title: ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients.
abstract: BACKGROUND
  Respiratory syncytial virus (RSV) infection in lung transplant (LTx) patients is associated with an increased incidence of bronchiolitis obliterans syndrome (BOS). ALN-RSV01 is a small interfering RNA targeting RSV replication that was shown in an earlier Phase 2a trial to be safe and to reduce the incidence of BOS when compared with placebo.
  
  
  METHODS
  We performed a Phase 2b randomized, double-blind, placebo-controlled trial in RSV-infected LTx patients to examine the impact of ALN-RSV01 on the incidence of new or progressive BOS. Subjects were randomized (1:1) to receive aerosolized ALN-RSV01 or placebo daily for 5 days.
  
  
  RESULTS
  Of 3,985 symptomatic patients screened, 218 were RSV-positive locally, of whom 87 were randomized to receive ALN-RSV01 or placebo (modified intention-to-treat [mITT] cohort). RSV infection was confirmed by central laboratory in 77 patients (ALN-RSV01, n = 44; placebo, n = 33), which comprised the primary analysis cohort (central mITT [mITTc]). ALN-RSV01 was found to be safe and well-tolerated. At Day 180, in ALN-RSV01-treated patients, compared with placebo, in the mITTc cohort there was a trend toward a decrease in new or progressive BOS (13.6% vs 30.3%, p = 0.058), which was significant in the per-protocol cohort (p = 0.025). Treatment effect was enhanced when ALN-RSV01 was started <5 days from symptom onset, and was observed even without ribavirin treatment. There was no significant impact on viral parameters or symptom scores.
  
  
  CONCLUSIONS
  These results confirm findings of the earlier Phase 2a trial and provide further support that ALN-RSV01 reduces the risk of BOS after RSV in LTx recipients.
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School, Biomedical Research in End stage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Germany. Electronic address: gottlieb.jens@mh-hannover.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Gottlieb
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado at Denver Health Sciences Center, Aurora, Colorado.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Zamora
authors.affiliation: Center for Thoracic Transplantation at the Heart & Lung Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.
authors.forename: Tony
authors.initials: T
authors.lastname: Hodges
authors.affiliation: Department of Respiratory Medicine, Royal Perth Hospital, Perth, Australia.
authors.forename: A W
authors.initials: AW
authors.lastname: Musk
authors.affiliation: Department of Pneumology, Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitaetsklinikum Essen GmbH, Essen, Germany.
authors.forename: Urte
authors.initials: U
authors.lastname: Sommerwerk
authors.affiliation: Departemnt of Medicine, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dilling
authors.affiliation: Department of Medicine, New York-Presbyterian Hospital/Columbia University Medical Center, New York, NY.
authors.forename: Selim
authors.initials: S
authors.lastname: Arcasoy
authors.affiliation: Department of Pediatrics, University of Tennessee Center for Health Sciences, Memphis, Tennessee.
authors.forename: John
authors.initials: J
authors.lastname: DeVincenzo
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Verena
authors.initials: V
authors.lastname: Karsten
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Shaily
authors.initials: S
authors.lastname: Shah
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Bettencourt
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cehelsky
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Sara
authors.initials: S
authors.lastname: Nochur
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Jared
authors.initials: J
authors.lastname: Gollob
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Akshay
authors.initials: A
authors.lastname: Vaishnaw
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Simon
authors.affiliation: Lung Transplant Unit, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Glanville
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000517:prevention & control*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D018357:Respiratory Syncytial Virus Infections / Q000150:complications*; D013577:Syndrome; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D034741:RNA, Small Interfering
keywords: RNA interference; bronchiolitis obliterans; community-acquired infections; lung transplantation; respiratory syncytial virus; ribavirin