SBIR-STTR Award

Rates of obesity have steadily increased in the United States, with approximately 50 percent of Americans projected to be classified as obese by 2030. Interestingly, obesity even seems to be a risk factor for the severity of illness in response to COVID-19 disease. Although behavioral (dieting and exercise), pharmacological, and surgical approaches exist for weight loss, many individuals who lose weight are unable to sustain this weight loss due to compensatory behavioral, autonomic, and neuroendocrine pathways promoting rebound weight gain. Pathways preventing these compensatory adaptations would provide a wholly novel approach to the challenges of obesity treatment. The melanocortin-4 receptor (MC4R) agonist drug setmelanotide is highly effective in the treatment of rare obesity syndromes such as POMC and leptin deficiency, or Bardet-Biedl syndrome, but lacks adequate potency in dietary obesity. More potent MC4R agonists have demonstrated an unacceptable target-mediated pressor response. Recently, we demonstrated the melanocortin-3 receptor (MC3R) is a negative regulator of a subset of MC4R neurons by virtue of its activities in AgRP neurons, and thus is a novel target for development of obesity therapeutics. Two advantages of MC3R as a target are 1) MC3R has less pressor liability than MC4R, and 2) MC3R has been demonstrated to be required for the compensatory behavioral and neuroendocrine responses mediating weight regain following fasting and caloric restriction. Here, we show that a recently published MC3R antagonist, compound 11 (C11) produces profound 24hr inhibition of feeding, and weight loss, that is dependent on the MC3R. In this application we design a panel of melanocortin peptides (Aim 1), and test the modified analogues for improved receptor-subtype specificity and potency as MC3R antagonists (Aim 2), to advance through a process of lead optimization from tool compound C11 to MC3R peptide antagonist development candidates. The product of this Phase I STTR will be one or more patentable MC3R antagonist lead development candidates that can go into animal testing and advanced ADME/PK as a novel proprietary class of obesity therapeutics (Phase II). Success in Phase I will enable Courage Therapeutics to seek institutional funding, in advance of human clinical trials following a successful Phase II.

Public Health Relevance Statement:
Rates of obesity have steadily increased in the United States, with approximately 50 percent of Americans projected to be classified as obese by 2030. Although behavioral (dieting and exercise), pharmacological, and surgical approaches exist for weight loss, many individuals who lose weight are unable to sustain this weight loss due to compensatory behavioral, autonomic, and neuroendocrine pathways promoting rebound weight gain. The product of this Phase I STTR will be patentable MC3R antagonist lead development candidates that may be used as novel agents for the maintenance of weight loss.

Project Terms:
alpha-Melanocyte stimulating hormone; Melanocortin-1; alpha-MSH; alpha-Melanotropin; a-MSH; a-Melanocyte stimulating hormone; Biological Assay; Assay; Bioassay; Biologic Assays; Brain; Brain Nervous System; Encephalon; Cells; Cell Body; Clinical Trials; Diet; dietary; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Eating; Food Intake; Exercise; Fasting; fasted; fasts; Human; Modern Man; Hybrids; In Vitro; Lead; Pb element; heavy metal Pb; heavy metal lead; Ligands; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Neurosecretory Systems; Neuroendocrine; Neuroendocrine System; Obesity; adiposity; corpulence; corpulency; corpulentia; obese; obese people; obese person; obese population; Patients; Peptides; Periodicity; Cyclicity; Rhythmicity; Pharmacology; Publishing; Risk Factors; Specificity; Structure-Activity Relationship; chemical structure function; structure function relationship; Synapses; Synaptic; synapse; Syndrome; Testing; United States; Weight Gain; Weight Increase; body weight gain; body weight increase; wt gain; Body Weight decreased; Weight Loss; Weight Reduction; body weight loss; wt-loss; Weight; Mediating; G(s), alpha Subunit; G(s), a Subunit; G(s)alpha; G(s)a; GTP-Binding Protein a Subunits, Gs; Gs alpha Family G-Protein; Gsa; Gas; Regulatory Ns Protein; Stimulatory Gs G-Protein; alpha Subunit Stimulatory GTP-Binding Protein; alpha-Gs; a-Gs; GTP-Binding Protein alpha Subunits, Gs; improved; Peripheral; Penetration; Phase; Series; Peptide Receptor; Chemicals; insight; Individual; analog; Funding; Agonist; MC3 Receptor; Receptor, Melanocortin, Type 3; Melanocortin 3 Receptor; melanocortin receptor; Therapeutic; tool; Complex; disease severity; Severity of illness; SHU9119; SHU 9119; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Operative Surgical Procedures; American; peptide analog; Receptor Protein; receptor; success; Arg-Arg; arginyl-L-arginine; arginylarginine; MC4 Receptor; Receptor, Melanocortin, Type 4; Melanocortin 4 Receptor; Structure; novel; Modality; Position; Positioning Attribute; Bardet Biedel syndrome; Bardet-Biedl Syndrome; Property; response; caloric restricted; calorically restricted; calorie restricted; calorie restriction; Caloric Restriction; Molecular Interaction; Binding; preventing; prevent; Animal Testing; Data; in vivo; STTR; Small Business Technology Transfer Research; Process; Modification; developmental; Development; Behavioral; pathway; Pathway interactions; weight maintenance; obesity treatment; feeding; Leptin deficiency; designing; design; diet and exercise; new approaches; novel approaches; novel strategy; novel strategies; Coupling; comparative; lead optimization; lead candidate; obesity development; COVID19; corona virus disease 2019; coronavirus disease 2019; COVID-19; Scenesse; afamelanotide

