Glucagon-receptor selective polypeptides and methods of use thereof
Inventors
Blackwell, William • Srivastava, Ved P. • Paulik, Mark A. • Young, Andrew • Hunter, III, Robert Neil • Dock, Steven Thomas
Assignees
Intarcia Assignment For Benefit Of Creditors LLC • I2O Therapeutics Inc
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Publication Number
US-11840559-B2
Publication Date
2023-12-12
Expiration Date
Abstract
This invention relates to isolated polypeptides that are glucagon-receptor selective analogs and peptide derivatives thereof. These analogs are selective for human glucagon receptor with improved solubility, thermal stability, and physicochemical properties as compared to native endogenous glucagon. This invention also relates to methods of using such polypeptides in a variety of therapeutic and diagnostic indications, as well as methods of producing such polypeptides. These analogs are useful, alone or in combination with other therapeutic peptides, in methods of treating obesity, diabetes, metabolic disorders, and other disorders or disease.
Core Innovation
The invention relates to an isolated glucagon-receptor selective polypeptide analog, including a sequence-defined polypeptide specified as SEQ ID NO:151, or a pharmaceutically acceptable salt thereof, with defined allowable amino acid substitutions at X1, X3, X10, X16, X17, X18, X21, X24, X31, X33, and X34. The polypeptide framework includes a C-terminal sequence ending in PPPPS-OH.
Selected lysine residues are acylated on a lysine amino group with a lipophilic substituent through spacers defined by Formula II or Formula III, and the acylation is described as involving a covalent amide linkage to the lysine ε-amino group or β-amino group, as stated. The disclosed embodiments also include C-terminal albumin-binding extension motifs, pharmaceutical compositions, and pharmaceutically acceptable salts such as trifluoroacetate, acetate, and/or hydrochloride salts.
The polypeptides are designed to provide glucagon-receptor agonism with minimal or no GLP-1 receptor binding. The document also states co-formulation with exenatide under fixed glucagon analog:exenatide ratio constraints, as well as continuous delivery from an osmotic delivery device for treatment or addressing of type 2 diabetes mellitus.
Claims Coverage
The provided claim coverage centers on one independent claim directed to a sequence-defined isolated polypeptide (SEQ ID NO:151) with specified allowable substitutions, and includes dependent claims that add pharmaceutical composition, osmotic delivery device, and therapeutic use embodiments. The main inventive features are drawn from the independent polypeptide definition and the explicitly referenced dependent embodiments.
Sequence-defined isolated glucagon-receptor selective agonist polypeptide
An isolated polypeptide comprising the amino acid sequence SEQ ID NO:151, or a pharmaceutically acceptable salt thereof, with allowable substitutions at X1, X3, X10, X16, X17, X18, X21, X24, X31, X33, and X34, and a C-terminal PPPPS-OH.
Pharmaceutical composition with suitable carrier
A pharmaceutical composition including the isolated polypeptide of the sequence-defined claim, or a pharmaceutically acceptable salt thereof, together with a suitable carrier.
Osmotic delivery device containing the isolated polypeptide
An osmotic delivery device that includes the isolated polypeptide of the sequence-defined claim, or a pharmaceutically acceptable salt thereof.
Osmotic delivery device structural arrangement
The osmotic delivery device includes an impermeable reservoir with a semi-permeable membrane, an internal osmotic engine and a piston dividing the reservoir into two chambers, wherein a flowable suspension formulation containing the isolated polypeptide is in a chamber and a diffusion moderator is placed adjacent the suspension formulation at an open end.
Treatment of type 2 diabetes mellitus
A therapeutic embodiment that treats or addresses type 2 diabetes mellitus using the claimed subject matter.
Across the claims shown, coverage is anchored in a sequence-defined isolated polypeptide (SEQ ID NO:151) with specified allowable substitution constraints, and extends to pharmaceutical composition embodiments, an osmotic delivery device with a diffusion moderator adjacent to a suspension formulation, and a therapeutic indication for type 2 diabetes mellitus.
Stated Advantages
Reductions in fasting plasma glucose concentration.
Glucagon-receptor agonism with minimal or no GLP-1R binding.
Ability to extend half-life and improve solubility and stability via C-terminal albumin-binding extension motifs and optional lysine-linked lipophilic conjugates with spacers.
Use in treating obesity and diabetes, including type 2 diabetes mellitus, and metabolic disorders and other diseases.
Documented Applications
Treatment or addressing of type 2 diabetes mellitus using continuous delivery from an osmotic delivery device containing the disclosed glucagon analog polypeptide.
Co-formulation of the glucagon analogs with exenatide under fixed glucagon analog:exenatide ratio constraints.
Therapeutic use for obesity and diabetes, including type 2 diabetes mellitus.
Treatment of metabolic disorders and other diseases.
Therapeutic delivery use via pharmaceutical compositions and an osmotic delivery device for delivering the isolated polypeptide.
Diagnostic use is mentioned, but no specific diagnostic modality is provided in the provided excerpt.
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