RESUMO
AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.
Assuntos
Aminopeptidases/antagonistas & inibidores , Depressores do Apetite/uso terapêutico , Cinamatos/uso terapêutico , Cicloexanos/uso terapêutico , Compostos de Epóxi/uso terapêutico , Glicoproteínas/antagonistas & inibidores , Hiperfagia/prevenção & controle , Obesidade/prevenção & controle , Síndrome de Prader-Willi/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Sesquiterpenos/uso terapêutico , Adolescente , Adulto , Aminopeptidases/metabolismo , Depressores do Apetite/administração & dosagem , Depressores do Apetite/efeitos adversos , Índice de Massa Corporal , Cinamatos/administração & dosagem , Cinamatos/efeitos adversos , Cicloexanos/administração & dosagem , Cicloexanos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Término Precoce de Ensaios Clínicos , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/efeitos adversos , Feminino , Glicoproteínas/metabolismo , Humanos , Hiperfagia/etiologia , Hiperfagia/fisiopatologia , Análise de Intenção de Tratamento , Masculino , Metionil Aminopeptidases , Obesidade/etiologia , Síndrome de Prader-Willi/fisiopatologia , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/efeitos adversos , Sesquiterpenos/administração & dosagem , Sesquiterpenos/efeitos adversos , Índice de Gravidade de Doença , Trombose Venosa/induzido quimicamente , Trombose Venosa/fisiopatologia , Redução de Peso/efeitos dos fármacos , Adulto JovemRESUMO
AIMS: 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. MATERIALS AND METHODS: 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. RESULTS: Participants were 64% female, with a mean (SD) age of 32 (9) years, BMI of 43 (7) kg/m2 and 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. CONCLUSION: 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.