title: Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease.
abstract: BACKGROUND
  Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7.
  
  
  METHODS
  In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28.
  
  
  RESULTS
  The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease.
  
  
  CONCLUSIONS
  We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.).
authors.affiliation: From the Department of Systems Medicine, University of Tor Vergata (G.M., M.C.F., S.O., L.B., F.P.), Gastroenterology Unit-Azienda Ospedaliera San Camillo-Forlanini (M.L.S.), Inflammatory Bowel Disease Unit, Complesso Integrato Columbus, Catholic University (A.A.), and Inflammatory Bowel Disease Unit, Department of Internal Medicine, Division of Gastroenterology, Sandro Pertini Hospital Rome (R.P.), Rome, Department of Surgery, L. Sacco University Hospital (S.A., M.F.), Department of Pathophysiology and Transplantation, University of Milan and Ospedale Policlinico di Milano (F. Caprioli), and Department of Biomedical Sciences for Health, University of Milan, and Gastroenterology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Policlinico San Donato, San Donato Milanese (M.V.), Milan, First Department of Internal Medicine, St. Matteo Hospital Foundation, University of Pavia, Pavia (A.D.S., G.R.C.), Gastroenterologia, Università Federico II di Napoli, Naples (F. Castiglione), Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche-Unita' Operativa di Gastroenterologia-Universita' degli Studi di Padova, Padua (G.C.S.), Department of Medical and Surgical Specialties, Gastroenterology SOD2, Azienda Ospedaliero Universitaria Careggi, Florence (F.R.), Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, IRCCS, San Giovanni Rotondo (F.B.), Department of Internal Medicine, Gastroenterology and Hepatology Unit, University of Genoa, Genoa (V.S.), and the Division of Internal Medicine Villa Sofia-Cervello Hospital, University of Palermo, Palermo (A.O.) - all in Italy; and the Department of Medicine, Medical Clinic 1, University of Erlangen-Nürnberg, Erlangen, Germany (M.F.N., R.A.).
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.forename: Sandro
authors.initials: S
authors.lastname: Ardizzone
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Sabatino
authors.forename: Massimo C
authors.initials: MC
authors.lastname: Fantini
authors.forename: Fabiana
authors.initials: F
authors.lastname: Castiglione
authors.forename: Maria L
authors.initials: ML
authors.lastname: Scribano
authors.forename: Alessandro
authors.initials: A
authors.lastname: Armuzzi
authors.forename: Flavio
authors.initials: F
authors.lastname: Caprioli
authors.forename: Giacomo C
authors.initials: GC
authors.lastname: Sturniolo
authors.forename: Francesca
authors.initials: F
authors.lastname: Rogai
authors.forename: Maurizio
authors.initials: M
authors.lastname: Vecchi
authors.forename: Raja
authors.initials: R
authors.lastname: Atreya
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bossa
authors.forename: Sara
authors.initials: S
authors.lastname: Onali
authors.forename: Maria
authors.initials: M
authors.lastname: Fichera
authors.forename: Gino R
authors.initials: GR
authors.lastname: Corazza
authors.forename: Livia
authors.initials: L
authors.lastname: Biancone
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Savarino
authors.forename: Roberta
authors.initials: R
authors.lastname: Pica
authors.forename: Ambrogio
authors.initials: A
authors.lastname: Orlando
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000032:analysis; D003424:Crohn Disease / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000009:adverse effects; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D012074:Remission Induction; D051906:Smad7 Protein / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D002097:C-Reactive Protein; C000588548:GED0301