

Conclusion

Acknowledgements and questions

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DPI and nebuliser productsChippenham, UK

Vectura Group

OVERVIEW

Proprietary formulation and device technologies with developing wholly-owned specialist portfolio

Partnered and wholly-owned pipeline is well positioned in key growth respiratory segments

Accessed through uniquely integrated proprietary formulation, device and development technology and capability

FTSE 250 company established in 1997

EXTENSIVE COLLABORATIONS/LICENSING

20 REVENUE GENERATING IN-MARKET ASSETS

8 KEY INHALED PARTNERED IN-MARKET PRODUCTS DRIVING RECURRING REVENUE GROWTH

flutiform®Ultibro®Breezhaler®

Seebri®Breezhaler®

AirFluSal®Forspiro®

Anoro®Ellipta®

Relvar® Ellipta®/Breo® Ellipta®

Incruse®Ellipta®

Breelib®

c.450 employees

Merger with Skyepharma PLCcompleted June 2016

COMPANY PROFILE

Device developmentCambridge

Nebuliser device developmentGermany

pMDI product developmentSwitzerland

Respiratory diseases

1. Acute Respiratory Distress Syndrome (ARDS)

2. Alpha-1 Antitrypsin Deficiency (AAT-Deficiency)

3. Allergic Rhinitis

4. Alveolitis/Hypersensitivity Pneumonitis (HPs)

5. Asthma

6. Bronchiectasis (BE)

7. Bronchitis

8. Bronchopulmonary dysplasia (BPD)

9. Bronchospasm

10. Congenital lung disease

11. Chronic cough

12. Cystic Fibrosis (CF)

13. Dyspnea

14. Idiopathic Pulmonary Fibrosis (IPF)

15. COPD

16. Emphysema

17. Lung Cancer

18. Lung immune dificiencies (deficit of IgG and IgA)

19. Lung transplantation rejection

20. Obstructive Sleep Apnea

21. Pneumonia

22. Pulmonary Alveolar Proteinosis (PAP)

23. Lung Infections of the immune-compromised Host (LICH)

24. Pulmonary Arterial Hypertension (PAH)

25. Pulmonary Embolism

26. Pulmonary hemorrhage

27. Respiratory Tract Infectionso Upper respiratory tract infection

o Lower respiratory tract infection

28. Sarcoidosis

29. Silicosis

30. Vasculitis of the lung (Panarteritis nodosa and Churg Strauss Sindrom)

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Causes and pathophysiology

• Chronic condition (cause unknown) - progressive scarring of the lung tissue rendering the lungs thick and inflexible

• Poor prognosis - 2 to 5 years median survival, worse than many cancers including colon and bladder

Epidemiology

• Affects male > female, 7-16 per 100,000 (USA), 5-7 per 100,000 (EU)

• Growth driven by population increase & better diagnosis

• Equates to 30-35K new cases per annum

Symptoms

• Dry cough on exertion, breathlessness

• Abnormal lung function tests

• Chronic oxygen deficiency in blood

https://www.youtube.com/watch?v=0mrrqnfykJk

Idiopathic Pulmonary Fibrosis (IPF)Causes, pathophysiology, epidemiology & symptoms

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Treatments - reduce symptoms, slow progression, prolong survival – no cure

• Pirfenidone & Nintedanib

- Challenging side effects (nausea & vomiting, loss of appetite)

• Oxygen therapy – helps with symptoms

• Lung transplant – viable treatment but only a few patients qualify

Devastating disease with bleak outlook for sufferers – a death sentence

Urgent need for more effective treatments – lots of new therapies in development

Huge potential to exploit inhaled delivery

• Deliver directly to the site of action – increased efficacy

• Reduced dose – decrease systemic side effects

If inhaled delivery to work well in IPF, must carefully consider delivery platform most effective at getting drug where it needs to go

Treatments & unmet medical need

IPF

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Focussed on fulfilling unmet patient needs

• In mainstream disease e.g. severe asthma, paediatric asthma

• Speciality diseases e.g. IPF, PAH

Good understanding of what is likely to work well for asthma/COPD

Less understanding of what might be best in IPF

Desire to make a more informed data driven choice of delivery system

Full spectrum of delivery technologies but which is best for IPF?

