Seattle Children's Research Institute, Seattle, WA, USA; Division of Endocrinology, Department of Pediatrics, University of Washington, Seattle, WA, USA.
Rhythm Pharmaceuticals, Boston, MA, USA.
Lancet Diabetes Endocrinol. 2024 Jun;12(6):380-389. doi: 10.1016/S2213-8587(24)00087-1. Epub 2024 Apr 30.
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 ClinicalTrials.gov (NCT04725240) 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 (NCT03651765), 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.
由下丘脑损伤引起的下丘脑肥胖可能会影响黑皮质素信号。我们研究了促黑素细胞皮质素 4 受体激动剂 setmelanotide 用于治疗下丘脑肥胖。
这是一项在美国五个中心进行的 2 期、开放标签、多中心试验。符合条件的患者年龄在 6 至 40 岁之间，患有肥胖症和下丘脑损伤史，或患有影响下丘脑的非恶性肿瘤的诊断，该肿瘤已通过手术、化疗或放射治疗。setmelanotide 滴定至 3.0mg 剂量，并每天皮下给药一次，总持续时间为 16 周。主要终点是与该人群中历史对照率低于 5%相比，16 周后 BMI 降低至少 5%的患者比例。主要终点使用全分析集进行分析，全分析集包括所有基线数据至少接受过一次 setmelanotide 治疗的患者。所有接受至少一剂研究药物的患者均进行了安全性评估。该试验在 ClinicalTrials.gov（NCT04725240）注册，现已完成。
在 2021 年 6 月 6 日至 2022 年 1 月 13 日期间，有 19 名患者接受了入组筛选。有 1 名患者被排除，18 名患者入组并接受了至少一剂 setmelanotide 治疗。患者主要为白人（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 38.0kg/m（SD 6.5）。18 名入组患者中，16 名（89%）完成了研究并达到了 16 周后 BMI 至少降低 5%的主要终点（p<0.0001）。所有患者的 BMI 平均降低 15%（SD 10）。复合患者比例有临床意义的变化（89%，90%CI 69-98%；p<0.0001），包括年龄小于 18 岁的患者 BMI Z 评分至少降低 0.2 分（92%，68-100%；p<0.0001）和年龄大于 18 岁的患者体重减轻至少 5%（80%，34-99%；p<0.0001）。12 岁及以上的患者平均饥饿评分降低 45%。常见的不良事件包括恶心（61%）、呕吐（33%）、皮肤色素沉着过度（33%）和腹泻（22%）。在一项长期扩展研究（NCT03651765）中继续治疗的 14 名患者中，有 12 名在发表时至少完成了 12 个月的治疗，从指数试验基线开始 BMI 平均变化为-26%（SD 12）。
这些发现支持 setmelanotide 作为治疗下丘脑肥胖的一种新的有效方法。
Rhythm 制药公司。
