Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy

Abstract

Objective: Recombinant human leptin (metreleptin) improves glycaemia and hypertriglyceridaemia in patients with generalized lipodystrophy; antibody development with in vitro neutralizing activity has been reported. We aimed to characterize antimetreleptin 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: A total of 579 metreleptin-treated patients with obesity and 134 metreleptin-treated patients with lipodystrophy (antibody/neutralizing activity data: n = 105).

Measurements: Antimetreleptin antibodies, in vitro neutralizing activity.

Results: Antimetreleptin antibodies developed in most patients (obese: 96-100%; lipodystrophy: 86-92%). Peak antibody titers (approximately 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.

Trial registration: ClinicalTrials.gov NCT00392925 NCT00673387 NCT00819234 NCT00025883 NCT00677313.

© 2015 John Wiley & Sons Ltd.

Figures

Fig. 1

Peak binding antibody titer and time to peak titer in (A, B) patients with obesity (Study DFA101) and (C, D) patients with lipodystrophy (Study FHA101). Study DFA101: black bar, metreleptin 5 mg BID and pramlintide 360 mcg BID + metreleptin 5 mg BID combined (N=55). Study FHA101: black bar, metreleptin treatment (N=24). BID, twice daily.

Fig. 1

Peak binding antibody titer and time to peak titer in (A, B) patients with obesity (Study DFA101) and (C, D) patients with lipodystrophy (Study FHA101). Study DFA101: black bar, metreleptin 5 mg BID and pramlintide 360 mcg BID + metreleptin 5 mg BID combined (N=55). Study FHA101: black bar, metreleptin treatment (N=24). BID, twice daily.

Fig. 1

Peak binding antibody titer and time to peak titer in (A, B) patients with obesity (Study DFA101) and (C, D) patients with lipodystrophy (Study FHA101). Study DFA101: black bar, metreleptin 5 mg BID and pramlintide 360 mcg BID + metreleptin 5 mg BID combined (N=55). Study FHA101: black bar, metreleptin treatment (N=24). BID, twice daily.

Fig. 1

Peak binding antibody titer and time to peak titer in (A, B) patients with obesity (Study DFA101) and (C, D) patients with lipodystrophy (Study FHA101). Study DFA101: black bar, metreleptin 5 mg BID and pramlintide 360 mcg BID + metreleptin 5 mg BID combined (N=55). Study FHA101: black bar, metreleptin treatment (N=24). BID, twice daily.

Fig. 2

Fasting leptin concentrations vs antibody titer at baseline and during metreleptin treatment in (A) patients with obesity (DFA101 and DFA102/E studies) and patients with lipodystrophy in the (B) NIH study and (C) FHA101 study. Red circles around individual plots denote patients who developed in vitro NAc. Black circles around individual plots denote patients with very high antibody titer who did not develop in vitro NAc. NAc, neutralizing activity; Neg, negative.

Fig. 2

Fasting leptin concentrations vs antibody titer at baseline and during metreleptin treatment in (A) patients with obesity (DFA101 and DFA102/E studies) and patients with lipodystrophy in the (B) NIH study and (C) FHA101 study. Red circles around individual plots denote patients who developed in vitro NAc. Black circles around individual plots denote patients with very high antibody titer who did not develop in vitro NAc. NAc, neutralizing activity; Neg, negative.

Fig. 2

Fasting leptin concentrations vs antibody titer at baseline and during metreleptin treatment in (A) patients with obesity (DFA101 and DFA102/E studies) and patients with lipodystrophy in the (B) NIH study and (C) FHA101 study. Red circles around individual plots denote patients who developed in vitro NAc. Black circles around individual plots denote patients with very high antibody titer who did not develop in vitro NAc. NAc, neutralizing activity; Neg, negative.

Fig. 3

Changes in body weight, fasting leptin concentration, and antibody titer over time in (A–C) three patients with obesity with evidence of in vitro NAc. (■), fasting leptin concentration; (▼), antibody titer; (●), body weight. Solid rectangle above the plot represents time on metreleptin treatment. Hashed rectangle represents time off metreleptin treatment. Circles around individual plots denote the detection of in vitro NAc. NAc, neutralizing activity.

Fig. 3

Changes in body weight, fasting leptin concentration, and antibody titer over time in (A–C) three patients with obesity with evidence of in vitro NAc. (■), fasting leptin concentration; (▼), antibody titer; (●), body weight. Solid rectangle above the plot represents time on metreleptin treatment. Hashed rectangle represents time off metreleptin treatment. Circles around individual plots denote the detection of in vitro NAc. NAc, neutralizing activity.

Fig. 3

Changes in body weight, fasting leptin concentration, and antibody titer over time in (A–C) three patients with obesity with evidence of in vitro NAc. (■), fasting leptin concentration; (▼), antibody titer; (●), body weight. Solid rectangle above the plot represents time on metreleptin treatment. Hashed rectangle represents time off metreleptin treatment. Circles around individual plots denote the detection of in vitro NAc. NAc, neutralizing activity.

Fig. 4

Changes in A1C, triglycerides, and antibody titer over time in (A–D) four patients with lipodystrophy with evidence of in vitro NAc. (●), A1C; (■), triglycerides; (▼), antibody titer. Solid rectangle above the plot represents time on metreleptin treatment. Circles around individual plots denote the detection of in vitro NAc. A1C, glycated hemoglobin; NAc, neutralizing activity.

Fig. 4

Changes in A1C, triglycerides, and antibody titer over time in (A–D) four patients with lipodystrophy with evidence of in vitro NAc. (●), A1C; (■), triglycerides; (▼), antibody titer. Solid rectangle above the plot represents time on metreleptin treatment. Circles around individual plots denote the detection of in vitro NAc. A1C, glycated hemoglobin; NAc, neutralizing activity.

Fig. 4

Changes in A1C, triglycerides, and antibody titer over time in (A–D) four patients with lipodystrophy with evidence of in vitro NAc. (●), A1C; (■), triglycerides; (▼), antibody titer. Solid rectangle above the plot represents time on metreleptin treatment. Circles around individual plots denote the detection of in vitro NAc. A1C, glycated hemoglobin; NAc, neutralizing activity.

Fig. 4

Changes in A1C, triglycerides, and antibody titer over time in (A–D) four patients with lipodystrophy with evidence of in vitro NAc. (●), A1C; (■), triglycerides; (▼), antibody titer. Solid rectangle above the plot represents time on metreleptin treatment. Circles around individual plots denote the detection of in vitro NAc. A1C, glycated hemoglobin; NAc, neutralizing activity.