2000 2010 20202013 2016

Study background

Vectura desire to move beyond the confines of mainstream asthma/COPD

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Delivery technologies cover wide dose range but with limitations

Always practical limitations dictating device choice• Biologics not compatible with certain formulation types

• Insoluble drugs

• Biologics not compatible with jet nebulisation

Evaluation not constrained by practical limitations – assumes all options possible

0.001 0.01 0.1 1 10 100 1000Nominal Dose (mg)

Limit of MDI technology

Limit of carrier based

DPI technology

Limit of engineered particle DPI technology

Jet NebulisationMesh nebulisation

Region of interest

Vectura device technology evolution

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IPF lung deposition modelling study

MDI not evaluated - performance not ideal for dose range of interest

Engineered particle DPI not studied

Introduction of “equivalent” aerosols to a series of lung

models in-silico using representative inhalation

manoeuvresMathematically derived lung

deposition & product performance to allow for direct a comparison between delivery

platforms for IPF patients

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Devices studied

Long-slow-deep inhalation maximises peripheral lung deposition

Vectura smart nebulisers & multi-unit dose DPI plus standard jet nebuliser

AKITA JET® FOX® LOMI™

Flow-And-Volume-Regulated-Inhalation-Technology – FAVORITE™

Positive pressure used to guide patient inhalation

Representative performance from these devices/formulations used in the modelling study - compared alongside a standard jet nebuliser

Lever OperatedMulti-doseInhaler

Force Control Agent - High performing formulation used

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Creation of data set for in-silico evaluation

AKITA® JET

FOX®

LOMI™

Standard jet nebuliser

Representative performance data

Normalise

FAVORITE (AKITA & FOX) – Long-Slow-Deep

DPI fast

DPI slow

Standard nebuliser –Regular & quite rapid in IPF

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Different degrees of disease severity as expressed by FVC

Five IPF patients; two different extrathroacic airways geometries

Mean

Narrow

FluidDa IPF lung CT scans of differing disease severity

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Deposition simulation

Deposition simulations4 devices, 5 pairs of lungs, 2 throat geometries, representative performance

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Exhaled fraction (% of emitted dose)Very high for standard nebuliser (continuous aerosolisation)

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Extrathoracic deposition (% of emitted dose)

Standard jet nebuliser, low extrathoracic deposition (% of emitted) because so much is being lost on exhalation (around 40% of inhaled dose)

High for DPI reflecting high inhalation flow rates (impaction)

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Intrathoracic deposition (% of emitted dose)

DPI gives equivalent deposition – interaction between particle size and flow

FAVORITE™ technology - high lung deposition versus DPI & std. nebuliser

Device FPF [%]MMAD

[mm]GSD Start Time End Time

LOMI slow 45.9 2.9 1.9 t=0 t=0.35s

LOMI fast 61.0 2.3 1.9 t=0 t=0.35s

FOX 68.0 4.0 1.7 t=0 min(4,max(tinsp/2,tinsp-1))

AKITA 52.0 4.7 1.9 t=0 min(5,max(tinsp/2,tinsp-1))

LC Sprint 55.0 5.0 1.9 t=0 t=tend

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Central deposition – Smart neb. > DPI > standard neb. – fairly consistent

Central lung deposition (% of emitted dose)

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Deep lung deposition (% of emitted dose)

4 times higher than for standard nebuliser. At least twice as high as for DPI

Long-slow-deep FAVORITE™ inhalation (Akita & FOX) targets small airways

Device FPF [%]MMAD

[mm]GSD Start Time End Time

LOMI slow 45.9 2.9 1.9 t=0 t=0.35s

LOMI fast 61.0 2.3 1.9 t=0 t=0.35s

FOX 68.0 4.0 1.7 t=0 min(4,max(tinsp/2,tinsp-1))

AKITA 52.0 4.7 1.9 t=0 min(5,max(tinsp/2,tinsp-1))

LC Sprint 55.0 5.0 1.9 t=0 t=tend

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Central to peripheral - C/P ratio

DPI spreads drug evenly between central and small airways

Akita® and FOX® target small airways, standard nebuliser targets centrally

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Influence of extrathorcic airways dimension

Nebulisers more affected than DPI reflecting larger droplet size

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Smart nebulisation using FAVORITE™ (long-slow-deep) inhalation offers a number of advantages: -

• Higher overall whole lung deposition

• Greatly enhanced targeting of small airways

DPI performance (FCA formulation) offers reasonable lung deposition

• Even split between central and peripheral

Standard nebuliser less good at targeting small airways

Deposition modelling

FAVORITE ™ inhalation(slow and deep

inhalation)

Summary and overall conclusions

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Summary and overall conclusions

Based on the variants studied here we would use a FAVORITE™ equipped smart nebuliser to target the small airways in IPF therapy

Deposition characteristics may not be everything. Other factors must be considered

• CoGs and manufacturing volumes

• Fit with patient lifestyle

• Treatment time

• Product wastage

Fast into clinic with standard nebuliser or basic DPI may be a flawed approach without first really trying to understand the disease and the optimal delivery platform – does the drug get to where it needs to?

Lung deposition modelling and Functional Respiratory Imagining (FRI) using CT scans offers significant potential in device selection & optimisation or to explain clinical data. FRI could potentially be used as a clinical endpoint

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Acknowledgements

At Vectura

• Mark Main

• Dan Lock & Craig Fulton

At FluidDa

• Wim Vos

Questions?