Allas Soraya, Caixàs Assumpta, Poitou Christine, Coupaye Muriel, Thuilleaux Denise, Lorenzini Françoise, Diene Gwenaëlle, Crinò Antonino, Illouz Frédéric, Grugni Graziano, Potvin Diane, Bocchini Sarah, Delale Thomas, Abribat Thierry, Tauber Maithé
Alizé Pharma, Ecully, France.
Department of Endocrinology and Nutrition, Parc Taulí Hospital Universitari, Institut d'Investigació in Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.
PLoS One. 2018 Jan 10;13(1):e0190849. doi: 10.1371/journal.pone.0190849. eCollection 2018.
Prader-Willi syndrome (PWS) is characterized by early-onset hyperphagia and increased circulating levels of the orexigenic Acylated Ghrelin (AG) hormone with a relative deficit of Unacylated Ghrelin (UAG). AZP-531, a first-in-class UAG analog, was shown to inhibit the orexigenic effect of AG in animals, to improve glycemic control and decrease body weight in humans. We aimed to investigate the safety and efficacy of AZP-531 in patients with PWS for whom no approved treatment for hyperphagia is currently available.
Multi-center, randomized, double-blind, placebo-controlled trial. Forty-seven patients with genetically confirmed PWS and evidence of hyperphagia received daily subcutaneous injections of AZP-531 (3 and 4 mg for 50-70 kg and >70 kg body weight, respectively) or matching placebo for 14 days. Assessments included adverse events, vital signs, safety laboratory tests, the Hyperphagia Questionnaire (HQ), patient-reported appetite, body composition and glycemic measures.
AZP-531 was well tolerated. There was a significant improvement with AZP-531 versus placebo in the mean total score, the 9-item score and the severity domain score of the HQ (p < .05). The highest reduction in the total and 9-item scores was observed in AZP-531 subjects with the highest hyperphagia score at baseline. Findings were supported by a reduction in appetite scores observed with AZP-531 only. Body weight did not change in both groups while a significant reduction in waist circumference and fat mass was observed only with AZP-531. AZP-531 significantly decreased post-prandial glucose levels in a baseline glucose dependent fashion.
AZP-531 may constitute a new treatment strategy to improve hyperphagia and metabolic issues in patients with PWS. These findings support further investigation in longer-term clinical trials.
普拉德-威利综合征（PWS）的特征为早发性食欲亢进，以及食欲促进性酰基化胃饥饿素（AG）激素的循环水平升高，同时未酰基化胃饥饿素（UAG）相对缺乏。AZP-531是首个同类UAG类似物，已证实在动物实验中可抑制AG的食欲促进作用，在人体中可改善血糖控制并减轻体重。我们旨在研究AZP-531对目前尚无获批的食欲亢进治疗方法的PWS患者的安全性和疗效。
多中心、随机、双盲、安慰剂对照试验。47例经基因确诊为PWS且有食欲亢进证据的患者，每天接受皮下注射AZP-531（体重50 - 70 kg和>70 kg者分别为3 mg和4 mg）或匹配的安慰剂，为期14天。评估内容包括不良事件、生命体征、安全性实验室检查、食欲亢进问卷（HQ）、患者报告的食欲、身体成分和血糖指标。
AZP-531耐受性良好。与安慰剂相比，AZP-531在HQ的平均总分、9项评分和严重程度领域评分方面有显著改善（p < 0.05）。在基线时食欲亢进评分最高的AZP-531受试者中，观察到总分和9项评分的降幅最大。仅AZP-531组观察到食欲评分降低，这支持了上述结果。两组体重均未变化，而仅AZP-531组观察到腰围和脂肪量显著降低。AZP-531以基线血糖依赖的方式显著降低餐后血糖水平。
AZP-531可能构成一种新的治疗策略，用于改善PWS患者食欲亢进和代谢问题。这些发现支持在长期临床试验中进一步研究。
