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

用于治疗神经性厌食症的 Melanocortin-3 受体肽激动剂的开发

• 批准号: 10260147
• 负责人: TOMI K SAWYER
• 金额: $ 25.05万
• 依托单位: COURAGE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260147
• 关键词: Acute; Adipose tissue; Age of Onset; Agonist; Animal Testing; Animals; Anorexia; Anorexia Nervosa; Anxiety; Attitude; Automobile Driving; Behavioral; Biological Availability; Body Image; Brain; C-terminal; Characteristics; Chemicals; Chronic; Clinical; Clinical Treatment; Clinical Trials; Cyclization; Data; Data Set; Development; Disease; Dose; Drug Kinetics; Eating; Eating Disorders; Engineering; Etiology; Exhibits; FDA approved; Female; Fright; Funding; Gastric Emptying; Goals; Half-Life; High Prevalence; Hospitalization; Hospitals; Hypoactive Sexual Desire Disorder; In Vitro; Lead; MSH4 gene; Measures; Melanocortin 3 Receptor; Mental disorders; Metabolic; Modeling; Modification; Morbidity - disease rate; Motivation; Mus; N-terminal; Neurobiology; Neurons; Obesity; Parents; Pathologic; Patient Self-Report; Patients; Peptide Receptor; Peptides; Periodicity; Peripheral; Pharmaceutical Preparations; Pharmacology; Phase; Preclinical Testing; Prevalence; Property; Proteolysis; Puberty; Questionnaires; Recovery; Resistance; Rewards; Safety; Satiation; Series; Serum; Small Business Technology Transfer Research; Specificity; Stress; Structure of nucleus infundibularis hypothalami; Syndrome; Testing; Therapeutic; Therapeutic Agents; Thinness; Time; Weight; Weight Gain; Woman; afamelanotide; analog; arginylarginine; base; behavioral study; cognitive process; design; drug development; effectiveness testing; efficacy testing; feeding; gamma-Aminobutyric Acid; genome wide association study; ghrelin; hedonic; improved; in vivo; in vivo evaluation; men; metabolic abnormality assessment; mortality; neuropsychiatric disorder; neuropsychiatry; novel; peptide analog; peptide drug; pre-clinical; presynaptic; randomized placebo controlled study; receptor; sexual dimorphism; subcutaneous; success; therapeutically effective; trend; weight restoration

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.

神经性厌食症 (AN) 是一种毁灭性的神经精神疾病，患病率很高（高达 2.2%） 女性）以及显着的发病率和死亡率。目前尚无有效的治疗药物 紊乱。 Courage Therapeutics 的目标是开发黑皮质素 3 受体 (MC3R) 特异性 用于治疗神经性厌食症的激动剂肽。 STTR第一阶段的产品将是可专利的 MC3R 激动剂主要开发候选药物，可进入高级动物测试和 ADME/PK 在 II 期 STTR 期间开发神经性厌食症的治疗方法。初步结果显示 在这里，我们发现 MC3R 在弓状核中几乎所有 AgRP 神经元中表达。激活这些 弓状区表达 MC3R 的神经元可以刺激食物摄入，同时减少焦虑。此外，我们 证明给予 MC3R 特异性肽可有效刺激小鼠的食物摄入 即 AgRP 神经元依赖性。黑皮质素肽药物似乎是安全有效的治疗药物 许多其他适应症，但尚未开发出 MC3R 特异性疗法。基于这些 根据数据，我们建议MC3R特异性激动剂肽可以开发成安全有效的治疗药物 饮食失调，例如神经性厌食症。我们已经确定了四个有前途的 MC3R 激动剂起点， 包括 D-Trp8--MSH 和 Ac-Arg-Arg-D-Phe(4-I)-D-Tic-NH2 作为示例性母体先导化合物 刺激饱腹动物的食物摄入。为了实现这一应用的目标之一，Courage Therapeutics 将设计 基于这两种 MC3R 特异性激动剂的类似物作为有前途的线性肽来改善其整体 效力、功效和受体亚型特异性。 Courage还将对两个循环进行类似的研究 缺乏受体特异性的黑皮质素肽，与 Setmelanotide (Rhythm) 相关，该肽已被高度评价。 治疗综合征性肥胖的临床试验取得成功。在这种情况下，起始肽是 已知具有类似药物的特性，化学目标将是设计 MC3R 特异性 黑皮质素肽的化学类别。在目标 2 中，具有适当药理学特性的肽（EC50 低于 10nM、Emax>50% 和 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。然后将测试肽在体内对进食、体重增加和焦虑的功效。 正常动物和应激性厌食症模型。还将测试肽的半衰期和 体内分布于血清和脑中。 STTR一期产品将是可申请专利的MC3R激动剂先导药物 开发候选者可以进行高级临床前测试和完整的 ADME/PK 和安全性 AN 治疗方法的开发，将在本申请的第二阶段完成。一项临床试验 成功的开发候选人将在安慰剂对照随机研究中测试有效性 女性在急性住院康复后限制神经性厌食症。主要试验终点将 包括实现体重恢复、进餐完成、自我报告的 EDE-Q（饮食）改善的时间 疾病检查问卷）和相关的自我报告的饮食态度分数。