6533b7ddfe1ef96bd1274031
RESEARCH PRODUCT
Mongersen, an oral SMAD7 antisense oligonucleotide, and crohn's disease
Fabrizio BossaFabiana CastiglioneMassimo FantiniRaja AtreyaAntonio Di SabatinoFrancesco PalloneSara OnaliGiacomo Carlo SturnioloMaria Lia ScribanoMarkus F. NeurathMaurizio VecchiFrancesca RogaiAmbrogio OrlandoGiovanni MonteleoneSandro ArdizzoneLivia BianconeRoberta PicaFlavio CaprioliAlessandro ArmuzziGino Roberto CorazzaMaria FicheraVincenzo Savarinosubject
MaleSMAD7 antisense oligonucleotidemedicine.medical_treatmentOligonucleotidesPharmacologyPLACEBO-CONTROLLED TRIALTHERAPYGastroenterologylaw.inventionACTIVATIONImmunosuppressive AgentGlucocorticoidRandomized controlled trialCrohn DiseaselawOligonucleotideMedicineYoung adultCrohn's diseaseSettore MED/12 - GastroenterologiabiologyINDUCTIONMedicine (all)Remission InductionGeneral MedicineMiddle AgedCrohn's diseaseCytokineC-Reactive ProteinCombinationDrug Therapy CombinationFemaleDrugImmunosuppressive AgentsCOLITISHumanAdultmedicine.medical_specialtyAdolescentINFLAMMATORY-BOWEL-DISEASE PLACEBO-CONTROLLED TRIAL NECROSIS-FACTOR-ALPHA TGF-BETA-1-MEDIATED SUPPRESSION COLITIS INDUCTION ACTIVATION EFFICACY THERAPY MICEPlaceboSmad7 ProteinDose-Response RelationshipYoung AdultPharmacotherapyDouble-Blind MethodDrug TherapyInternal medicineHumansAntisenseGlucocorticoidsAgedDose-Response Relationship Drugbusiness.industryC-reactive proteinNECROSIS-FACTOR-ALPHAOligonucleotides AntisenseTGF-BETA-1-MEDIATED SUPPRESSIONEFFICACYmedicine.diseaseClinical trialMICEbiology.proteinbusinessAdolescent; Adult; Aged; C-Reactive Protein; Crohn Disease; Dose-Response Relationship Drug; Double-Blind Method; Drug Therapy Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Oligonucleotides; Oligonucleotides Antisense; Remission Induction; Smad7 Protein; Young Adult; Medicine (all)INFLAMMATORY-BOWEL-DISEASEdescription
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.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.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 (P0.001). 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, P0.001, and P0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease.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.).
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-03-19 |