Phase III Double-Blind RCT of BI 1015550 in Progressive Pulmonary Fibrosis Patients (FIBRONEER-ILD)

At December 17, 2024

Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with progressive pulmonary fibrosis (FIBRONEER-ILD)

PMID: 37709661

Abstract:

Introduction: Progressive pulmonary fibrosis (PPF) includes any diagnosis of progressive fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF). However, disease progression appears comparable between PPF and IPF, suggesting a similar underlying pathology relating to pulmonary fibrosis. Following positive results in a phase II study in IPF, this phase III study will investigate the efficacy and safety of BI 1015550 in patients with PPF (FIBRONEER-ILD).

Methods and analysis: In this phase III, double-blind, placebo-controlled trial, patients are being randomised 1:1:1 to receive BI 1015550 (9 mg or 18 mg) or placebo twice daily over at least 52 weeks, stratified by background nintedanib use. Patients must be diagnosed with pulmonary fibrosis other than IPF that is progressive, based on predefined criteria. Patients must have forced vital capacity (FVC) ≥45% predicted and haemoglobin-corrected diffusing capacity of the lung for carbon monoxide ≥25% predicted. Patients must be receiving nintedanib for at least 12 weeks, or not receiving nintedanib for at least 8 weeks, prior to screening. Patients on stable treatment with permitted immunosuppressives (eg, methotrexate, azathioprine) may continue their treatment throughout the trial. Patients with clinically significant airway obstruction or other pulmonary abnormalities, and those using immunosuppressives that may confound FVC results (cyclophosphamide, tocilizumab, mycophenolate, rituximab) or high-dose steroids will be excluded. The primary endpoint is absolute change from baseline in FVC (mL) at week 52. The key secondary endpoint is time to the first occurrence of any acute ILD exacerbation, hospitalisation for respiratory cause or death, over the duration of the trial.

Ethics and dissemination: The trial is being carried out in accordance with the ethical principles of the Declaration of Helsinki, the International Council on Harmonisation Guideline for Good Clinical Practice and other local ethics committees. The study results will be disseminated at scientific congresses and in peer-reviewed publications.

Related News

Phase III Double-Blind RCT of BI 1015550 in Idiopathic Pulmonary Fibrosis Patients (FIBRONEER-IPF)

Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with idiopathic pulmonary fibrosis (FIBRONEER-IPF) PMID: 37597969 Abstract: IntroductionThere is an unmet need for new treatments for idiopathic pulmonary fibrosis (IPF). The oral preferential phosphodiesterase 4B inhibitor, BI 1015550, prevented a decline in forced vital capacity (FVC) in a phase II study in patients with IPF. This study design describes the subsequent pivotal phase III study of BI 1015550 in patients with IPF (FIBRONEER-IPF). Methods and analysis: In this placebo-controlled, double-blind, phase III trial, patients are being randomised in a 1:1:1 ratio to receive 9 mg or 18 mg of BI 1015550 or placebo two times per day over at least 52 weeks, stratified by use of background antifibrotics (nintedanib/pirfenidone vs neither). The primary endpoint is the absolute change in FVC at week 52. The key secondary endpoint is a composite of time to first acute IPF exacerbation, hospitalisation due to respiratory cause or death over the duration of the trial. Ethics and dissemination: The trial is being carried out in compliance with the ethical principles of the Declaration of Helsinki, in accordance with the International Council on Harmonisation Guideline for Good Clinical Practice and other local ethics committees. The results of the study will be disseminated at scientific congresses and in peer-reviewed publications. Trial registration number: NCT05321069.

Potential of PDE4B Inhibitors for Treating ILD Associated with Autoimmune Diseases

PMID: 39212123 Abstract: Patients with autoimmune disease-related interstitial lung disease may develop pulmonary fibrosis, which may become progressive. Progressive pulmonary fibrosis (PPF) is associated with poor outcomes. Antifibrotic therapies have shown efficacy as treatments for PPF in patients with autoimmune diseases, but new treatments are needed to slow or halt disease progression. Phosphodiesterases (PDEs) are enzymes that mediate the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Pre-clinical data suggest that preferential inhibition of PDE4B has the potential to slow the progression of pulmonary fibrosis by inhibiting inflammatory and fibrotic pathways, with a lower risk of gastrointestinal adverse events than associated with pan-PDE4 inhibitors. Nerandomilast (BI 1015550) is a preferential PDE4 inhibitor that has demonstrated anti-inflammatory and antifibrotic effects in pre-clinical studies. In a phase II trial in patients with idiopathic pulmonary fibrosis, nerandomilast (given alone or on top of background antifibrotic therapy) prevented a decrease in lung function over 12 weeks with an acceptable safety and tolerability profile. The phase III FIBRONEER-ILD trial is evaluating the efficacy and safety of nerandomilast, given alone or on top of nintedanib, in patients with PPF, including PPF associated with autoimmune diseases. In this article, we review the potential of PDE4B inhibition in the treatment of ILD associated with autoimmune diseases, including the pre-clinical and early clinical data available to date.

