Genetic Variant is Risk Factor for Two Different Types of Interstitial Lung Disease

MedicalResearch.com Interview with:

Joyce S. Lee, MD Associate Professor Director, Interstitial Lung Disease Program Department of Medicine Division of Pulmonary Sciences and Critical Care Medicine University of Colorado School of Medicine

Dr. Lee

Joyce S. Lee, MD
Associate Professor
Director, Interstitial Lung Disease Program
Department of Medicine
Division of Pulmonary Sciences and Critical Care Medicine
University of Colorado School of Medicine

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: Rheumatoid arthritis (RA) is a common inflammatory arthritis that can be complicated by interstitial lung disease (ILD). Patients with RA-ILD share clinical characteristics with another ILD called idiopathic pulmonary fibrosis (IPF).

Given the similar clinical phenotype, our goal was to see if these lung diseases (IPF and RA-ILD) shared a common genetic risk factor. The MUC5B promoter variant is the most common risk factor (genetic and otherwise) for the development of IPF.

Our findings demonstrate the MUC5B promoter variant is also a strong risk factor for the development of RA-ILD among patients with RA.

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Nintedanib (OFEV®) May Offer Survival Advantage for IPF Patients

MedicalResearch.com Interview with:

Christopher J. Ryerson, M.D. Assistant Professor Centre for Heart Lung Innovation University of British Columbia Vancouver, Canada

Dr. Ryerson

Christopher J. Ryerson, M.D.
Assistant Professor
Centre for Heart Lung Innovation
University of British Columbia
Vancouver, Canada

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: A new Idiopathic pulmonary fibrosis (IPF) mortality analysis presented at the American Thoracic Society’s 2018 annual conference suggests that treatment with nintedanib may be associated with reduced risk of death in patients with the rare lung disease idiopathic pulmonary fibrosis (IPF).

Pooled data from the two Phase II INPULSIS trials and the Phase II TOMORROW study compared the number of deaths observed versus the number predicted based on GAP stage over one year. GAP stage is used to predict IPF prognosis and is based on gender, age and lung function (as measured by forced vital capacity [FVC] decline predicted and DLco % predicted). Higher stages of GAP are associated with an increased risk of death.

Across the population in the analysis (n=1,228), there were fewer deaths observed in each treatment group than predicted based on GAP stage at baseline (nintedanib: 42 vs. 89.9; placebo: 41 vs. 64.2). In the treated group, the number of observed deaths was 46.7% of the number predicted based on GAP stage, while in the placebo group the number of observed deaths was 63.9% of the number predicted. Based on these observations, the analysis suggests that nintedanib may be associated with a 26.8% relative reduction in the risk of death compared with placebo over one year.  Continue reading

Antifibrotic Drug Stabilized Lung Function For Patients with Idiopathic Pulmonary Fibrosis

MedicalResearch.com Interview with:

Pierre Laurin, CEO Prometic

Pierre Laurin

Pierre Laurin, CEO
Prometic Life Sciences

MedicalResearch.com: What is the background for this study? Would you briefly explain what is meant by idiopathic pulmonary fibrosis?

Response: Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating, and ultimately fatal disease characterized by a progressive decline in lung function. It is a specific type of interstitial lung disease in which the small air sacs of the lung, the “alveoli,” gradually become replaced by fibrotic (scar) tissue and is the cause of worsening dyspnea (shortness of breath). The 5-year mortality rate for patients with IPF is estimated to range from 50% to 70%.

Small molecule candidate PBI-4050’s anti-fibrotic activity has been observed in various fibrosis models in different organs: lung, kidney, heart, liver, and pancreas. PBI-4050 has been shown to improve forced vital capacity (FVC) in an open-label Phase 2 study in IPF.

The main objective of this exploratory study was to determine whether treatment with PBI-4050 alters the level of key biomarkers in patients with IPF. Subjects with a confirmed diagnosis of IPF received daily oral doses of 800 mg PBI-4050 with or without nintedanib or pirfenidone for 12 weeks. The biomarkers chosen for measurement can be divided into two main groups: cytokines and matrix metalloproteinases associated with fibrosis and inflammation.

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IPF: Combination of Nintedanib and Pirfenidone May Have Added Benefit With Manageable Side Effects

MedicalResearch.com Interview with:

Professor Carlo Vancheri Professor of Respiratory Medicine, University of Catania, Italy and Director of the Regional Referral Centre for Rare Lung Diseases and the Laboratory of Experimental Respiratory Medicine.

Prof. Vancheri

Professor Carlo Vancheri
Professor of Respiratory Medicine,
University of Catania, Italy and Director of the Regional Referral Centre for Rare Lung Diseases and the Laboratory of Experimental Respiratory Medicine.

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: The aim of Boehringer Ingelheim’s INJOURNEY trial was to investigate the safety profile of Ofev (nintedanib) in combination with pirfenidone in treating patients with idiopathic pulmonary fibrosis (IPF). Nintedanib and pirfenidone, the only two FDA-approved drugs for the treatment of IPF, are able to slow down the progression of the disease, reducing the forced vital capacity (FVC) decline of about 50%, but this is not a cure. The target for the future is to have even more effective treatments. In the meanwhile, it is necessary to optimize the use of the available drugs. The medical treatment of other pulmonary diseases such as COPD, asthma or pulmonary hypertension is already based on different combinations of drugs.

This 12-week, open-label, randomized study was designed to evaluate the safety, tolerability and pharmacokinetics of nintedanib with add-on pirfenidone, compared with nintedanib alone in patients with IPF. Change in FVC, the established efficacy endpoint in IPF trials, was evaluated as an exploratory endpoint.

