Emerging Therapies for Lung Fibrosis Helen Garthwaite Respiratory - PowerPoint PPT Presentation

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

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

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

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

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

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

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

Rituximab for Treatment- Refractory ILD Retrospective review of Click to edit Master text styles 50 patients who received Second level ● Third level Rituximab ● Fourth level ● Fifth level 33 with connective tissue disease – 8 scleroderma FVC pre treatment demonstrated a median decline of -13.3% FVC post treatment demonstrated a median Respirology April 2014. 19 (3) p353-359. Keir GJ et al improvement of +8.9%

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

EUSTAR analysis of Rituximab Treatment

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: 271-280. Daoussis et al.

Experience with rituximab in scleroderma: results from a 1 year, proof of principle study. Rheumatology 2010; 49: 271-280. Daoussis D et al

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

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

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

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

• 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

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

nd Change from Baseline over Time in Forced Vital Capacity (FVC) in INPULSIS-1 and INPULSIS-2, Accord Richeldi L et al. N Engl J Med 2014;370:2071-2082.

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

Activation of immune pathways MMF Inflammation Scar tissue formation - fibrosis Immune dyregulation Rituximab Pirfenidone CY LC Nintedanib O T ocilizumab Amplifies autoimmunity Aberrant tissue repair Vascular protective Vasculopathy drugs

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