Marianne S Muhlebach1, J P Clancy2, Sonya L Heltshe3, Assem Ziady2, Tom Kelley4, Frank Accurso5, Joseph Pilewski6, Nicole Mayer-Hamblett7, Elizabeth Joseloff8, Scott D Sagel5. 1. Division of Pulmonology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Electronic address: marianne_muhlebach@med.unc.edu. 2. Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. 3. Division of Pulmonary, Department of Pediatrics, University of Washington, Seattle, WA, United States. 4. Department of Biostatistics, University of Washington, Seattle, WA, United States. 5. Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, United States. 6. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States. 7. Division of Pulmonary, Department of Pediatrics, University of Washington, Seattle, WA, United States; Division of Pulmonology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH, United States. 8. Cystic Fibrosis Foundation, Bethesda, MD, United States.
Abstract
PURPOSE: To provide a review of the status of biomarkers in cystic fibrosis drug development, including regulatory definitions and considerations, a summary of biomarkers in current use with supportive data, current gaps, and future needs. METHODS: Biomarkers are considered across several areas of CF drug development, including cystic fibrosis transmembrane conductance regulator modulation, infection, and inflammation. RESULTS: Sweat chloride, nasal potential difference, and intestinal current measurements have been standardized and examined in the context of multicenter trials to quantify CFTR function. Detection and quantification of pathogenic bacteria in CF respiratory cultures (e.g.: Pseudomonas aeruginosa) are commonly used in early phase antimicrobial clinical trials, and to monitor safety of therapeutic interventions. Sputum (e.g.: neutrophil elastase, myeloperoxidase, calprotectin) and blood biomarkers (e.g.: C reactive protein, calprotectin, serum amyloid A) have had variable success in detecting response to inflammatory treatments. CONCLUSIONS: Biomarkers are used throughout the drug development process in CF, and many have been used in early phase clinical trials to provide proof of concept, detect drug bioactivity, and inform dosing for later-phase studies. Advances in the precision of current biomarkers, and the identification of new biomarkers with 'omics-based technologies, are needed to accelerate CF drug development. Copyright Â
PURPOSE: To provide a review of the status of biomarkers in cystic fibrosis drug development, including regulatory definitions and considerations, a summary of biomarkers in current use with supportive data, current gaps, and future needs. METHODS: Biomarkers are considered across several areas of CF drug development, including cystic fibrosis transmembrane conductance regulator modulation, infection, and inflammation. RESULTS:Sweat chloride, nasal potential difference, and intestinal current measurements have been standardized and examined in the context of multicenter trials to quantify CFTR function. Detection and quantification of pathogenic bacteria in CF respiratory cultures (e.g.: Pseudomonas aeruginosa) are commonly used in early phase antimicrobial clinical trials, and to monitor safety of therapeutic interventions. Sputum (e.g.: neutrophil elastase, myeloperoxidase, calprotectin) and blood biomarkers (e.g.: C reactive protein, calprotectin, serum amyloid A) have had variable success in detecting response to inflammatory treatments. CONCLUSIONS: Biomarkers are used throughout the drug development process in CF, and many have been used in early phase clinical trials to provide proof of concept, detect drug bioactivity, and inform dosing for later-phase studies. Advances in the precision of current biomarkers, and the identification of new biomarkers with 'omics-based technologies, are needed to accelerate CF drug development. Copyright Â