The primary endpoint of the INJOURNEY trial was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to week 12 of randomized treatment, and the results showed that the combination of nintedanib and add-on pirfenidone resulted in a manageable safety and tolerability profile, similar to the profile of each drug individually in the majority of patients. Results also indicated there may be a slower decline in FVC in patients treated with pirfenidone along with nintedanib compared with nintedanib alone, suggesting a potential benefit of the combination. However, further research will be necessary to fully evaluate the efficacy of the combination.

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IPF Patients Treated With Nintedanib (Ofev) More Likely To Have Stable Lung Function

MedicalResearch.com Interview with:

Kevin R. Flaherty

Dr. Flaherty

Kevin R. Flaherty, M.D., M.S.
Professor, Department of Internal Medicine
Associate Director, T32 Multidisciplinary Training Program in Lung Diseases
Chair, Pulmonary Fibrosis Foundation Clinical Care Network Steering Committee
University of Michigan Medicine 

MedicalResearch.com: What is the background for this study? What are the main findings?
Response: This is a new post-hoc analysis, recently presented at the 2017 American Thoracic Society (ATS) conference, which sought to further assess the efficacy of Ofev (nintedanib), an FDA-approved drug treatment for idiopathic pulmonary fibrosis (IPF), and its effect on lung function in those with this disease.

IPF is a rare and serious lung disease that causes permanent scarring of the lungs and affects as many as 132,000 Americans.

The analysis examined pooled data from the two placebo-controlled, global Phase III INPULSIS trials, which evaluated the efficacy and safety of 52 weeks’ treatment with nintedanib in people with IPF. In both trials, a higher proportion of people treated with placebo than nintedanib had disease progression from baseline to week 52, as defined by the proportions of patients with ≥5% or ≥10% declines in lung function, as measured by forced vital capacity (FVC) % predicted. Additionally, a lower proportion of patients treated with placebo than nintedanib had no decline or an improvement in FVC % predicted.

These data support the initial findings from the Phase III INPULSIS trials which found that more patients treated with nintedanib versus placebo had an absolute decline in FVC of less than 5%.

In this subgroup analysis, we assessed the proportions of patients from the two INPULSIS trials treated with nintedanib and placebo who had no decline or an improvement in lung function from baseline to week 52 using pooled data for this post-hoc analysis. In terms of those who participated, a total of 864 patients were included (519 treated with nintedanib, 345 treated with placebo). Baseline characteristics including age, gender and FVC were similar between the subgroups of patients who had no decline or an improvement in FVC and those whose FVC declined, and between the nintedanib and placebo groups within each subgroup.

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Pulmonary Fibrosis: High Resolution CT Diagnosis

Ganesh Raghu, M.D.,FCCP, FACP Professor of Medicine & Lab Medicine (Adjunct) Division of Pulmonary & Critical Care Medicine University of Washington(UW) Director,CENTER for Interstitial Lung Disease(ILD),UW Medicine, ILD, Sarcoid and Pulmonary Fibrosis Program Co-Director, Scleroderma Clinic, UW Medical center(UWMC) Seattle, WA 98195MedicalResearch.com Interview with:
Ganesh Raghu, M.D.,FCCP, FACP
Professor of Medicine & Lab Medicine (Adjunct)
Division of Pulmonary & Critical Care Medicine
University of Washington(UW)
Director,CENTER for Interstitial Lung Disease (ILD),UW Medicine,
ILD, Sarcoid and Pulmonary Fibrosis Program
Co-Director, Scleroderma Clinic, UW Medical center(UWMC)
Seattle, WA 98195

MedicalResearch.com: What are the main findings of the study?

Dr. Raghu: In a subgroup of patients with typical clinical features of Idiopathic pulmonary fibrosis ( IPF) , further evaluation by a thorough evlauation by regional experts experienced in management of idiopathic pulmonary fibrosis and related diseases may lead to a diagnosis of idiopathic pulmonary fibrosis without the need for surgical lung biopsy if the HRCT features have a Possible-UIP pattern AND if there are no suspicion for environmental factors or collagen vascular diseases to explain the pulmonary fibrosis .
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Pulmonary Fibrosis: Strongly Associated with a Herpes Virus

Gerard Nuovo MD Professor College of Medicine, The Ohio State University Satellite Laboratory, Ohio State Univ Comprehensive Cancer Center Phylogeny Inc, Powell, OhioMedicalResearch.com Interview with:
Gerard Nuovo MD
Professor College of Medicine, The Ohio State University
Satellite Laboratory, Ohio State Univ Comprehensive Cancer Center
Phylogeny Inc, Powell, Ohio

MedicalResearch.com: What are the main findings of the study?

Dr. Nuovo: The main finding of the study was that idiopathic pulmonary fibrosis was strongly associated with an infection by a herpesvirus.  The data that supported this main finding included:

  • 1) detection of the viral DNA by in situ hybridization in each case of idiopathic pulmonary fibrosis (IPF) and in none of the controls;
  • 2) the localization of the viral DNA to the nucleus of the cell that orchestrates IPF, the regenerating epithelial cell (herpes viruses localize to the nucleus of the target cell);
  • 3) the demonstration that the viral DNA co-localized with “pirated proteins” that the virus makes during productive infection (these were IL-17. cyclin D, dihydrofolate reductase, and thymidylate synthase); this combination of proteins are rarely if ever co-expressed in lung disease and  their co-expression per se was highly suggestive of a viral infection;
  • 4) the demonstration by RTPCR that the cyclin D RNA in IPF comes from the virus and not the human cells;
  • 5) the recognition that this family of herpesviruses (called gammaherpesvirus) causes IPF in other animals including horses, mice, and donkeys;
  • 6) the cloning of part of the gene of the virus from a clinical IPF sample that showed 100% homology to the published sequence of the likely viral pathogen – herpesvirus saimiri.
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