SAT-658 - A 36-Month, Multicenter, Open Label Phase 4 Study to Evaluate the Immunogenicity of Daily Metreleptin Treatment in Patients with Generalized Lipodystrophy

Background. Metreleptin, a recombinant human leptin analog, is recommended as a first-line treatment (with diet) for the metabolic complications of generalized lipodystrophy (GL), a rare disorder characterized by a near-complete lack of adipose tissue. Previous clinical studies showed that the majority of patients with GL developed anti-drug antibodies (ADA) to metreleptin. ADA with neutralizing activity (NAb) to metreleptin have been detected in metreleptin-treated patients; however, their impact on safety and efficacy has not been fully characterized. Here, we evaluated the immunogenicity of metreleptin in previously untreated patients with GL using two methods measuring NAb activity.
Methods. In this multicenter, open label, Phase 4 study, immunogenicity to metreleptin was assessed up to 36 months. Patients aged ≥ 1 year with a clinical diagnosis of GL were eligible for inclusion; patients previously treated with metreleptin or who were pregnant/breastfeeding were excluded. Serum samples were tested for ADA to metreleptin and native human leptin via immunoassay (at Months 1, 2, 4, 6, 9, 12, 18, 24, 30 and 36 after metreleptin initiation). Thereafter, NAb activity to metreleptin was tested in ADA-positive samples using: (1) an in vitro cell-based (CB) assay in which cell proliferation is measured following metreleptin exposure; and (2) a more sensitive, electrochemiluminescent leptin receptor blocking (RB) assay. Study outcomes included time to peak titer (i.e., the largest sample dilution at which ADA and RB NAb positivity was detected), and resolution of ADA and RB NAb activity. The impact of immunogenicity on safety and efficacy outcomes was also assessed.
Results. 11 patients (6 congenital GL, 5 acquired GL; 9 females; mean ± SD age, 28±13 years) were assessed. The median duration of metreleptin exposure was 35.1 months (range, 4 days to 37.5 months; minimum-maximum dose, 1.25-7.5 mg/day). 10 patients (91%) were positive for ADA to metreleptin/native leptin at ≥ 1 timepoint and were also positive for RB NAb activity at some point. The median time to peak titer for ADA and RB NAb was 4.2 and 6.6 months, respectively. A trend of decline was observed in ADA response after peak titer in ≥ 50% of patients, resolving in 1 patient. Similarly, a trend of decline in the RB NAb response was seen after peak titer in ≥ 70% of ADA-positive patients, resolving in 5 patients. CB NAb activity was detected only in 1 ADA-positive patient (at Month 24) who later tested negative for NAb activity (at Month 30). No persistent impact on metabolic response or safety was observed over the study duration in patients with RB- or CB-NAb activity.
Conclusion. NAb testing confirmed the greater sensitivity of the RB assay. The lack of a consistent association between ADA/NAb and treatment outcomes supports no new safety signals beyond existing knowledge and experience with metreleptin.

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