title: A randomized, placebo-controlled trial of beloranib for the treatment of hypothalamic injury-associated obesity.
abstract: Hypothalamic injury-associated obesity (HIAO) results from damage to the hypothalamus that often occurs with surgical removal/radiation therapy of tumours in the hypothalamic region, such as craniopharyngioma. There is currently no rigorously studied pharmaceutical treatment for the intractable weight gain and cardiometabolic consequences that occur in patients with HIAO. We aimed to assess efficacy, safety and tolerability of beloranib treatment for 4 to 8 weeks in patients with HIAO.
  
  
  
  This Phase 2a, double-blind, placebo-controlled study included 14 patients with HIAO, randomized to receive beloranib 1.8 mg or placebo subcutaneously twice weekly for 4 weeks with an optional 4-week open-label extension in which all patients received beloranib. The primary endpoint was change in weight from baseline to Week 4.
  
  
  
  Participants were 64% female, with a mean (SD) age of 32 (9) years, BMI of 43 (7) kg/m2and weight of 126 (22) kg. Compared with placebo (N = 4), beloranib 1.8 mg (N = 8) resulted in a mean (95% CI) difference in weight of -3.2 (-5.4, -0.9) kg after 4 weeks. Weight loss continued through the 8 weeks in patients randomized to beloranib (mean -6.2 [-8.2, -4.1] kg). Beloranib treatment was associated with improvements in high-sensitivity CRP. Adverse events were mild to moderate. No patients who received beloranib discontinued treatment.
  
  
  
  Beloranib treatment resulted in progressive weight loss in patients with HIAO that was comparable to that observed with beloranib in patients with exogenous obesity. These findings indicate a novel mechanism for treating obesity in patients with HIAO.
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Ashley
authors.identifier: 0000-0003-1628-3677
authors.initials: A
authors.lastname: Shoemaker
authors.affiliation: Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Australia.
authors.forename: Joseph
authors.initials: J
authors.lastname: Proietto
authors.affiliation: McNeely Pediatric Diabetes Center and Endocrine Clinic, Children's Hospitals and Clinics of Minnesota, St. Paul, Minnesota.
authors.forename: M Jennifer
authors.initials: MJ
authors.lastname: Abuzzahab
authors.affiliation: Boden Institute of Nutrition, Exercise & Eating Disorders, University of Sydney, Sydney, Australia.
authors.forename: Tania
authors.initials: T
authors.lastname: Markovic
authors.affiliation: Zafgen Inc., Boston, Massachusetts.
authors.forename: Jaret
authors.initials: J
authors.lastname: Malloy
authors.affiliation: Zafgen Inc., Boston, Massachusetts.
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Kim
mesh_terms: D000328:Adult; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001067:Appetite Depressants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control*; D002934:Cinnamates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015331:Cohort Studies; D003510:Cyclohexanes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000293:injuries*; D007279:Injections, Subcutaneous; D008297:Male; D024821:Metabolic Syndrome / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control*; D063208:Methionyl Aminopeptidases; D009767:Obesity, Morbid / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000075082:Proof of Concept Study; D012306:Risk; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015431:Weight Loss / Q000187:drug effects; D055815:Young Adult
chemical_list: D001067:Appetite Depressants; D015415:Biomarkers; D002934:Cinnamates; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D006023:Glycoproteins; D012717:Sesquiterpenes; D000626:Aminopeptidases; C081311:METAP2 protein, human; D063208:Methionyl Aminopeptidases; C487952:CKD732
keywords: antiobesity drug; appetite control; clinical trial; obesity therapy; phase I to II study; randomised trial