The Risk of Lung Cancer in RA and RA-Associated Interstitial Lung Disease

Arthritis Rheumatol. 2024 Dec;76(12):1730-1738. doi: 10.1002/art.42961. Epub 2024 Aug 16. Rebecca T Brooks 1, Brent Luedders 2, Austin Wheeler 2, Tate M Johnson 2, Yangyuna Yang 2, Punyasha Roul 2, Apar Kishor Ganti 2, Namrata Singh 3, Brian C Sauer 4, Grant W Cannon 4, Joshua F Baker 5, Ted R Mikuls 2, Bryant R England 2 Affiliations • 1 Mayo Clinic, Rochester, Minnesota. • 2 The Department of Veterans Affairs Nebraska-Western Iowa Health Care System and the University of Nebraska Medical Center, Omaha. • 3 University of Washington, Seattle. • 4 Salt Lake City Department of Veterans Affairs and the University of Utah. • 5 Corporal Michael J. Crescenz Department of Veterans Affairs and the University of Pennsylvania, Philadelphia. Abstract Objective: We aimed to evaluate lung cancer risk in patients with rheumatoid arthritis (RA) and RA-interstitial lung disease (ILD). Methods: We performed a retrospective, matched cohort study of RA and RA-ILD within the Veterans Health Administration (VA) between 2000 and 2019. Patients with RA and RA-ILD were identified with validated administrative-based algorithms, then matched (up to 1:10) on age, gender, and VA enrollment year to individuals without RA. Lung cancers were identified from a VA oncology database and the National Death Index. Conditional Cox regression models assessed lung cancer risk adjusting for race, ethnicity, smoking status, Agent Orange exposure, and comorbidity burden among matched individuals. Several sensitivity analyses were performed. Results: We matched 72,795 patients with RA with 633,937 patients without RA (mean age 63 years; 88% male). Over 4,481,323 patient-years, 17,099 incident lung cancers occurred. RA was independently associated with an increased lung cancer risk (adjusted hazard ratio [aHR] 1.58 [95% confidence interval (CI) 1.52-1.64]), which persisted in never smokers (aHR 1.65 [95% CI 1.22-2.24]) and in those with incident RA (aHR 1.54 [95% CI 1.44-1.65]). Compared to non-RA controls, prevalent RA-ILD (n = 757) was more strongly associated with lung cancer risk (aHR 3.25 [95% CI 2.13-4.95]) than RA without ILD (aHR 1.57 [95% CI 1.51-1.64]). Analyses of both prevalent and incident RA-ILD produced similar results (RA-ILD vs non-RA aHR 2.88 [95% CI 2.45-3.40]). Conclusion: RA was associated with a >50% increased risk of lung cancer, and those with RA-ILD represented a particularly high-risk group with an approximate three-fold increased risk. Increased lung cancer surveillance in RA, and especially RA-ILD, may be a useful strategy for reducing the burden posed by the leading cause of cancer death.

Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis

Abstract: Background: Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis. Methods: In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent. Results: A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, –39.1 to 50.5) in the BI 1015550 group and –81.7 ml (95% credible interval, –133.5 to –44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, –32.8 to 38.2) in the BI 1015550 group and –59.2 ml (95% credible interval, –111.8 to –17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups. Conclusions: In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis. (Funded by Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.) Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible lung disease with high mortality.1,2 Currently, there are two approved antifibrotic drugs — nintedanib and pirfenidone — that slow, but do not stop, the progression of fibrosis.3-5 Therefore, there is a need for additional treatments that can be used alone or with existing antifibrotic therapies.6 Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic properties.7,8 Preferential inhibition of the PDE4B subtype may be beneficial in the treatment of IPF because it may harness these properties9,10 and is also associated with a more acceptable safety profile than nonselective PDE4 inhibitors.7,10 IPF is a rare disease, which makes the recruitment of large numbers of patients in early-phase clinical trials a challenge. In this trial, we used Bayesian analysis11,12 to incorporate informative historical data from phase 2–4 clinical trials of nintedanib for the control groups. Consistent decreases in the forced vital capacity (FVC) that have been observed in the placebo groups of these trials3,4,13–16 make such an approach suitable for proof-of-concept studies of new drug candidates for the treatment of IPF. In this multicenter, randomized, double-blind, phase 2 trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of PDE4B,17 in patients with IPF according to background nonuse or use of an antifibrotic agent.

