Hypothalamic obesity resulting from hypothalamic damage might affect melanocortin signalling. We investigated the melanocortin-4 receptor agonist setmelanotide for treatment of hypothalamic obesity. This phase 2, open-label, multicentre trial was done in five centres in the USA. Eligible patients were aged between 6 and 40 years with obesity and history of hypothalamic injury or diagnosis of a non-malignant tumour affecting the hypothalamus that was treated with surgery, chemotherapy, or radiation. Setmelanotide was titrated up to a dose of 3·0 mg and administered subcutaneously once a day for a total duration of 16 weeks. The primary endpoint was the proportion of patients with a reduction in BMI of at least 5% from baseline after 16 weeks, compared with a historic control rate of less than 5% in this population. The primary endpoint was analysed using the full analysis set, which includes all patients with baseline data who received at least one dose of setmelanotide. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with () and is complete. Between June 6, 2021, and Jan 13, 2022, 19 patients were screened for inclusion. One patient was excluded, and 18 were enrolled and received at least one dose of setmelanotide. Patients were primarily White (n=14 [78%]) and male (n=11 [61%]). Enrolled patients had a mean age of 15·0 years (SD 5·3) and a mean BMI of 38·0 kg/m (SD 6·5). Of 18 patients enrolled, 16 (89%) of 18 patients completed the study and met the primary endpoint of reduction in BMI of at least 5% from baseline after 16 weeks (p<0·0001). The mean reduction in BMI across all patients was 15% (SD 10). A composite proportion of patients had a clinically meaningful change (89%, 90% CI 69–98%; p<0·0001), comprising a reduction in BMI Z score of at least 0·2 points for patients younger than 18 years (92%, 68–100%; p<0·0001) and reduction in bodyweight of at least 5% for patients aged 18 years or older (80%, 34–99%; p<0·0001). Patients aged 12 years or older had a mean reduction in hunger score of 45%. Frequent adverse events included nausea (61%), vomiting (33%), skin hyperpigmentation (33%), and diarrhoea (22%). Of 14 patients who continued treatment in a long-term extension study (), 12 completed at least 12 months of treatment at the time of publication and had a mean change in BMI of −26% (SD 12) from index trial baseline. These findings support setmelanotide as a novel effective treatment of hypothalamic obesity. Rhythm Pharmaceuticals.

中文翻译：

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Setmelanotide 用于治疗获得性下丘脑肥胖：2 期、开放标签、多中心试验


下丘脑损伤导致的下丘脑肥胖可能会影响黑皮质素信号传导。我们研究了黑皮质素 4 受体激动剂 setmelanotide 治疗下丘脑肥胖的作用。这项第二阶段、开放标签、多中心试验在美国的五个中心进行。符合条件的患者年龄在 6 至 40 岁之间，患有肥胖症，有下丘脑损伤史，或诊断为影响下丘脑的非恶性肿瘤，并接受过手术、化疗或放疗。 Setmelanotide 剂量逐渐调整至 3·0 mg，每天皮下注射一次，总持续时间为 16 周。主要终点是 16 周后 BMI 较基线降低至少 5% 的患者比例，而该人群的历史控制率低于 5%。使用完整分析集对主要终点进行分析，其中包括所有接受至少一剂setmelanotide的具有基线数据的患者。对所有接受至少一剂研究药物的患者进行安全性评估。本次试验已注册（）并已完成。 2021年6月6日至2022年1月13日期间，筛选了19名患者纳入。一名患者被排除，另外 18 名患者被纳入并接受了至少一剂setmelanotide。患者主要是白人（n=14 [78%]）和男性（n=11 [61%]）。入组患者的平均年龄为 15·0 岁 (SD 5·3)，平均 BMI 为 38·0 kg/m (SD 6·5)。在入组的 18 名患者中，18 名患者中有 16 名 (89%) 完成了研究，并达到了 16 周后 BMI 较基线降低至少 5% 的主要终点 (p<0·0001)。所有患者的 BMI 平均降低了 15% (SD 10)。 患者的复合比例出现了有临床意义的变化（89%，90% CI 69–98%；p<0·0001），其中 18 岁以下患者的 BMI Z 评分降低了至少 0·2 分（ 92%、68–100%；p<0·0001），18 岁或以上患者体重至少减少 5%（80%、34–99%；p<0·0001）。 12 岁或以上的患者饥饿评分平均降低 45%。常见的不良事件包括恶心（61%）、呕吐（33%）、皮肤色素沉着（33%）和腹泻（22%）。在一项长期延伸研究中继续治疗的 14 名患者中，有 12 名在发表时完成了至少 12 个月的治疗，并且 BMI 相对于指标试验基线的平均变化为 -26% (SD 12)。这些发现支持setmelanotide作为下丘脑肥胖的新型有效治疗方法。节奏制药公司。