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Diabetologia ; 61(9): 1918-1922, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29992370

RESUMEN

AIMS/HYPOTHESIS: This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m2) and type 2 diabetes (HbA1c 53-97 mmol/mol [7-11%] and fasting glucose <15.6 mmol/l). METHODS: Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. RESULTS: In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was -3.1 ± 1.2% with placebo (n = 22) vs -13.5 ± 1.1% and -12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA1c (baseline 67 mmol/mol [8.3%]) was -6.6 ± 2.2 mmol/mol (-0.6 ± 0.2%) with placebo vs -21.9 ± 2.2 mmol/mol (-2.0 ± 0.2%) or -21.9 ± 3.3 mmol/mol (-2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism. CONCLUSIONS/INTERPRETATION: MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA1c. TRIAL REGISTRATION: ClinicalTrials.gov NCT02324491 FUNDING: The study was funded by Zafgen, Inc.


Asunto(s)
Aminopeptidasas/antagonistas & inhibidores , Cinamatos/uso terapéutico , Ciclohexanos/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Compuestos Epoxi/uso terapéutico , Metaloendopeptidasas/antagonistas & inhibidores , Sesquiterpenos/uso terapéutico , Adolescente , Adulto , Anciano , Aminopeptidasas/metabolismo , Fármacos Antiobesidad/uso terapéutico , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Método Doble Ciego , Femenino , Glucosa/metabolismo , Hemoglobina Glucada/metabolismo , Glicoproteínas , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Metaloendopeptidasas/metabolismo , Metionil Aminopeptidasas , Persona de Mediana Edad , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Pérdida de Peso/efectos de los fármacos , Adulto Joven
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