Development of Melanocortin-3 Receptor Peptide Agonists for the Treatment of Anorexia Nervosa

神经性厌食症(ANN)是一种破坏性很高的神经精神疾病(高达2.2% (妇女)和严重的发病率和死亡率。目前还没有有效的治疗剂来治疗这种疾病 无序。勇气治疗公司的目标是开发特定于黑素皮质素-3受体(MC3R)的药物 治疗神经性厌食症的激动肽。这一阶段STTR的产品将成为可申请专利的 MC3R激动剂领先开发候选药物，可进入高级动物试验和ADME/PK用于 开发一种治疗神经性厌食症的药物，在第二阶段STTR期间。在提交的初步结果中 在这里，我们发现MC3R在弓状核中几乎所有的AgRP神经元中都有表达。激活这些 弓状核中表达MC3R的神经元可以刺激食物的摄取，同时减少焦虑。此外，我们 证明给予MC3R特异性多肽可以有效刺激小鼠的摄食量 这是AgRP神经元依赖的。黑素皮质素多肽药物似乎是安全有效的治疗方法。 其他一些适应症，然而，还没有开发出MC3R特异性疗法。基于这些 数据，我们建议MC3R特异性激动肽可能被开发成安全有效的治疗药物 进食障碍，如神经性厌食症。我们已经确定了四个有希望的MC3R激动剂起点， 包括D-Trp8--MSh和Ac-Arg-Arg-D-Phe(4-I)-D-Tic-NH2作为示范母体，有效地实现了这一点 刺激饱足动物的食物摄入量。在这项申请的一个目标中，勇气治疗公司将设计 基于这两种MC3R特异性激动剂的类似物作为有望改善其整体性能的线性多肽 效力、疗效和受体亚型特异性。勇气也将对两个周期进行类似的研究 缺乏受体特异性的黑素皮质肽，与塞特黑素(节律)有关，已被高度 治疗综合征性肥胖的临床试验取得成功。在本例中，起始肽是 已知具有类似药物的特性，化学目标将是在这种情况下工程MC3R的特异性 黑素皮质素多肽的化学类别。在目标2中，具有适当药理特性的多肽(EC50 10 nm以下，Emax&gt；50%，以及1000x MC3R/MC4R激动剂特异性)将被修改以提高稳定性 和生物利用度。然后将对两种动物的进食、体重增加和焦虑的体内效果进行测试 正常动物和应激性厌食症模型。多肽也将进行半衰期测试和 在血清和脑内的体内分布。这一第一阶段STTR的产品将是可申请专利的MC3R激动剂Lead 可以进入高级临床前测试和完整的ADME/PK和安全性的开发候选者 开发一种治疗AN的药物，将在本申请的第二阶段完成。一项临床试验 成功的开发候选者随后将在安慰剂对照的随机研究中测试有效性 女性在急性住院后康复中限制神经性厌食症。主要试验终点为 包括实现体重恢复时间、进餐完成时间、改善自我报告的EDE-Q(饮食 精神障碍检查问卷)和相关的自述进食态度得分。

Anorexia nervosa (AN) is a devastating neuropsychiatric disease with a high prevalence (up to 2.2% of women) and significant morbidity and mortality. There are currently no effective therapeutic agents for the disorder. The goal of Courage Therapeutics is the development of melanocortin-3 receptor (MC3R) -specific agonist peptides for the treatment of anorexia nervosa. The product of this Phase I STTR will be a patentable MC3R agonist lead development candidate that can go into advanced animal testing and ADME/PK for development of a therapeutic for anorexia nervosa, during a Phase II STTR. In preliminary results presented here, we show that MC3R is expressed in nearly all AgRP neurons in the arcuate nucleus. Activation of these MC3R-expressing neurons in the arcuate can stimulate food intake while reducing anxiety. Further, we demonstrate that administration of a MC3R-specific peptide results in potent stimulation of food intake in mice that is AgRP neuron dependent. Melanocortin peptide drugs appear to be safe and effective therapeutics for a number of other indications, however no MC3R specific therapeutics have been developed. Based on these data, we propose that MC3R-specific agonist peptides may be developed into safe and effective therapeutics for eating disorders such as anorexia nervosa. We have identified four promising MC3R agonist starting points, including both D-Trp8--MSH and Ac-Arg-Arg-D-Phe(4-I)-D-Tic-NH2 as exemplary parent leads that potently stimulate food intake in sated animals. In one aim of this application, Courage Therapeutics will design analogues based on these two MC3R-specific agonists as promising linear peptides to improve their overall potency, efficacy, and receptor-subtype specificity. Courage will also conduct similar studies on two cyclic melanocortin peptides lacking receptor specificity, related to Setmelanotide (Rhythm), which has been highly successful in clinical trials for the treatment of syndromic obesity. In this case, the starting peptides are already known to have drug-like properties, and the chemical goal will be engineer MC3R-specificity in this chemical class of melanocortin peptides. In Aim 2, peptides with appropriate pharmacological properties (EC50 below 10nM, Emax>50%, and a 1000x MC3R/MC4R agonist specificity) will be modified to improve stability and bioavailability. Peptides will then be tested for in vivo efficacy on feeding, weight gain, and anxiety in both normal animals and a model of stress-induced anorexia. Peptides will also be tested for half life and distribution in vivo in serum and brain. The product of this Phase I STTR will be patentable MC3R agonist lead development candidates that can go into advance preclinical testing and full ADME/PK and safety for development of a therapeutic for AN, to be completed under Phase II of this application. A clinical trial for the successful development candidate would then test effectiveness in a placebo controlled randomized study for female Restricting Anorexia Nervosa in post-acute hospitalization recovery. Primary trial end-points would include time to achieve weight restoration, meal completion, improvement of self reported EDE-Q (Eating Disorder Examination Questionnaire) and related self-reported eating attitude scores.