Supplementary Material for: A Melanocortin-4 Receptor Agonist Induces Skin and Hair Pigmentation in Patients with Monogenic Mutations in the Leptin-Melanocortin Pathway

<b><i>Background and Objectives:</i></b> Gene mutations within the leptin-melanocortin signaling pathway lead to severe early-onset obesity. Recently, a phase 2 trial evaluated new pharmacological treatment options with the MC4R agonist <i>setmelanotide</i> in patients with mutations in the genes encoding proopiomelanocortin (POMC) and leptin receptor (LEPR). During treatment with <i>setmelanotide,</i> changes in skin pigmentation were observed, probably due to off-target effects on the closely related melanocortin 1 receptor (MC1R). Here, we describe in detail the findings of dermatological examinations and measurements of skin pigmentation during this treatment over time and discuss the impact of these changes on patient safety. <b><i>Methods:</i></b> In an investigator-initiated, phase 2, open-label pilot study, 2 patients with loss-of-function POMC gene mutations and 3 patients with loss-of-function variants in LEPR were treated with the MC4R agonist <i>setmelanotide</i>. Dermatological examination, dermoscopy, whole body photographic documentation, and spectrophotometric measurements were performed at screening visit and approximately every 3 months during the course of the study. <b><i>Results:</i></b> We report the results of a maximum treatment duration of 46 months. Skin pigmentation increased in all treated patients, as confirmed by spectrophotometry. During continuous treatment, the current results indicate that elevated tanning intensity levels may stabilize over time. Lips and nevi also darkened. In red-haired study participants, hair color changed to brown after initiation of <i>setmelanotide</i> treatment. <b><i>Discussion:</i></b> <i>Setmelanotide</i> treatment leads to skin tanning and occasionally hair color darkening in both POMC- and LEPR-deficient patients. No malignant skin changes were observed in the patients of this study. However, the results highlight the importance of regular skin examinations before and during MC4R agonist treatment.

**背景与目的**：瘦素-黑皮质素信号通路内的基因突变可导致严重的早发性肥胖。近期一项II期临床试验针对编码阿黑皮素原（POMC）与瘦素受体（LEPR）基因存在突变的患者，评估了黑皮质素4受体（MC4R）激动剂塞美拉肽（setmelanotide）这一新的药理学治疗方案。在使用塞美拉肽治疗期间，研究人员观察到患者皮肤色素出现改变，这可能是由于其对密切相关的黑皮质素1受体（MC1R）产生了脱靶效应所致。本研究详细阐述了该治疗周期内不同时间节点的皮肤科检查结果与皮肤色素测量数据，并探讨了这些色素改变对患者安全性的影响。
**方法**：本项由研究者发起的II期开放标签预试验中，共纳入2名携带功能丧失型POMC基因突变患者与3名携带LEPR功能丧失型变异体的患者，给予MC4R激动剂塞美拉肽治疗。研究过程中，在筛选访视及之后约每3个月的访视节点，均对患者进行皮肤科检查、皮肤镜检查、全身摄影记录以及分光光度法色素测量。
**结果**：本研究报告的患者最长治疗时长可达46个月。分光光度法检测证实，所有接受治疗的患者皮肤色素均出现加深。持续治疗期间，现有结果显示色素沉着（晒黑样）强度的升高可随时间趋于稳定。唇部与痣体颜色也出现加深。红发受试者在开始塞美拉肽治疗后，头发颜色转为棕褐色。
**讨论**：塞美拉肽治疗可导致POMC缺陷与LEPR缺陷患者出现皮肤色素沉着加深，偶可伴随毛发颜色变深。本研究的患者中未观察到恶性皮肤病变。但本研究结果凸显了在MC4R激动剂治疗前及治疗期间定期进行皮肤检查的重要性。