Metreleptin-Neutralizing Antibodies Do Not Impact Treatment Outcomes in Generalized Lipodystrophy

Patients with generalized lipodystrophy (GL) who have been treated with metreleptin and have developed anti-drug antibodies do not exhibit worse treatment outcomes, according to a recent phase 4 study.1

This trial, presented at the Endocrine Society (ENDO) Annual Meeting 2026 in Chicago, Illinois, by Elif Oral, MD, a professor in the Division of Metabolism, Endocrinology, and Diabetes at the University of Michigan, was mandated by the US Food and Drug Administration (FDA) following the release of data highlighting the frequency of anti-drug antibody development in treated patients. Additionally, the disease’s rarity prompted further research into the specific treatment methods and mechanisms metreleptin provides.1

“Generalized lipodystrophy is really rare – we see it in maybe a few patients per million,” Oral told HCPLive in an exclusive interview. “Overall, we’re estimating about 300 to 400 patients maximum in the US, and that may even be an overestimate. When something is so rare, it’s hard to recognize. Clinicians need to know the pattern.”

Metreleptin, a recombinant analog of human leptin with an additional methionine, is a subcutaneous daily injection that was initially studied as a treatment for obesity. However, failing to achieve clinically meaningful weight loss, it later displayed substantially improved insulin resistance, diabetes, and hypertriglyceridemia in later clinical studies in patients with lipodystrophy. The drug received FDA approval for this indication in 2014.2

The anti-drug antibodies developed in patients with GL explicitly neutralize the effects of metreleptin – however, their impact on safety and efficacy has not been sufficiently characterized. The present study worked to evaluate the drug’s immunogenicity via 2 separate methods of measuring neutralizing activity.1

Oral and colleagues included patients aged ≥1 year with a clinical GL diagnosis, excluding those who had previously been treated with metreleptin. These patients were assessed for ≤36 months, with serum samples tested for antibodies to metreleptin and native human leptin via immunoassay at months 1, 2, 4, 6, 9, 12, 18, 24, 30, and 36 after treatment initiation.1

Following this, neutralizing activity was tested in anti-drug-antibody-positive patients using either an in vitro cell-based (CB) assay, wherein cell proliferation was measured following metreleptin exposure, or a more sensitive electro-chemiluminescent leptin receptor blocking (RB) assay. The study’s outcomes included time to peak titer and the resolution of anti-drug antibody and RB neutralizing activity.1

A total of 11 patients – 6 of whom had congenital GL and 5 with acquired GL – were assessed. The mean age (+/- standard deviation [SD]) among these patients was 28 +/- 13 years. 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). Of these patients, 10 were positive for anti-drug antibodies to metreleptin or native leptin at ≥1 timepoint while being positive for RB neutralizing activity.1

Oral and colleagues recorded a median time to peak titer of 4.2 months for anti-drug antibodies and 6.6 months for RB neutralizing activity. Decline was observed in anti-drug antibody response after peak titer in ≥50% of patients, resolving in 1. A similar trend was observed in the RB neutralizing activity response after peak titer in ≥70% of antibody-positive patients, resolving in 5. CB neutralizing activity was detected in only 1 patient, who later tested negative at month 30.1

Ultimately, the team concluded that neutralizing antibody activity testing confirmed the greater sensitivity of the RB assay. Additionally, the lack of a significant correlation between neutralizing activity and treatment outcomes indicates no need for further safety signals beyond existing knowledge.1

“Our study showed that we do need to follow our patients closely for the emergence of what we call a lack of efficacy,” Oral said. “If a patient has been responding really well and all of a sudden loses efficacy, that may be the time that we should think about the neutralizing antibody presence, and what that would mean for the patient.”

Editors’ Note: Oral reports disclosures with Ionis, Akcea, Regeneron, Third Rock Ventures, Amryt Pharmaceuticals, Novo Nordisk, and others.

References

1. Oral E, Christofides E, Wyne K, et al. A 36-Month, Multicenter, Open Label Phase 4 Study to Evaluate the immunogenicity of Daily Metreleptin Treatment in Patients with Generalized Lipodystrophy. Abstract presented at the Endocrine Society (ENDO) Annual Meeting 2026, Chicago, IL. June 13-15, 2026.

2. Chan JL, Koda J, Heilig JS, et al. Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy. Clin Endocrinol (Oxf). 2016;85(1):137-149. doi:10.1111/cen.12980