Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy

Abstract

Summary Objective Recombinant human leptin (metreleptin) improves glycemia and hypertriglyceridemia in patients with generalized lipodystrophy; antibody development with in vitro neutralizing activity has been reported. We aimed to characterize anti-metreleptin antibody development, including in vitro neutralizing activity. Design Two randomized controlled studies in patients with obesity (twice-daily metreleptin ± pramlintide for 20–52 weeks; 2006–2009); two long-term, open-label studies in patients with lipodystrophy (once-daily or twice-daily metreleptin for 2 months to 12.3 years; 2000–2014). Patients 579 metreleptin-treated patients with obesity, 134 metreleptin-treated patients with lipodystrophy (antibody/neutralizing activity data: n=105). Measurements Anti-metreleptin antibodies, in vitro neutralizing activity. Results Anti-metreleptin antibodies developed in most patients (obese: 96–100%; lipodystrophy: 86–92%). Peak antibody titers (~1:125 to 1:3125) generally occurred within 4–6 months and decreased with continued therapy (lipodystrophy). Antibody development did not adversely impact efficacy or safety (patients with obesity), except for inflammatory injection site reactions, but was associated with elevated leptin concentrations. Three patients with obesity developed in vitro neutralizing activity coincident with weight gain. Weight later returned to baseline in one patient despite persistent neutralizing activity. Four patients with generalized lipodystrophy developed in vitro neutralizing activity concurrent with worsened metabolic control; two with confounding comorbidities had sepsis. One patient with lipodystrophy had resolution of neutralizing activity on metreleptin. Conclusions Development of in vitro neutralizing activity could be associated with loss of efficacy but has not been consistently associated with adverse clinical consequences. Whether neutralization of endogenous leptin with clinical consequences occurs remains unclear.

The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline

“…In vivo neutralizing antibody activity to leptin has been reported (58, 59). The clinical implications remain unclear, but may include treatment failure and sepsis (59).…”

“…The clinical implications remain unclear, but may include treatment failure and sepsis (59). Additional serious adverse events occurring during metreleptin treatment are likely related to the underlying lipodystrophy syndrome, rather than metreleptin.…”

Renaissance of leptin for obesity therapy

“…As one example for key areas warranting intense future studies, major efforts will be necessary to understand how cell types such as tanycytes, microglia and astrocytes interact with neurons to meaningfully integrate existing knowledge of leptin biology with neuroendocrine pathologies resulting from-and driving-metabolic disease. Importantly, for leptin to (re)enter clinical studies as anti-obesity therapy, previously reported adverse effects associated with leptin administration, including hypertension and immunogenicity, will have to be carefully assessed [64,65].…”

Lipodystrophie-Erkrankungen

“…Weiterhin wurde das Vorkommen einer neutralisierenden Antikörperaktivi-tät gegen Leptin berichtet [62,63]. Die klinische Bedeutung dieses Befundes ist noch unklar.…”

“…Die klinische Bedeutung dieses Befundes ist noch unklar. Ein mangelndes Ansprechen auf die Behandlung sowie das Auftreten einer Sepsis können Folgen davon sein [63].…”