Patient Support Day Nottingham March 2012

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

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

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

What is IPF?

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: http://www.dailymail.co.uk/health/article-1385311/New-killer-baffling-doctors-And-warning-sign-feeling-breath-.html#ixzz1oNbdwE00

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

ILD Olympics CTD Asbestosis Sarcoidosis IPF NSIP HSP Drugs The rest

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

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

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

Interstitial Lung Disease Unit

Goodwin and Jenkins Biochem Soc Trans 2009 Interstitial Lung Disease Unit

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

What happens when your cell gets injured?

Cell dies (apoptosis)

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

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

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

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

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

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

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

IPF is the second commonest indication for lung transplantation COPD 34-38% IPF 17-23% CF 17-19% Alpha1-AT deficiency 9% Registry Data ISHLT lung transplantation 22nd report 2005. LAIA 2002 Interstitial Lung Disease Unit

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

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

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

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

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

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

Research in IPF

5 year survival rates from IPF compared with various cancers. Vancheri ERJ 2010 35(3):496-504

Interstitial Lung Disease Unit

CRUK

CRUK

Spending on cancer research by cancer type CRUK

CRUK

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

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

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

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

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

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

Thankyou!