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

神经性厌食症（AN）是一种破坏性的神经精神疾病，发病率很高（高达2.2%）

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.