High-Dose Leptin Reversed Severe Genetic Obesity in Two Patients

Personalized recombinant leptin treatment helped reverse severe, early-onset obesity in two children carrying rare antagonistic leptin genetic variants, a study showed.

In the double case report, two unrelated children -- a 14-year-old boy and a 2-year-old girl -- presented with what appeared to be leptin dysfunction, marked by intense hyperphagia, lack of satiety, and severe obesity, Martin Wabitsch, MD, PhD, of Ulm University Medical Center in Germany, and colleagues detailed in a New England Journal of Medicine (NEJM) brief report.

Of note, the parents of the boy were second-degree cousins and parents of the girl were first-degree cousins.

The researchers confirmed that both patients had abnormally high levels of circulating leptin. Conditions like Prader-Willi and Bardet-Biedl syndromes were both ruled out.

Based on in vitro experiments they performed, Wabitsch's group found that these patients had impaired binding between leptin proteins and leptin receptors. Treatment was started at the recommended dose of 0.03 mg/kg of lean body weight, but because of the agonist activity, the initial metreleptin treatment -- a recombinant human leptin -- given to these patients flopped, having virtually no effect.

Following the in vitro results, the researchers opted to bump up the doses for both patients.

For the boy (a carrier of leptin variant P64S), the dose was increased to 0.14 mg/kg on day 2 of treatment, to 0.70 mg/kg on day 5, and was tapered down starting on day 131, reaching an end dose of 0.15 mg/kg.

For the girl (a carrier of leptin variant G59S), the dose was increased to 0.15 mg/kg on day 2 of treatment, and tapered down starting on day 264, with an ending dose of 0.07 mg/kg.

In addition to the increased metreleptin doses, both patients participated in exercise programs and "vigorous" fasts in order to magnify the effect of exogenous leptin. After achieving a therapeutic response, patients lost weight, normalized food intake, and achieved satiety. Both also developed antibodies against metreleptin.

After 1,188 days of treatment, the 14-year-old boy achieved a near-normal weight of 94.1 kg (207.5 lb). He lost 49.9 kg (110 lb) -- a weight loss of 27.8% -- by day 131, and lost 72.9 kg (160.7 lb) -- a weight loss of 40.5% -- by day 264. The boy's body mass index (BMI) also dropped from 54.3 at baseline to 26.9 by day 1,188.

After 1,260 days of treatment, the 2-year-old girl achieved a near-normal weight of 23.2 kg (51.1 lb). She lost 9.6 kg (21.2 lb) -- a weight loss of 36.5% -- by day 238 of treatment. The girl's BMI dropped from 31.6 at baseline to 17.6 on day 1,260.

"To be honest, after our initial description of biologically inactive leptin variants in 2015, we had expected that sooner or later a patient would present at our Centre for Genetic Obesity who had an antagonizing leptin variant," Wabitsch told MedPage Today. "Based on the knowledge of the molecular ligand-receptor interaction of leptin and its receptor, the existence of antagonizing variants of leptin in humans was likely."

"We hypothesized that specific rare human gene variants in the leptin gene will result in leptin molecules with an impaired interaction with interaction site III of the leptin receptor responsible for receptor activation but with high affinity to the interaction site II responsible for receptor binding. We further hypothesized that these leptin variants would block the receptor when metreleptin treatment is initiated and behave as antagonizing ligands at the receptor level," he explained. "The fact that we were then presented with two patients within a short period of time with two different variants that had these characteristics was a surprise."

"But that was only the first step," Wabitsch added. "Our elaborate in vitro experiments then paved the way for a successful therapy. Based on the in vitro results, we were able to calculate the dose we needed to overcome the antagonism in vivo by substituting metreleptin."

"This was the basis for a successful treatment," he said, noting that this was the first time this had been done in humans. "This is exciting and a novelty for human medicine."

In an accompanying editorial, Clifford J. Rosen, MD, of the MaineHealth Institute for Research in Scarborough and an associate editor for NEJM, pointed out how leptin "was once hailed as a treatment for most cases of childhood obesity but quickly lost favor when resistance to leptin was noted."

"It is apparent that there is a narrow appropriate dose-response effect of leptin on leptin-receptor signaling in the hypothalamus. Further research into the use of monoclonal antibodies as a potential therapeutic tool for obesity is warranted," he suggested, also noting that these findings have implications for more general treatments of obesity.

Wabitsch advised that clinicians "should first think of and look for a genetic cause in children with extreme obesity and hyperphagia."

"In the rare case of a pathogenic leptin gene variant, the effects of this variant should be examined in detail. Colleagues are welcome to contact our center," he added. "If necessary, in vitro experiments can help to determine the therapy with leptin."

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