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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41MH124449-01A1
Agency Tracking Number: R41MH124449
Amount: $250,538.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 101
Solicitation Number: PA20-265
Timeline
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-05-01
Award End Date (Contract End Date): 2022-04-30
Small Business Information
64 HOMER ST
Newton, MA 02459-1517
United States
DUNS: 117214311
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: Yes
Principal Investigator
 TOMI SAWYER
 (617) 216-9921
 sawyerkrt@aol.com
Business Contact
 DAN HOUSMAN
Phone: (617) 216-9921
Email: dhousman@couragetx.com
Research Institution
 UNIVERSITY OF MICHIGAN
 
1600 HURON PARKWAY
ANN ARBOR, MI 48109-5001
United States

 Nonprofit College or University
Abstract

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, Emaxandgt;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.Anorexia nervosa 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
product of this Phase I STTR will be patentable MC3R agonist lead development candidates that can go into
advanced animal testing and ADME/PK for development of a therapeutic for anorexia nervosa.

* Information listed above is at the time of submission. *

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