Authors: Eline Thomson; Siobhain Brennan; Revathy Senthilmohan; Catherine L Gangell; Anna L Chapman; Peter D Sly; Anthony J Kettle; Elizabeth Balding; Luke J Berry; John B Carlin; Rosemary Carzino; Nick de Klerk; Tonia Douglas; Clara Foo; Luke W Garratt; Graham L Hall; Jo Harrison; Anthony Kicic; Ingrid A Laing; Karla M Logie; John Massie; Lauren S Mott; Conor Murray; Faith Parsons; Naveen Pillarisetti; Srinivas R Poreddy; Sarath C Ranganathan; Colin F Robertson; Roy Robins-Browne; Philip J Robinson; Billy Skoric; Stephen M Stick; Erika N Sutanto; Elizabeth Williamson Journal: Free Radic Biol Med Date: 2010-07-18 Impact factor: 7.376
Authors: Emily M DeBoer; Waldemar Swiercz; Sonya L Heltshe; Margaret M Anthony; Paul Szefler; Rebecca Klein; John Strain; Alan S Brody; Scott D Sagel Journal: Chest Date: 2014-03-01 Impact factor: 9.410
Authors: Patrick A Flume; John P Clancy; George Z Retsch-Bogart; D Elizabeth Tullis; Mark Bresnik; P Alex Derchak; Sandra A Lewis; Bonnie W Ramsey Journal: J Cyst Fibros Date: 2016-05-24 Impact factor: 5.482
Authors: Samuel M Moskowitz; Julia C Emerson; Sharon McNamara; Richard D Shell; David M Orenstein; Daniel Rosenbluth; Marcia F Katz; Richard Ahrens; Douglas Hornick; Patricia M Joseph; Ronald L Gibson; Moira L Aitken; Wade W Benton; Jane L Burns Journal: Pediatr Pulmonol Date: 2010-10-20
Authors: Elliott C Dasenbrook; William Checkley; Christian A Merlo; Michael W Konstan; Noah Lechtzin; Michael P Boyle Journal: JAMA Date: 2010-06-16 Impact factor: 56.272
Authors: Peter D Sly; Siobhain Brennan; Catherine Gangell; Nicholas de Klerk; Conor Murray; Lauren Mott; Stephen M Stick; Philip J Robinson; Colin F Robertson; Sarath C Ranganathan Journal: Am J Respir Crit Care Med Date: 2009-04-16 Impact factor: 21.405
Authors: Eitan Kerem; Michael W Konstan; Kris De Boeck; Frank J Accurso; Isabelle Sermet-Gaudelus; Michael Wilschanski; J Stuart Elborn; Paola Melotti; Inez Bronsveld; Isabelle Fajac; Anne Malfroot; Daniel B Rosenbluth; Patricia A Walker; Susanna A McColley; Christiane Knoop; Serena Quattrucci; Ernst Rietschel; Pamela L Zeitlin; Jay Barth; Gary L Elfring; Ellen M Welch; Arthur Branstrom; Robert J Spiegel; Stuart W Peltz; Temitayo Ajayi; Steven M Rowe Journal: Lancet Respir Med Date: 2014-05-15 Impact factor: 30.700
Authors: Scott D Sagel; Brandie D Wagner; Assem Ziady; Tom Kelley; John P Clancy; Monica Narvaez-Rivas; Joseph Pilewski; Elizabeth Joseloff; Wei Sha; Leila Zelnick; Kenneth D R Setchell; Sonya L Heltshe; Marianne S Muhlebach Journal: J Cyst Fibros Date: 2019-12-20 Impact factor: 5.482
Authors: Ann Chen Wu; James P Kiley; Patricia J Noel; Shashi Amur; Esteban G Burchard; John P Clancy; Joshua Galanter; Maki Inada; Tiffanie K Jones; Jonathan A Kropski; James E Loyd; Lawrence M Nogee; Benjamin A Raby; Angela J Rogers; David A Schwartz; Don D Sin; Avrum Spira; Scott T Weiss; Lisa R Young; Blanca E Himes Journal: Am J Respir Crit Care Med Date: 2018-12-15 Impact factor: 21.405
Authors: Sarah A Keaton; Zachary B Madaj; Patrick Heilman; LeAnn Smart; Jamie Grit; Robert Gibbons; Teodor T Postolache; Kimberly Roaten; Eric D Achtyes; Lena Brundin Journal: J Affect Disord Date: 2019-01-03 Impact factor: 4.839
Authors: Eric W F W Alton; A Christopher Boyd; Jane C Davies; Deborah R Gill; Uta Griesenbach; Tracy E Harman; Stephen Hyde; Gerry McLachlan Journal: Hum Gene Ther Date: 2020-09 Impact factor: 5.695
Authors: John Paul Clancy; Calvin U Cotton; Scott H Donaldson; George M Solomon; Donald R VanDevanter; Michael P Boyle; Martina Gentzsch; Jerry A Nick; Beate Illek; John C Wallenburg; Eric J Sorscher; Margarida D Amaral; Jeffrey M Beekman; Anjaparavanda P Naren; Robert J Bridges; Philip J Thomas; Garry Cutting; Steven Rowe; Anthony G Durmowicz; Martin Mense; Kris D Boeck; William Skach; Christopher Penland; Elizabeth Joseloff; Hermann Bihler; John Mahoney; Drucy Borowitz; Katherine L Tuggle Journal: J Cyst Fibros Date: 2018-06-20 Impact factor: 5.482