The melanocortin peptide therapeutic setmelanotide, (ImcivreeTM), is highly effective in the treatment of the rare obesity syndromes, POMC and leptin receptor deficiency. However, the drug is ineffective for the most common syndromic obesity, melanocortin-4 receptor (MC4R) deficiency (MC4R haploinsufficiency), found at a prevalence greater than 1/1000 individuals. Further, the drug is ineffective in the treatment of dietary obesity. In addition to the fact that Imcivree does not address the unmet medical needs in patients with syndromic obesity due to MC4R deficiency, Imcivree is a pan-agonist of four melanocortin receptors and causes hyperpigmentation by activating the melanocortin-1 receptor (MC1R) on dermal and follicular melanocytes. Lastly, the formulation of Imcivree is not ideal, requiring daily subcutaneous administration. In our Phase I application, we proposed to develop melanocortin-3 receptor antagonists as peptide therapeutics for MC4R deficiency, since the MC3R is a negative regulator of MC4R neurons. However, in the course of developing these molecules, currently still in progress, we made a striking discovery. Based on the extensive structure-activity relationship (SAR) work initiated in Phase 1, we also identified four novel families of MC4R agonists. Characterizing select peptides in a validated obese mouse model of human MC4R deficiency (MC4R+/- mice), we discovered two families of these MC4R agonist peptides that, unlike Imcivree, have significant weight loss efficacy in MC4R haploinsufficiency, as well as in dietary obesity. More recent work provides modified versions of these peptides that have reduced MC1R efficacy as well. Finally, we have shown that melanocortin peptides can be formulated in injectable PLGA microspheres by a new remote-loading technique, yielding steady release of peptide for more than 30 days offering the potential for optimizing the therapeutic window, improving patient compliance, and reducing cost. In this phase II application, we propose to 1) complete the chemical development of MC4R agonist peptides for the treatment of MC4R deficiency, 2) complete pre-GLP safety studies for up to three peptide development candidates for MC4R deficiency, and 3) formulate and characterize the pharmacokinetics, efficacy, and side effect profile of these peptides in our mouse model of human MC4R deficiency. The product of this Phase II STTR proposal will be one or more therapeutic candidates for the treatment of MC4R haploinsufficiency, and a pathway to commercialization of these therapeutics.

Public Health Relevance Statement:
Rates of obesity have steadily increased in the United States, with approximately 50 percent of Americans projected to be classified as obese by 2030. While a recently approved drug Imcivree is effective for rare forms of syndromic obesity, it lacks efficacy for the most common obesity syndrome, haploinsufficiency of the melanocortin-4 receptor (MC4R), effecting more than as 1 in 1000 individuals. The product of this Phase II STTR will be MC4R agonist therapeutics that may be used as novel agents for the treatment of human MC4R haploinsufficiency.

Project Terms:
Biological Assay; Assay; Bioassay; Biologic Assays; Brain; Brain Nervous System; Encephalon; Clinical Research; Clinical Study; Drug Evaluation; Drug Evaluation Studies; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Eating; Food Intake; Exhibits; Family; Half-Life; Human; Modern Man; In Vitro; melanocyte; Methods; Obese Mice; ob/ob mouse; Microspheres; Microbeads; Mus; Mice; Mice Mammals; Murine; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Neurons; adiposity; corpulence; Obesity; Patients; Peptides; Pharmacokinetics; Drug Kinetics; Wistar Rats; Safety; Mass Photometry/Spectrum Analysis; Mass Spectrometry; Mass Spectroscopy; Mass Spectrum; Mass Spectrum Analyses; Mass Spectrum Analysis; chemical structure function; structure function relationship; Structure-Activity Relationship; Syndrome; Testing; Toxicology; United States; Body Weight decreased; Weight Loss; Weight Reduction; body weight loss; wt-loss; Work; Roentgen Rays; X-Radiation; X-Ray Radiation; X-ray; Xray; Injectable; Hyperpigmentation; Hypermelanoses; Hypermelanosis; base; improved; Acute; Chronic; Phase; Medical; Peptide Receptor; Chemicals; Dermal; Blood Serum; Serum; Individual; Data Bases; data base; Databases; analog; Agonist; MC3 Receptor; Receptor, Melanocortin, Type 3; Melanocortin 3 Receptor; melanocortin receptor; Abnormal Assessment of Metabolism; Metabolic Studies; Metabolism Studies; metabolic abnormality assessment; Therapeutic; Contracting Opportunities; Contracts; Rivers; HuB219; LEP-R; LEPR Protein; OB Receptor; OB-R; leptin-binding protein; leptin receptor; subdermal; subcutaneous; Techniques; American; Receptor Protein; receptor; Cryo-electron Microscopy; Electron Cryomicroscopy; cryo-EM; cryoEM; Cryoelectron Microscopy; Toxicities; Toxic effect; MC4 Receptor; Receptor, Melanocortin, Type 4; Melanocortin 4 Receptor; Structure; novel; MC1 Receptor; Melanocyte Melanocortin Receptor; Melanocortin 1 Receptor; Pharmacodynamics; Cardiac Toxicity; Cardiotoxic; Cardiotoxicity; Patient Compliance; patient adherence; patient cooperation; therapy compliance; therapy cooperation; treatment compliance; compliance behavior; Dose; Data; in vivo; Small Business Technology Transfer Research; STTR; Development; developmental; safety study; Pathway interactions; pathway; cost; design; designing; Prevalence; mouse model; murine model; commercialization; screening; Formulation; peptide drug; Peptide-based drug; therapeutic peptide; therapeutic candidate; human model; model of human; in vivo evaluation; in vivo testing; side effect; dietary; antagonist