Financial Interest Disclosure (over the past 24 months) Before we begin. Background What is ILD? 8/18/2016

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1 Financial Interest Disclosure (over the past 24 months) SCLERODERMA LUNG DISEASE UPDATE Company Speaker Advisory Research Boehringer-Ingelheim September 2016 Hoffman La-Roche Intermune Shane Shapera, MD, FRCPC Interstitial Lung Disease Program Director Toronto General Hospital, University Health Network Assistant Professor, University of Toronto Medimmune Prometic Sanofi I have taken many images from the internet for this talk full links are provided At the end of this session, participants will be able to: Describe Scleroderma-related interstitial lung disease (SSc-ILD) Before we begin I will need to define some medical terms Understand the risk factors for SSc-ILD development and its progression Discuss current evidence of treatment of SSc-ILD Anticipate future treatments for SSc-ILD Appreciate the role of lung transplant in SSc-ILD Background What is ILD? (Interstitial Lung Disease) Background What is ILD? What is it? Chronic, progressive scarring of the scaffolding of the lung Cause may be known (Scleroderma, RA, exposures, etc ) Cause often unknown (idiopathic interstitial pneumonia - IPF) Why is it bad? Stiff lungs more work to breathe breathless Scarred lungs poor gas exchange low Oxygen levels Progressive lung function can get worse over time &cad=rja&uact=8&ved=0ahukewj4rsn0gzfoahuiwt4khqn9dtuqjr wibw&url=http%3a%2f%2fwww.fpnotebook.com%2flung%2fanato my%2flngantmy.htm&bvm=bv ,d.cww&psig=afqjcnf6y PEOCpwoIJb9miiGxRV-b_NPlQ&ust= ges&cd=&cad=rja&uact=8&ved=0ahukewja5uw3gzfoahum ET4KHQSBAroQjRwIBw&url=http%3A%2F%2Fdepts.washing ton.edu%2fenvh%2flung.html&psig=afqjcnh1xbj2fr_e6td pwfnb3rrnwjunfq&ust=

2 Scarring diseases (like ILD) cause the lungs to become stiff and shrink We measure this shrinkage of the lungs to diagnose and monitor ILD Total lung capacity (TLC) is a measure of all of the air in the lungs We measure TLC using a machine called a plathysmograph (Body Box) ahukewjukrdyg5foahvbmz4khthxbyaqjrwibw&url=http%3a%2f%2fmemim.com%2fbody -plethysmography.html&bvm=bv ,d.cww&psig=afqjcnfvivci_uha1dbwpdeth- FfZ2-GsA&ust= KHD4KHYU1AxwQjRwIBw&url=http%3A%2F%2Fwww.tiem.utk.edu%2F~gross%2Fbioed%2Fwebmodules%2Flungcapa city.html&bvm=bv ,d.cww&psig=afqjcnf2xcjnyvcy6gdujexnub3t0wdt6a&ust= In ILD, the lungs stiffen and shrink The Total Lung Capacity (TLC) gets smaller Other measures (like FVC) go down with TLC FVC is easier and cheaper to measure than TLC We use FVC to monitor for progression of ILD Who gets SSc-ILD? SSc-ILD occurs in up to half of patients with SSc Many patients have mild ILD without symptoms Some can have severe and/or progressive disease ILD is a major cause of disability and death in SSc Not everyone with SSc-ILD needs treatment We only treat patients who are getting worse over time How do we predict who will have mild disease and who will progress over time? Wells AU, et al, Semin Repir Crit Care Med 2014;35:

3 Risk Factors For Progressive ILD Ms. S.C. Recent diagnosis of SSc (within 4-5 years) High volume of abnormal lung (> 20%) Low lung function at baseline (FVC < 70%) Dropping lung function (FVC drops 10%) over 6-12 months 58 year old woman with Scleroderma Lives in Thunder Bay and flies to Toronto for visits Referred to my clinic in 2008 for lung assessment Fit and active with no lung symptoms Comes back 3 years later Breathless for about 6 months Dry hacking cough Slowly getting worse Not improving after antibiotics and puffers Wells AU, et al, Semin Repir Crit Care Med 2014;35: Treatment of SSc-ILD Date Dec Dec May FVC 2.3 L 2.0L 1.7 L Many treatments for SSc have no impact on ILD Some treatments for SSc may be harmful in ILD There are some drugs that we think may help improve lung function: Azathioprine Cyclophosphamide Mycophenolate Prednisone Rituximab 3

