Pharmacokinetics and pharmacodynamics of mibavademab (a leptin receptor agonist): Results from a first-in-human phase I study.

Mibavademab (previously known as REGN4461), a fully human monoclonal antibody, is being investigated for the treatment of conditions associated with leptin deficiency. Here, we report pharmacokinetics (PKs), pharmacodynamics, and immunogenicity from a phase I study in healthy participants (NCT03530514). In part A, lean or overweight healthy participants were randomized to single-ascending-dose cohorts of 0.3, 1.0, 3.0, 10, and 30 mg/kg intravenous (i.v.), or 300 and 600 mg subcutaneous doses of mibavademab or placebo. In part B, overweight or obese participants were randomized to receive multiple doses of mibavademab (15 mg/kg i.v. loading dose and 10 mg/kg i.v. at weeks 3, 6, and 9) or placebo, stratified by body mass index and baseline leptin levels: low leptin (<5 ng/mL) or relatively low leptin (5-8 ng/mL in men and 5-24 ng/mL in women). Fifty-six and 55 participants completed the single-ascending-dose and multiple-dose parts, respectively. In the single-ascending-dose cohorts, mibavademab PKs were nonlinear with target-mediated elimination, greater than dose-proportional increases in exposure, and there were no dose-dependent differences in total soluble leptin receptor (sLEPR) levels in serum over time. Following multiple-dose administration of mibavademab in participants with leptin <8 ng/mL, lower mean mibavademab concentrations, higher mean total sLEPR concentrations, and larger mean decreases in body weight than in the relatively low leptin cohorts were observed. Baseline leptin was correlated with mibavademab PKs and pharmacodynamics. No treatment-emergent anti-mibavademab antibodies were observed in any mibavademab-treated participant. Results from this study collectively inform further development of mibavademab to treat conditions associated with leptin deficiency.

Relação entre leptina, obesidade e exercício físico / Relationship between leptin, obesity and physical exercise

A obesidade é uma doença complexa, com etiologia multifatorial, que afeta todas as idades e classes sociais. No Brasil, o crescimento da obesidade e sobrepeso é preocupante, sendo o Rio Grande do Sul (RS) o estado com os maiores índices. O tecido adiposo é responsável pela síntese de leptina, um hormônio participante da inibição da fome via hipotálamo. O excesso de peso na obesidade eleva a síntese hormonal dos adipócitos e, consequentemente, os níveis plasmáticos de leptina. Contudo, a demasiada estimulação da leptina em seus receptores centrais origina uma resistência à sua ação no organismo. Assim, este excesso acarreta um desequilíbrio entre a ingestão de alimentos e o gasto energético, além de efeitos pró-inflamatórios. A perda de peso é capaz de reestabelecer este equilíbrio, melhorando a qualidade de vida dos indivíduos. O treinamento físico vem sendo estudado como uma alternativa não farmacológica para essa modulação, entretanto muitos resultados controversos são encontrados. O objetivo deste artigo é mostrar a relação da leptina com a obesidade e sua modulação pelo exercício, por meio de uma revisão em torno de artigos científicos sobre este tema (AU)

Obesity is a complex disease with multifactorial etiology which affects people of all ages and classes. In Brazil, the growth in overweight and obesity rates is alarming, and Rio Grande do Sul (RS) presents the highest rates among states. The adipose tissue is responsible for the synthesis of leptin, a hormone which acts in the hypothalamus to inhibit appetite. In overweight people, leptin synthesis is increased, leading to high plasma leptin levels. However, excessive stimulus of leptin central receptors results in resistance to the effects of leptin. This leads to an imbalance between food intake and energetic expenditure, in addition to proinflammatory effects. Weight loss is enough to restore balance and improve quality of life. Physical training is one of the most studied nonpharmacological alternatives to this modulation, although many controversial results have been found. This paper aimed to conduct a review of articles on the relationship between leptin and obesity and its modulation through exercise (AU)