Elif Oral, MD, is a professor in the Division of Metabolism, Endocrinology, and Diabetes at the University of Michigan.

Elif Oral, MD

Implications of the Phase 4 Trial of Metreleptin in Patients With General Lipodystrophy

The recently completed phase 4 analysis of the impact of drug-neutralizing antibodies created during metreleptin treatment on patient outcomes has provided a window into the efficacy of metreleptin and its clinical implications for 

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, after the conclusion of the aforementioned phase 4 study, which was mandated by the 

 following metreleptin’s approval in 2014.1

“I think our new assay that was developed appears to be super sensitive and maybe detecting a signal that may not be clinically significant,” Oral told 

 in an exclusive interview. “Where do you draw the line of clinical significance? It’s only through studies like these, which are done longitudinally and followed over long periods of time, that we could potentially come up with the cutoff for clinical significance.”

Metreleptin is a recombinant analog of human leptin, differing from naturally produced leptin by an additional methionine. Administered by either a once or twice daily subcutaneous injection, metreleptin received approval for general lipodystrophy as an adjunct to diet in 2014 after demonstrating improvements to insulin resistance, diabetes, and hypertriglyceridemia.2

The current study implemented 2 separate assays to analyze anti-drug-antibody-positive patients. The first, an in vitro cell-based assay, was an established system measuring cell proliferation after exposure to metreleptin. The second, a more sensitive electro-chemiluminescent leptin receptor blocking (RB) assay, was largely developed for the purpose of the study, and ultimately provided what the team determined to be more accurate and informative data.1

The trial screened 11 patients, of whom 6 had congenital GL and 5 had acquired GL, and enrolled and assessed 10. 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). These patients were monitored for ≤36 months – Oral and colleagues took and tested serum samples for antibodies to both metreleptin and natural leptin via an immunoassay, conducted at months 1, 2, 4, 6, 9, 12, 18, 24, 30, and 36.1

Median time to peak titer for anti-drug antibodies was 4.2 months, compared to 6.6 months for RB neutralizing activity. Oral and colleagues saw a decline in anti-drug antibody response after peak titer in over half of patients, resolving in 1 patient. RB neutralizing activity also decreased after peak titer in ≥70% of antibody-positive patients, resolving in 5. The CB assay only detected neutralizing activity in 1 patient, who later tested negative at month 30.1

Ultimately, the team concluded that testing based on neutralizing antibody activity had confirmed that the RB assay was significantly more sensitive. Additionally, they failed to find a correlation between the neutralizing activity of these antibodies and treatment outcomes, indicating no need for further safety signals outside of what is currently known.1

Oral also addressed the lack of a consistent association between the neutralizing antibodies and loss of metabolic response. She noted that, while the current trial was unable to fully answer whether this lack of association will become a clinical issue, further research over longer periods of time will likely be capable of providing further information.

“Some of these answers, I think, will emerge over a longer period of time, and with the collation of more data now that this new assay is developed,” Oral said. “We’re actually compiling data that stands over a course of a decade and a half of patient trajectories, so I’m hoping that we’ll be able to give better answers to these questions soon.”

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

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.

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. 

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Elif Oral, MD, discusses the clinical implications of the recent data emphasizing metreleptin’s anti-drug antibodies and their llack of impact on efficacy.

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

 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.

 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.

“Generalized lipodystrophy is really rare – we see it in maybe a few patients per million,” Oral told 

 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.

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.

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.

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.

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.

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.

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.

“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.”

Elif Oral, MD, discusses her recent presentation at ENDO 2026 covering a phase 4 trial of the immunogenicity of metreleptin in this rare disease.

Elif Oral, MD

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