Mibavademab
Mibavademab (REGN4461), leptin receptor agonist antibody
Written by Aaron CuhaReviewed Sep 2026
Also known as: REGN4461
It reduced weight only in people whose leptin was already low, below 8 ng/mL, and did nothing in those with higher leptin. A rare case of a drug that identified who it is for.
Overview
Leptin is the hormone fat tissue uses to tell the brain how much fat there is. In the rare people who make none, giving it back is transformative. In ordinary obesity, leptin is high and the brain has stopped listening, which is why leptin failed as an obesity drug decades ago.
This antibody activates the leptin receptor directly, with or without leptin present. The phase 1 result is the interesting part, and it is a finding about population rather than about dose. Treatment reduced body weight over 12 weeks in participants with low circulating leptin, under 8 ng/mL, and had no effect on body weight in those with higher baseline leptin.
That is a drug telling you exactly who it works for, which almost nothing in this field does. It also explains why it is being studied in combination with tirzepatide: rapid weight loss lowers leptin, which may create the low-leptin state where this antibody does something.
Mechanism of action
A fully human monoclonal antibody that activates the human leptin receptor, LEPR, in the absence or presence of leptin. That distinguishes it from metreleptin, which is recombinant leptin and therefore useless where the receptor is unresponsive or where neutralising antibodies to leptin have developed. In leptin knockout mice it normalised body weight, food intake, blood glucose and insulin sensitivity, and in a generalised lipodystrophy model it relieved hyperphagia, hyperglycaemia, insulin resistance, dyslipidaemia and hepatic steatosis.
Human evidence
A randomised placebo-controlled phase 1 with a clear population-dependent result, a dedicated pharmacokinetic report, one compassionate-use case, and a terminated phase 2.
- Randomised, double-blind, placebo-controlled two-part phase 1. Well tolerated with an acceptable safety profile.
- Body weight fell over 12 weeks in participants with circulating leptin under 8 ng/mL.
- No effect on body weight in participants with higher baseline leptin, which is most people with obesity.
- One compassionate-use patient with atypical partial lipodystrophy and neutralising antibodies to metreleptin showed improvements in triglycerides and hepatic steatosis.
- A combination study with tirzepatide is registered, on the logic that weight loss lowers leptin into the responsive range.
- One lipodystrophy phase 2 record carries status TERMINATED.
What this does not tell you: The low-leptin weight loss result comes from a subgroup within a phase 1 study, which is the weakest place to find a population effect and the most likely to be a chance finding. It needs replication in a trial designed around that threshold. The compassionate-use case is one patient and cannot support any general claim. And the population where this worked is small: most people with obesity have high leptin, which is exactly where the antibody did nothing.
Reading the research record
Leptin is the cautionary tale of obesity pharmacology. Its discovery in 1994 looked like the answer, and then giving it to people with ordinary obesity did almost nothing, because their leptin was already high and the brain had stopped responding. Everything since has had to work around that.
What makes this antibody interesting is that it did not repeat the mistake. The phase 1 found the boundary rather than averaging across it: below 8 ng/mL of leptin it worked, above that it did not. Most drug development would report a modest overall effect and obscure both halves. Reporting the threshold is more useful and also more limiting, because it defines a small population.
The tirzepatide combination is the interesting consequence. If losing weight fast drops leptin into the range where this antibody acts, then a drug that fails in obesity might work in people who have already lost weight, which is a different question from the one leptin failed at.
The evidence, charted
Fig. 1 · evidence composition
4of 4 citations (100%) are in people
Every citation cited here is Human work; no other study type is cited on this page. This count is of our own citation list and understates any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 3 distinct years, 2023 to 2026, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Human2023
Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency
A fully human antibody activating the leptin receptor with or without leptin. In obese leptin knockout mice it normalised body weight, food intake, blood glucose and insulin sensitivity. In a randomised double-blind placebo-controlled two-part phase 1 it was well tolerated. Verbatim: treatment of individuals with overweight or obesity decreased body weight over 12 weeks in those with low circulating leptin concentrations, under 8 ng/mL, but had no effect on body weight in individuals with higher baseline leptin. Compassionate use in one patient with atypical partial lipodystrophy and neutralising antibodies to metreleptin was associated with improvements in triglycerides and hepatic steatosis.
Science Translational Medicine - Human2024
Pharmacokinetics and pharmacodynamics of mibavademab (a leptin receptor agonist): results from a first-in-human phase I study
The dedicated pharmacokinetic and pharmacodynamic report from the first-in-human programme.
Clinical and Translational Science - Human2026
A study of mibavademab in combination with tirzepatide in adults with obesity
The combination programme. Relevant because rapid weight loss lowers leptin, which is the state in which this antibody had an effect in phase 1.
ClinicalTrials.gov - Human2024
A study of REGN4461 in patients with lipodystrophy
Registry status TERMINATED. Reported because a terminated trial is part of the record.
ClinicalTrials.gov
Frequently asked questions
Does mibavademab cause weight loss?
Only in people whose leptin is already low, under 8 ng/mL. In participants with higher baseline leptin, which describes most people with obesity, it had no effect on body weight over 12 weeks. That is from a phase 1 subgroup, so it needs confirming in a trial built around that threshold.
How is it different from metreleptin?
Metreleptin is leptin itself, so it fails where the receptor is unresponsive or where a patient has developed neutralising antibodies against leptin. This antibody activates the receptor directly, with or without leptin present, which is why the one compassionate-use case involved a patient who had antibodies to metreleptin.
Why combine it with tirzepatide?
Because rapid weight loss lowers leptin, and low leptin is the state in which this antibody had an effect. If that holds, it would work in people after weight loss rather than in people with untreated obesity. That trial is registered and has not reported.
What does the terminated trial mean?
One lipodystrophy phase 2 record carries status TERMINATED on ClinicalTrials.gov. The reason is not in the public record and is not asserted here. The rest of the programme continues.