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. 2022 Apr 15;6(6):bvac057.
doi: 10.1210/jendso/bvac057. eCollection 2022 Jun 1.

Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide

Martin Wabitsch  1 , Sadaf Farooqi  2 , Christa E Flück  3 , Natasa Bratina  4 , Usha G Mallya  5 , Murray Stewart  5 , Jill Garrison  5 , Erica van den Akker  6 , Peter Kühnen  7
Affiliations

Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide

Martin Wabitsch et al. J Endocr Soc. .

Abstract

Context: Rare homozygous or biallelic variants in POMC, PCSK1, and LEPR can disrupt signaling through the melanocortin-4 receptor (MC4R) pathway, resulting in hyperphagia and severe early-onset obesity. In pivotal Phase 3 clinical trials, treatment with the MC4R agonist setmelanotide reduced hunger and weight in patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency.

Objective: To characterize the historical weight trajectory in these patients.

Methods: This analysis included data from 2 pivotal single-arm, open-label, Phase 3 trials (NCT02896192, NCT03287960). These were multicenter trials. Patients had obesity due to POMC/PCSK1 or LEPR deficiency. During the trial, patients were treated with setmelanotide. Historical data on measured weight and height were obtained during screening.

Results: A total of 17 patients (POMC, n = 8; PCSK1, n = 1; LEPR, n = 8) with historical weight and height data were included in this analysis. Before setmelanotide treatment, patients with obesity due to POMC/PCSK1 or LEPR deficiency were above the 95th percentile for weight throughout childhood, demonstrated continuous weight gain, and did not show long-term weight loss upon interventions (eg, diet, surgery, exercise). Setmelanotide treatment attenuated weight and body mass index trajectories over the observation period of 1 year.

Conclusion: In patients with POMC, PCSK1, or LEPR deficiency, traditional interventions for weight loss had limited impact on the trajectory of severe early-onset obesity. However, setmelanotide treatment attenuated weight and body mass index trajectories and led to weight loss associated with health benefits in most individuals.

Keywords: LEPR; MC4R pathway; POMC; obesity; setmelanotide.

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Figures

Figure 1.
Figure 1.
Historical weight, height, and BMI in patients with obesity due to POMC deficiency. Solid markers are historical data recorded prior to entry into the trial. Open markers are data at study screening and final study visit for which weight, height, or BMI were recorded after receiving treatment with setmelanotide. Centers for Disease Control and Prevention reference growth charts are shown for the 5th (bold), 10th, 25th, 50th (bold), 75th, 90th, and 95th (bold) percentiles for sex. Patient 8 was enrolled in the supplemental cohort and not reported in primary analysis. *Dietary intervention. †Exercise regimen. ‡Surgery for obesity. BMI, body mass index; POMC, proopiomelanocortin.
Figure 2.
Figure 2.
Change in obesity class due to setmelanotide treatment in patients aged ≥18 years with obesity caused by POMC or LEPR deficiency. Patient 16 was not part of the designated use set. Patient 17 did not have BMI data available following 1 year of treatment and was enrolled in the supplemental cohort and not reported in primary analysis. *Achieved primary endpoint of ≥10% weight loss after ~1 year of treatment. BMI, body mass index; LEPR, leptin receptor; N, normal; O/W, overweight; POMC, proopiomelanocortin.
Figure 3.
Figure 3.
Change in obesity category due to setmelanotide treatment in patients aged <18 years with obesity caused by POMC, PCSK1, or LEPR deficiency. BMI Z score data are adjusted for age and sex. Patient 8 was enrolled in the supplemental cohort and not reported in primary analysis. *Achieved primary endpoint of ≥10% weight loss after ~1 year of treatment. BMI, body mass index; LEPR, leptin receptor; PCSK1, proprotein convertase subtilisin/kexin type 1; POMC, proopiomelanocortin.
Figure 4.
Figure 4.
Historical weight, height, and BMI in patients with obesity due to LEPR deficiency. Solid markers are historical data recorded prior to entry into the trial. Open markers are data at study screening and final study visit for which weight, height, or BMI were recorded after receiving treatment with setmelanotide. Centers for Disease Control and Prevention reference growth charts are shown for the 5th (bold), 10th, 25th, 50th (bold), 75th, 90th, and 95th (bold) percentiles for sex. Patient 16 was not part of the designated use set. Patient 17 was enrolled in the supplemental cohort and not reported in primary analysis. *Dietary intervention. †Medication for obesity. ‡Surgery for obesity. §Exercise regimen. BMI, body mass index; LEPR, leptin receptor.
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