Update on Therapies: Clinical Trials Timothy PM Whelan Assistant Professor of Medicine Medical Director, Interstitial Lung Disease Program University of Minnesota

Outline Pathogenesis of pulmonary fibrosis Targets of treatment Measuring safety and efficacy of Rx Recent and current clinical trials Summary University of Minnesota

Pulmonary Fibrosis Scarring of the lungs produced by collagen deposition Once scar is well established, disrupts normal architecture of the lung Result: oxygen from the air does not transfer into the blood stream normally University of Minnesota

Microscopic injury to the lung Focal fibroblast proliferation Collagen deposition Return of normal lung architecture Normal Lung Repair Dissolution of the scaffolding University of Minnesota

Dissolution of the scaffolding Persistence of collagen scar Microscopic injury to the lung Focal fibroblast proliferation Collagen deposition Abnormal transfer of oxygen into the blood stream Cause of Pulmonary Fibrosis Recurrent microscopic injury University of Minnesota

Treatment Options Stop the cycle of recurrent injury Avoidance of known risk factors –Occupational exposures –Tobacco –Organic and inorganic dust exposures –Prevent infections: influenza, pneumococcus Treatment of medical conditions associated with development of fibrosis University of Minnesota

Treatment Options Stop continued deposition of collagen Affect mechanisms known to activate the fibroblast Increase removal of fibroblasts Boost the immune system? University of Minnesota

Treatment Options There are no proven medical therapies for the treatment of Idiopathic Pulmonary Fibrosis Future successful treatment relies on well designed clinical trials University of Minnesota

Clinical Trials Research protocols in human subjects Designed to answer a specific question Observational Trials Large groups of people in natural setting Interventional Trials Investigate experimental treatment effects Several phases or steps in drug development University of Minnesota

Phase I A new drug or treatment tested in a small group of people for the first time evaluate its safety determine a safe dosage range identify side effects may include healthy subjects University of Minnesota

Phase II Controlled clinical studies Evaluate the effectiveness of the drug for a particular indication or indications Tested in patients with the disease or condition under study Determine the common short-term side effects and risks. University of Minnesota

Phase III Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug gather additional information to evaluate the overall benefit-risk relationship of the drug provide an adequate basis for physician labeling University of Minnesota

Phase IV Post-marketing studies Delineate additional information including the drug's risks, benefits, and optimal use. University of Minnesota

Trial Design Basics Hypothesis Primary versus secondary endpoints “Power” Ability of study to determine a difference Assumptions made by researchers –Number of patients enrolled –Number of events that are expected to occur –Estimation of treatment effect of intervention University of Minnesota

Trial Design Basics Inclusion criteria Specific disease process Age, test results, symptoms Exclusion criteria Concomitant illnesses Known interactions with interventions University of Minnesota

Trial Design Basics Control Group Placebo Inactive compound Current standard regimen University of Minnesota

Benefits Well-designed and well-executed clinical trials allow eligible participants to: Play an active role in their own health care. Gain access to new research treatments before they are widely available. Obtain expert medical care at leading health care facilities during the trial. Help others by contributing to medical research. University of Minnesota

Risks There may be unpleasant, serious or even life-threatening side effects to experimental treatment. The experimental treatment may not be effective for the participant. The protocol may require more of their time and attention than would a non-protocol treatment, including trips to the study site, more treatments, hospital stays or complex dosage requirements. University of Minnesota

Trial Design Basics Informed Consent Process by which study participants are fully informed as to specific risks/benefits of a particular protocol Process does not stop once enrolled but continues throughout the study period Consent within a study is voluntary and can be withdrawn at any point University of Minnesota

Clinical Investigations - IPF Phase I FG-3019 – completed Phase II Bosentan (Tracleer ® ) – enrollment closed Etanercept (Enbrel ® ) – enrollment closed Imatinib (Gleevec ® ) – enrollment ongoing Pirfenidone – completed Phase III Gamma Interferon-1b (Actimmune ® ) -- ongoing University of Minnesota

Summary Pulmonary fibrosis results from the normal healing process going astray Treatment options once pulmonary fibrosis develops are limited Clinical trials involve multiple phases of investigation University of Minnesota

Summary Multiple promising drug therapies are already under investigation Well designed, large clinical trials are the key to obtaining answers for the future University of Minnesota

Resources to learn more University of Minnesota Center for Advanced Lung Disease Registry of Interested Persons University of Minnesota

Resources to learn more University of Minnesota Center for Advanced Lung Disease Registry of Interested Persons Contact Jenny or Joslyn: (612) Toll Free: University of Minnesota