Post on 31-Dec-2020
transcript
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?