Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers

Inventors

Tartaglia, Louis Anthony • Henderson, Bart

Assignees

Rhythm Pharmaceuticals Inc

Abstract

A method of treating a disorder in a subject. The method comprises administering to said subject an effective amount of an agonist of the melanocortin-4 receptor (MC4R). The subject is a heterozygous carrier of an MC4R mutation, and the disorder results from an attenuated response of MC4R to α-melanocortin stimulating hormone (α-MSH).

Core Innovation

The invention relates to MC4R agonists including Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140) and pharmaceutically acceptable salts, and to treatment of obesity or a metabolic syndrome by administering an effective amount of Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140) or a pharmaceutically acceptable salt. The subject is a heterozygous carrier of an MC4R mutation or has a gene mutation or a gene defect upstream of MC4R, within the leptin-melanocortin pathway involving MC4R, LEPR, and prohormone convertase PC1/3.

The disclosure characterizes MC4R mutations and their functional consequences, and frames the therapeutic approach as providing an MC4R agonist effect in subjects whose upstream or receptor-associated genetic factors lead to reduced MC4R responsiveness to α-MSH. It also includes hydantoin-modified and related scaffold formulas (IV–VIII), with hydrates, solvates, prodrugs, and cyclized Cys-containing variants such as cyclo(Cys-Cys) and c(Cys-Cys)/c(Cys-Pen)/c(Cys-Asp-Lys).

The document asserts clinical and physiological benefits associated with MC4R agonist treatment in MC4R+/- carriers, including sustained weight loss, improved insulin/glucose control, hyperphagia reduction, and improved cardiometabolic endpoints. It also discusses relevant cardiometabolic conditions and clinical measurements such as coronary artery disease, stroke, type 2 diabetes, sleep apnea, heart rate, and blood pressure.

Claims Coverage

The independent claims cover administration of Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140) or a pharmaceutically acceptable salt to treat obesity or a metabolic syndrome in subjects selected by MC4R-related genetic status. Across the independent claims, the coverage centers on 2 inventive feature themes: the specific peptide and the subject qualification tied to MC4R mutation status or upstream gene mutation or gene defect.

The independent claims provide treatment coverage using Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140) or a pharmaceutically acceptable salt while requiring subject selection based on MC4R mutation carrier status or upstream gene mutation or gene defect relating to MC4R. The claim set also supports subject qualification through reduced MC4R responsiveness to α-MSH and characterizes the administered peptide as an MC4R agonist.

Stated Advantages

Documented Applications