RA-ILD: Update on Prevalence, Risk Factors, Pathogenesis, and Therapy

Curr Rheumatol Rep. 2024 Sep 25. doi: 10.1007/s11926-024-01155-8. Online ahead of print. Daniel I Sullivan 1, Dana P Ascherman 2 Affiliations • 1Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, UPMC Montefiore Hospital, 3459 Fifth Ave, NW 628, Pittsburgh, PA, 15213, USA. dsulliva@pitt.edu. • 2Division of Rheumatology and Clinical Immunology, Department of Medicine, Abstract Purpose of review: Rheumatoid arthritis is frequently complicated by interstitial lung disease (RA-ILD), an underappreciated contributor to excess morbidity and mortality. The true prevalence of RA-ILD is difficult to define given the variability in diagnostic criteria used. The lack of standardized screening methods, an incomplete understanding of disease pathogenesis, and dearth of validated biomarkers have limited the development of controlled clinical trials for this disease. Recent findings: Numerous studies have focused on clinical, radiographic, genetic, molecular, and/or serologic markers of disease severity as well as risk of disease progression. In addition to defining valuable clinical biomarkers, these studies have provided insights regarding the pathogenesis of RA-ILD and potential therapeutic targets. Additional studies involving immunomodulatory and/or anti-fibrotic agents have assessed new therapeutic options for different stages of RA-ILD. RA-ILD continues to be a major contributor to the increased morbidity and mortality associated with RA. Advancements in our understanding of disease pathogenesis at a molecular level are necessary to drive the development of more targeted therapy.

2023 ACR/CHEST Guideline: Screening & Monitoring ILD in Systemic Autoimmune Rheumatic Diseases

"2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Screening and Monitoring of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases" Arthritis Rheumatol. 2024 Aug;76(8):1201-1213. doi: 10.1002/art.42860.Epub 2024 Jul 8. Sindhu R Johnson 1, Elana J Bernstein 2, Marcy B Bolster 3, Jonathan H Chung 4, Sonye K Danoff 5, Michael D George 6, Dinesh Khanna 7, Gordon Guyatt 8, Reza D Mirza 8, Rohit Aggarwal 9, Aberdeen Allen Jr 10, Shervin Assassi 11, Lenore Buckley 12, Hassan A Chami 5, Douglas S Corwin 13, Paul F Dellaripa 14, Robyn T Domsic 9, Tracy J Doyle 14, Catherine Marie Falardeau 15, Tracy M Frech 16, Fiona K Gibbons 3, Monique Hinchcliff 12, Cheilonda Johnson 6, Jeffrey P Kanne 17, John S Kim 18, Sian Yik Lim 19, Scott Matson 20, Zsuzsanna H McMahan 5, Samantha J Merck 21, Kiana Nesbitt 22, Mary Beth Scholand 23, Lee Shapiro 24, Christine D Sharkey 17, Ross Summer 25, John Varga 7, Anil Warrier 26, Sandeep K Agarwal 27, Danielle Antin-Ozerkis 12, Bradford Bemiss 28, Vaidehi Chowdhary 12, Jane E Dematte D'Amico 28, Robert Hallowell 3, Alicia M Hinze 29, Patil A Injean 30, Nikhil Jiwrajka 6, Elena K Joerns 31, Joyce S Lee 32, Ashima Makol 29, Gregory C McDermott 14, Jake G Natalini 33, Justin M Oldham 7, Didem Saygin 9, Kimberly Showalter Lakin 34, Namrata Singh 35, Joshua J Solomon 36, Jeffrey A Sparks 14, Marat Turgunbaev 37, Samera Vaseer 38, Amy Turner 37, Stacey Uhl 39, Ilya Ivlev 39 Affiliations • 1 University of Toronto, Schroeder Arthritis Institute, Toronto Western Hospital, Mount Sinai Hospital, Toronto, Ontario, Canada. • 2 Columbia University Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York City. • 3 Massachusetts General Hospital, Boston. • 4 The University of Chicago Medicine, Chicago, Illinois. • 5 Johns Hopkins University School of Medicine, Baltimore, Maryland. • 6 University of Pennsylvania, Philadelphia. • 7 University of Michigan, Ann Arbor. • 8 McMaster University, Hamilton, Ontario, Canada. • 9 University of Pittsburgh, Pittsburgh, Pennsylvania. • 10 Parlin, New Jersey. • 11 University of Texas Health Science Center at Houston. • 12 Yale School of Medicine, New Haven, Connecticut. • 13 St. Luke's University Health Network, Bethlehem, Pennsylvania. • 14 Brigham and Women's Hospital, Boston, Massachusetts. • 15 Kissimmee, Florida. • 16 Vanderbilt University Medical Center, Nashville, Tennessee. • 17 University of Wisconsin School of Medicine and Public Health, Madison. • 18 University of Virginia School of Medicine, Charlottesville. • 19 Hawaii Pacific Health, Aiea. • 20 University of Kansas Medical Center, Kansas City. • 21 Saint Francis Health System, Tulsa, Oklahoma. • 22 Lansdowne, Pennsylvania. • 23 University of Utah, Salt Lake City. • 24 Albany Medical College, Albany, New York. • 25 Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. • 26 Millennium Physicians, Huntsville, Texas. • 27 Baylor College of Medicine, Houston, Texas. • 28 Northwestern University, Chicago, Illinois. • 29 Mayo Clinic, Rochester, Minnesota. • 30 Cedars-Sinai, Los Angeles, California. • 31 UT Southwestern Medical Center, Dallas, Texas. • 32 University of Colorado Denver, Aurora. • 33 New York University Langone Health, New York City. • 34 Hospital for Special Surgery, Weill Cornell Medicine, New York City. • 35 University of Washington, Seattle. • 36 National Jewish Health, Denver, Colorado. • 37 American College of Rheumatology, Atlanta, Georgia. • 38 University of Oklahoma, Oklahoma City. • 39 ECRI, Center for Clinical Evidence and Guidelines, Plymouth Meeting, Pennsylvania. Abstract Objective: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. Methods: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. Results: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. Conclusion: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

