Emerging Therapies for Lung Fibrosis. Helen Garthwaite Respiratory Registrar/ Clinical Research Fellow

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1 Emerging Therapies for Lung Fibrosis Helen Garthwaite Respiratory Registrar/ Clinical Research Fellow

2 Lung Fibrosis/Interstitial Lung Disease Disease that affects the tissue that supports the lungs alveoli IMPORTANT Inflammation and/or scarring which interferes with breathing at the level of the alveoli CHALLENGIN G

3 Why is it important? lick to edit Master text styles cond level Third level Fourth level Fifth level Large number of patients affected with a broad spectrum of disease 12% develop significant disease Leading cause of morbidity and mortality

4 Why is it challenging? Difficult to diagnose Lungs have huge reserve Skin and joint symptoms may prevent early detection Multiple causes of breathlessness Difficult to treat Fibrosis once established largely irreversible Primary aim of treatment is to prevent progression and induce stability

5 Treatment of Interstitial Lung Disease Induction therapy Cyclophosphamide Maintenance therapy Mycophenolate mofetil Azathioprine

6 Potential New Therapies Induction therapy Mycophenolate (SLS II) Rituximab Cyclophosphamide Tocilizumab Maintenance therapy Mycophenolate Anti-fibrotic drugs; mofetil Azathioprine Pirfenidone Nintedanib

7 Rituximab Chimeric monoclonal antibody against CD20 expressed on B cells Increased B cells in lungs of scleroderma patients Intravenous therapy two doses two weeks apart

8 Rituximab for Treatment- Retrospective review of 50 patients who received Rituximab 33 with connective tissue disease 8 scleroderma FVC pre treatment demonstrated a median decline of -13.3% FVC post treatment demonstrated a median improvement of +8.9% Refractory ILD Click to edit Master text styles Second level Third level Fourth level Fifth level Respirology April (3) p Keir GJ et al

9 Not everyone responded 5 of the connective tissue disease patients progressed in spite of rituximab In those that did respond; FVC decline was less pronounced pre rituximab FVC was higher pre treatment

10 EUSTAR analysis of Rituximab Treatment

11 Proof of principle study 14 patients in total 8 patients received 2 cycles of Rituximab 6 months apart Importantly no deterioration in the Rituximab group versus 5 out of 6 who deteriorated in the control group Improvement in lung function tests; median improvement in FVC predicted 10% Experience with rituximab in scleroderma: results from a 1 year, proof of principle study. Rheumatology 2010; 49: Daoussis et al.

12 Experience with rituximab in scleroderma: results from a 1 year, proof of principle study. Rheumatology 2010; 49: Daoussis D et al

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14 Potential New Therapies Induction therapy Mycophenolate (SLS II) Tocilizumab Rituximab Maintenance therapy Anti-fibrotic drugs; Pirfenidone Nintedanib

15 Anti fibrotic agents Treatments developed for idiopathic pulmonary fibrosis Progressive fibrotic disease No effective treatment until recently Pirfenidone licensed for treatment of IPF in UK Nintedanib awaiting appraisal Slow rate of decline/progression

16 Pirfenidone Oral medication Three randomised controlled trials showed benefit in IPF Reduction in decline of FVC from -11% (placebo) to -8.5% with treatment Number of people with a significant decline in lung function was halved over a year of follow up

17 Pirfenidone in IPF Click to edit Master text styles Second level Third level Fourth level Fifth level

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19 Open label, 16 week study 2/3rds on concurrent MMF Mean FVC 76% predicted, DLCO 59.7% Median change in FVC was -0.5% (-42% to +12%) Safe and well tolerated BUT need to do more studies to assess efficacy

20 Nintedanib Oral medication Annual rate of FVC decline was 50% less in those taking the treatment

21 Change from Baseline over Time in Forced Vital Capacity (FVC) in INPULSIS-1 and INPULSIS-2, Acco Richeldi L et al. N Engl J Med 2014;370:

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23 Scleroderma associated Intersitial Lung Disease Definitely important Despite challenges current treatment can potentially achieve stability Future treatments may be better tolerated and more efficacous Research activity

24 Activation of immune pathways CY LC O MMF Inflammation Immune dyregulationrituximab Tocilizumab Amplifies autoimmunity Scar tissue formation - fibrosis Pirfenidone Nintedanib Aberrant tissue repair Vascular protective Vasculopathy drugs

25 Thank you for listening!