Method of treating melanocortin-4 receptor pathway-associated disorders
Inventors
Van Der Ploeg, Leonardus H. T. • Henderson, Bart
Assignees
Charite Universitaetsmedizin Berlin • Rhythm Pharmaceuticals Inc
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Publication Number
US-12263202-B2
Publication Date
2025-04-01
Expiration Date
Abstract
The disclosure is related to a method of treating a disorder, such as Prader Willi Syndrome (PWS), obesity or hyperphagia, in a subject using a melanocortin-4 receptor (MC4R) agonist. Also described is method of treating a subject having a deficiency in the pro-opiomelanocortin (POMC)-MC4R pathway, such as a POMC-null or a PCSK-null subject, using a MC4R agonist.
Core Innovation
The invention concerns agonists of the melanocortin-4 receptor (MC4R) for treating disorders in a subject in need thereof by administering an MC4R agonist at a daily dosage of about 0.1 mg to about 10 mg. The MC4R agonist is characterized by a specified Formula (I), with extensive definitions of substituent positions and variable substituent groups, and representative MC4R agonist compounds are described, including setmelanotide (RM-493) and Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).
The disclosure also describes hydantoin-modified MC4R agonists by Formula (V) and Formula (VI), including representative hydantoin-containing structures and peptide/peptidomimetic variants. The disclosed structural formulas define MC4R agonist compounds used in the disclosed context.
The disclosed MC4R agonists are positioned for treating disorders in subjects characterized by one or more mutations in a gene associated with Bardet-Biedl syndrome or Alstrom syndrome. The document also links the treatment indication to MC4R-pathway genetic disorders, including Prader-Willi Syndrome (PWS), and to disorder-associated genes and mutations in the POMC-MC4R pathway.
Claims Coverage
Two independent method claims are identified. Across the claims, the inventive coverage centers on administering an MC4R agonist at a daily dosage of about 0.1 mg to about 10 mg for disorders characterized by mutations in syndrome-associated genes, with Formula (I) and a specific peptide recited as the agonists.
MC4R agonist treatment of bardet-biedl syndrome characterized by gene mutations
Administering an agonist of the melanocortin-4 receptor (MC4R) at a daily dosage of about 0.1 mg to about 10 mg, wherein the disorder is characterized by one or more mutations in a gene associated with Bardet-Biedl syndrome, and wherein the agonist is a MC4R agonist having a structure of Formula (I).
MC4R agonist treatment of alstrom syndrome characterized by gene mutations
Administering an agonist of the melanocortin-4 receptor (MC4R) at a daily dosage of about 0.1 mg to about 10 mg, wherein the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140), and the disorder is characterized by one or more mutations in a gene associated with Alstrom syndrome.
Overall, the claim coverage centers on methods of treating syndromic disorders defined by mutation status using an MC4R agonist at a daily dosage range. For Bardet-Biedl syndrome, the agonist is defined by a Formula (I) structural framework; for Alstrom syndrome, the agonist is specifically Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).
Stated Advantages
Weight and hunger/food-intake reductions are expected after MC4R agonist therapy.
Waist circumference is expected to be reduced after MC4R agonist therapy.
Resting energy expenditure (REE) is stated as unchanged or increased after MC4R agonist therapy.
Blood pressure is stated as not increased or decreased after MC4R agonist therapy.
Documented Applications
Treating disorders in subjects characterized by one or more mutations in a gene associated with Bardet-Biedl syndrome using an MC4R agonist having a Formula (I) structure at about 0.1 mg to about 10 mg daily dosage.
Treating disorders in subjects characterized by one or more mutations in a gene associated with Alstrom syndrome using the MC4R agonist Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO:140) at about 0.1 mg to about 10 mg daily dosage.
Treating MC4R-pathway genetic obesity disorders, explicitly including Prader-Willi Syndrome (PWS), by administering an MC4R agonist.
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