title: Efficacy and safety of the glycine transporter type-1 inhibitor AMG 747 for the treatment of negative symptoms associated with schizophrenia.
abstract: To determine the safety and efficacy of AMG 747, an oral inhibitor of glycine transporter type-1 (GlyT1), as an add-on to antipsychotic therapy in clinically stable people with schizophrenia with enduring negative symptoms.
  
  
  
  Analysis of pooled data from two phase 2 studies. Adults diagnosed with schizophrenia stabilized on antipsychotic medication randomized (2:2:2:3) to orally receive daily AMG 747 (5mg, 15mg, or 40mg) or placebo. Primary endpoint was Negative Symptom Assessment (NSA)-16 total score change from baseline to week 12.
  
  
  
  Studies were terminated early after a report of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) in one participant (40-mg AMG 747). At termination, 232 participants had enrolled and 153 completed 12weeks of treatment. At week 12, change from baseline NSA-16 total score showed no differences between groups. Mean decrease in Positive and Negative Syndrome Scale (PANSS) Negative Symptom Factor Score (NSFS) and NSA-16 global score were greater with 15-mg AMG 747 than placebo (p<0.05). Changes in PANSS-Positive Symptom Factor Scale were not significantly different for any group. Changes in patient-reported outcomes (Sheehan Disability Scale and Quality of Life Enjoyment and Satisfaction Questionnaire) showed trends consistent with greater efficacy of 15-mg AMG 747 compared with placebo (p≤0.1). Adverse event rates were similar among all groups, with no clear differences observed.
  
  
  
  Significant treatment effects of 15-mg AMG 747, but not higher or lower doses, were observed on secondary endpoints but not on the primary outcome. These results replicate previous reports of an inverted-U dose response curve and suggest further evaluation of GlyT1 inhibitors in schizophrenia negative symptoms is warranted.
  
  
  
  Clinicaltrials.govNCT01568216 (https://clinicaltrials.gov/ct2/show/NCT01568216) and NCT01568229 (https://clinicaltrials.gov/ct2/show/NCT01568229?term=NCT01568229&rank=1); EudraCT number 2011-004844-23 and 2011-004845-42.
authors: Amgen Inc., Thousand Oaks, CA, United States. Electronic address: eduardo.dunayevich@takeda.com.
authors: Eduardo
authors: E
authors: Dunayevich
authors: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, United States.
authors: Robert W
authors: RW
authors: Buchanan
authors: Amgen Inc., Thousand Oaks, CA, United States.
authors: Chao-Yin
authors: CY
authors: Chen
authors: Amgen Inc., Thousand Oaks, CA, United States.
authors: Jun
authors: J
authors: Yang
authors: Amgen Inc., Thousand Oaks, CA, United States.
authors: Jon
authors: J
authors: Nilsen
authors: Amgen Inc., Thousand Oaks, CA, United States.
authors: Julie M
authors: JM
authors: Dietrich
authors: Amgen Inc., Thousand Oaks, CA, United States.
authors: Hong
authors: H
authors: Sun
authors: Semel Institute for Neuroscience at UCLA, Los Angeles, CA, United States; VA Desert Pacific Mental Illness Research, Education, and Clinical Center, Los Angeles, CA, United States.
authors: Stephen
authors: S
authors: Marder
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology*; D055815:Young Adult
chemical_list: C000625754:(R)-2-(4-(phenyl(3-(trifluoromethyl)phenyl)methyl)piperazin-1-yl)acetic acid; D014150:Antipsychotic Agents; D050487:Glycine Plasma Membrane Transport Proteins; D010879:Piperazines
keywords: Clinical trial; GlyT1; Glycine; Negative symptoms; Phase 2