1. Patient Support Day Nottingham March 2012

4. Contibutors Dr Gisli Jenkins Dr Vidya Navaratnam
Professor Simon Johnson
Carole Mallia
David Cashman
Dr Sanjay Agrawal
Geraldine Burge
Dr Helen Parfrey
Annette Duck
British Lung Foundation.
All funding from the Nottingham Respiratory Biomedical Research Unit

5. Program The Science of IPF Practical Management of IPF
How much IPF is there and how bad is it?
Why does IPF happen?
What have clinical trials in IPF taught us?
Practical Management of IPF
Lung Transplantation
Best Supportive/Palliative Care
Oxygen Therapy
Travelling, flying and exercising with IPF
The Future for IPF
Developing an IPF support network
Potential New Clinical Trials
Lung Tissue Research Proposals
Question Time

6. Aims of Today To inform patients of what we know.
To offer practical advice.
To answer questions.
To find out what’s important to you.
To develop a strategy to improve the care of people with IPF throughout the UK

9. What is IPF?

10. It's a new killer baffling doctors
It's a new killer baffling doctors. And the only warning sign is feeling out of breath... Read more:

12. Interstitial Lung Diseases
Idiopathic Pulmonary Fibrosis
Other Stuff
Average age > 60
Male > Female
No Known Cause
No proven therapy
Median survival 3 years
Also known as Cryptogenic Fibrosing Alveolitis
Sarcoidosis
Connective Tissue Disease
Asbestosis
Hypersensitivity Pneumonitis
Non Specific Interstitial Pneumonitis
Desquamative Interstitial Pneumonitis
Respiratory Bronchiolitis ILD
Cryptogenic Organising Pneumonia
Acute Interstitial Pneumonitis
Idiopathic Pleuroparenchymal Fibrosing Elastosis
LAM HX

13. ILD Olympics
CTD
Asbestosis
Sarcoidosis
IPF
NSIP
HSP
Drugs
The rest

14. Why do people get Idiopathic Pulmonary Fibrosis?
It is NOT infectious
It is genetic in a small minority of cases

15. Causes of IPF Idiopathic (and cryptogenic) means “we don’t know”
Genetics plays a role
Surfactant protein D
Muc5b
Telomerase
Other hypotheses include:
Viral infection
Gastro-Oesophageal Reflux Disease
Inhaled dust/smoke
Immune system going wrong
Problem is distinguishing cause from association

16. What about pulmonary fibrosis generally?
Immune reaction to birds
Immune reaction to drugs
Inhaled dusts leading to injury of the lung
Inhaled chemicals injuring the lung

17. Interstitial Lung Disease Unit

18. Goodwin and Jenkins Biochem Soc Trans 2009
Interstitial Lung Disease Unit

19. Wrong place, wrong time, and then some, hypothesis
If you have the wrong genes (?Muc5b polymorphism)
If you have the wrong exposure (?Metal dust)
And then your repair process breaks down! (epigenetics)
You develop IPF

20. What happens when your cell gets injured?

21. Cell dies (apoptosis)

22. Neighboring cell divides
Risky time for cells
DNA taken apart and then put back together
This can lead to the introduction of genetic mistakes
This can lead to reprogramming of cells

23. Sometimes just the DNA gets damaged
Again risky time for cells
Complex repair process can lead to errors
Even small mistake can have profound consequences
Average gene contains thousands of DNA molecules

24. Just one mistake can lead to an amino acid change which can completely change the function of a protein

25. Complex disease pathogenesis
You need to be on the road to have a RTA
BUT NOT ALL ROAD USERS WILL HAVE AN RTA.
The more you use the road the higher your chance of an RTA
A car is more likely to kill a pedestrian than a cyclist
A motorcyclist is more likely to die in RTA than any other road user

26. Complex disease pathogenesis
The more often your cells divide the more likely they are to acquire errors
The more often your cells get injured the more likely they are to acquire errors
Some things will injure certain cells/genes over others
Certain cells/genes are more prone to injury than others

27. So why do people get lung fibrosis?
They get older (more cell divisions)
Their lungs get injured (cigarette smoke, gastroesophageal reflux.)
They have susceptible genes

29. Lung transplantation http://www.uktransplant.org.uk/ukt/
Interstitial Lung Disease Unit

30. IPF is the second commonest indication for lung transplantation
COPD %
IPF %
CF %
Alpha1-AT deficiency 9%
Registry Data
ISHLT lung transplantation 22nd report 2005.
LAIA 2002
Interstitial Lung Disease Unit

31. ISHLT Guidelines for lung transplant in people with IPF
Referral
Histologic or radiographic evidence of UIP irrespective of vital capacity.
Absence of major CI
Transplantation
- Histologic or radiographic evidence of UIP and any of the following:
- A DLco of less than 39% predicted.
- 10% or > FVC during 6/12 follow-up.
- O2 Sats < 88% during a 6-MWT.
- Honeycombing on HRCT (fibrosis score of > 2).
JHLT, July 2006
Interstitial Lung Disease Unit

32. Lung transplant leads to improved survival in IPF
Thaboot et al 2003
Interstitial Lung Disease Unit

33. The number of patients with IPF being transplanted are increasing.
Interstitial Lung Disease Unit

34. The downside? High operative mortality (15% in first 3 months)
No. of donor organs available<< recipients.
median waiting period for the single lung transplantation
UK= 351 days (CI 293 to 427 days )
USA=3 months.
Large number of contraindications.
Interstitial Lung Disease Unit

35. Suitable organs Age (donor<65)
Minimal smoking history (<5 pack years)
Clear CXR
No evidence of sepsis
No PMH of malignancy/chronic lung disease/ Hep B/C HIV
Acceptable bronchoscopic and visual findings

36. Bridging to Transplant on ECMO
IPF, is a progressive diseases without effective therapy.
Transplant is often “only chance”.
ECMO is a bridge to transplant.

38. Research in IPF

39. 5 year survival rates from IPF compared with various cancers.
Vancheri ERJ (3):

40. Interstitial Lung Disease Unit

41. CRUK

42. CRUK

43. Spending on cancer research by cancer type
CRUK

44. CRUK

45. UK IPF research budgets
Maybe £2,000,000
British Lung Foundation £260,000 in 2012
However the profile is rising
Interstitial Lung Disease Unit

46. Two Broad Approaches 1) Choose available drug 2) See if it works
1) Define molecular pathogenesis
2) Design drug targeting offending molecule
3) Check drug engages mechanism
4) See if it works
Interstitial Lung Disease Unit

47. Chronic Myeloid Leukaemia
5 year survival figures
Busulphan 34.2%
Hydroxyurea 46.5%
Interferon  54.6%
Imatinib 89%

48. What do we need to study disease and discover new treatments
Imagination
Persistence
Translation
Priorities
Specific
Relevant
Achievable
Money
Tissue
Blood
Bronchoalveolar Lavage
Bits of lung

49. Randomised Clinical Trials in IPF
Pre-2000
Post-2000
Raghu et al 2004
Demendts et al 2005
Tashkin et al 2006
King et al 2009
Daniels et al 2010
Zisman et al 2010
Richeldi et al 2011
Noble et al 2011

50. Numerous therapies currently in clinical trials
BIBF-1120 (Boehringher)
IL13 antibody (Novartis)
Integrin antibody (Stromedix)
IL13 and IL4 antibody (Sanofi-Aventis)
PI3K antibody (Gilead)
Around 40 drugs currently being trialled worldwide

51. Thankyou!