ANCHOR-RA: Multi-National Cross-Sectional Study on ILD Screening in Rheumatoid Arthritis Patients

Design of ANCHOR-RA: a multi-national cross-sectional study on screening for interstitial lung disease in patients with rheumatoid arthritis BMC Rheumatol. 2024 May 21;8(1):19. doi: 10.1186/s41927-024-00389-4. Jeffrey A Sparks 1, Philippe Dieudé 2, Anna-Maria Hoffmann-Vold 3 4, Gerd R Burmester 5, Simon Lf Walsh 6, Michael Kreuter 7, Christian Stock 8, Steven Sambevski 9, Margarida Alves 9, Paul Emery 10 Affiliations • 1 Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, #6016U, Boston, MA, 02115, USA. jsparks@bwh.harvard.edu. • 2 Department of Rheumatology, Bichat-Claude Bernard University Hospital, Assistance Publique-Hôpitaux de Paris, INSERM UMR1152, University of Paris, Paris, France. • 3 Department of Rheumatology, Oslo University Hospital, University of Zurich, Oslo, Norway. • 4 Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. • 5 Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany. • 6 National Heart and Lung Institute, Imperial College London, London, UK. • 7 Center for Pulmonary Medicine, Departments of Pneumology, Critical Care & Sleep Medicine, Mainz University Medical Center and of Pulmonary, Marienhaus Clinic Mainz, Mainz, Germany. • 8 Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany. • 9 Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany. • 10 NIHR Leeds Biomedical Research Centre, Institute of Rheumatic and Musculoskeletal Medicine, Leeds Teaching Hospitals NHS Trust and Leeds, University of Leeds, Leeds, UK. Abstract Background: Patients with rheumatoid arthritis (RA) are at risk of developing interstitial lung disease (ILD), which is associated with high mortality. Screening tools based on risk factors are needed to decide which patients with RA should be screened for ILD using high-resolution computed tomography (HRCT). The ANCHOR-RA study is a multi-national cross-sectional study that will develop a multivariable model for prediction of RA-ILD, which can be used to inform screening for RA-ILD in clinical practice. Methods: Investigators will enrol consecutive patients with RA who have ≥ 2 of the following risk factors for RA-ILD: male; current or previous smoker; age ≥ 60 years at RA diagnosis; high-positive rheumatoid factor and/or anti-cyclic citrullinated peptide (titre > 3 x upper limit of normal); presence or history of certain extra-articular manifestations of RA (vasculitis, Felty's syndrome, secondary Sjögren's syndrome, cutaneous rheumatoid nodules, serositis, and/or scleritis/uveitis); high RA disease activity in the prior 12 months. Patients previously identified as having ILD, or who have had a CT scan in the prior 2 years, will not be eligible. Participants will undergo an HRCT scan at their local site, which will be assessed centrally by two expert radiologists. Data will be collected prospectively on demographic and RA-related characteristics, patient-reported outcomes, comorbidities and pulmonary function. The primary outcomes will be the development of a probability score for RA-ILD, based on a multivariable model incorporating potential risk factors commonly assessed in clinical practice, and an estimate of the prevalence of RA-ILD in the study population. It is planned that 1200 participants will be enrolled at approximately 30 sites in the USA, UK, Germany, France, Italy, Spain. Discussion: Data from the ANCHOR-RA study will add to the body of evidence to support recommendations for screening for RA-ILD to improve detection of this important complication of RA and enable early intervention. Trial registration: clinicaltrials.gov NCT05855109 (submission date: 3 May 2023).