Patient Support DayNottingham 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– 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. 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• Average age > 60• Male > Female• No Known Cause• No proven therapy• Median survival 3 years• Also known as Cryptogenic

Fibrosing Alveolitis

Other Stuff• 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

IPF Sarcoidosis

AsbestosisCTD

HSPDrugs

NSIP

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 DataISHLT 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 2006Interstitial 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

Vancheri ERJ 2010 35(3):496-504

.

5 year survival rates from IPF compared with various cancers.

Interstitial Lung Disease Unit

CRUK

CRUK

Spending on cancer research by cancer type

CRUK

1971-1975 1976-1980 1981-1985 1986-1990 1991-1995 1996-2000*0

10

20

30

40

50

60

70

80

90

100

Period of diagnosis

% survival

Figure 3.1: Age standardised relative survival (%) at one, five, ten and twenty years since diagnosis, female breast cancer, England and Wales, 1971-2003

* England only

Figure 3.3: Ten-year relative survival rate, female breast cancer, England and Wales, 1971-2000

CRUK

UK IPF research budgets

Interstitial Lung Disease Unit

Maybe £2,000,000

British Lung Foundation £260,000 in 2012

However the profile is rising

Two Broad Approaches 1) Choose available drug2) See if it works

1) Define molecular pathogenesis2) Design drug targeting offending molecule3) Check drug engages mechanism4) 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

• 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

Pre-2000 Post-2000

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!