4 FVC FVC 8/18/2016 SSc-ILD Treatment: SLS-1 Scleroderma Lung Study 1 acebo x 1 year Oral Cyclophosphamide vs. Placebo for 1 year Modest improvement in FVC at 1 year Further FVC increase at 18 months Benefits lost after 1 year without treatment Side effects common (low blood counts, bladder problems & risk of cancer) FVC<70% benefit most FVC 6.8% at 18 months versus placebo (p = 0.006) End of treatment Time 18 months 2 years SLS-1: Take Home Messages Cyclophosphamide was the first drug to show that we can improve lung function in patients with SSc-ILD Some benefits continue for months even after drug is stopped Lung improvement peaks 6 months after finishing treatment Patients with more severe disease and those most likely to progress seem to get the most benefit Side effects are common and can be serious Are there other less toxic treatments that work? Tashkin DP et al, N Engl J Med 2006;354: Tashki DP et al. Am J Respir Crit Care Med 2007;176: SSc-ILD Treatment: SLS-2 Scleroderma Lung Study 2 SLS-2: Take home messages Year 1 Year 2 Cyclophosphamide and Mycophenolate both improve lung function 142 patients Time A B Oral Cyclophosphamide 2mg/kg/day Mycophenolate 1.5g twice daily FVC improved similarly in both groups More side effects with Cyclophosphamide No treatment Mycophenolate 1.5g twice daily Low blood counts (RBC, WBC, platelets) More Cyclophosphamide patients had to stop drug for side effects (36 vs. 20 patients, p = 0.019) Tashkin DP, et al. Lancet Respir Med Jul 25. pii: S (16) [epub ahead of print] Cyclophosophamide has more side effects than Mycophenolate There are still a lot of unanswered questions Are there some patients that benefit more than others? When is the right time to start these drugs? Is there a role for Cyclophosphamide first followed by Mycophenolate maintenance therapy? Should Cyclophosphamide be used as salvage treatment for patients who are getting worse on Mycophenolate? Many doctors are using both drugs in sequence Cyclophosphamide followed by Mycophenolate Mycophenolate followed by Cyclophosphamide Studies looking at using both drugs will probably never happen Ms. S. C. Date Ms. S. C. had a detailed discussion with her doctor She decided to take 6 months of Cyclophosphamide Followed by long term Mycophenolate for over 2 years This is an example of using both drugs in sequence Dec 2008 Dec 2010 May 2011 Nov 2011 Feb 2012 June 2012 Jan 2013 May 2014 Dec 2014 FVC 2.3 L 2.0L 1.7 L 1.9 L 2.1 L 2.2 L 2.2 L 2.2 L 2.4 L The Future? Rituximab in SSc-ILD Rituximab is a biologic treatment use to treat Rheumatoid Arthritis Given as 2 injections 2 weeks apart every 6 months Makes the body stop making anti-bodies (B-cells) Increases risk of infection Very few other side effects Currently being studied in SSc-ILD (RECITAL trial) Comparing Rituximab vs. Cyclophosphamide Results expected in 2018 Cyclophosphamide Mycophenolate 4

5 Survival (%) Number of LTx '00 '01 '02 '03 '04 '05 '06 '07 '08 '09 '10 '11 '12 '13 '14 '15 8/18/2016 History of the Toronto Lung Transplant Program 1 st Single lung Dr. Joel Cooper in st Double lung Dr. Joel Cooper in 1986 Lung transport solution Dr. Shaf Keshavjee in 1989 Ex-Vivo lung perfusion Dr Shaf Keshavjee 2008 History of the Toronto Lung Transplant Program 1 st Single lung Dr. Joel Cooper in st Double lung Dr. Joel Cooper in 1986 Lung transport solution Dr. Shaf Keshavjee in 1989 Ex-Vivo lung perfusion Dr Shaf Keshavjee 2008 History of the Toronto Lung Transplant Program 1 st Single lung Dr. Joel Cooper in 1983 Lung transplants in Toronto per year ( ) 150 LTx/Year st Double lung Dr. Joel Cooper in Lung transport solution Dr. Shaf Keshavjee in Ex-Vivo lung perfusion Dr Shaf Keshavjee Year LTx/Year Slide courtesy of Sassan Azad Lung Transplantation Survival (TLTP vs. ISHLT) January 1990 June 2012 Lung transplantation: Who is a candidate? ISHLT (N=43,501) TLTP (N=1,180) Median survival (years): ISHLT = 5.6 vs. TLTP ~ 7.0 Severe and progressive ILD that is not responding to medical therapy Patients who are otherwise quite healthy 25 Willing to relocate close to a transplant center Years Slide courtesy of Sassan Azad 5

6 Summary SSc-ILD occurs in half of patients with SSc Risk factors for progression: early and severe disease SSc-ILD is a major cause of disability and death Progression of SSc-ILD is monitored using FVC Cyclophosphamide has been shown to improve FVC Side effects are very common Mycophenolate has recently been shown to also improve FVC Less side effects than Cyclophosphamide More patients are able to stay on treatment New treatments (Rituximab) are currently being studied Lung transplant can be a last resort option for some patients 6