Use of C-type natriuretic peptide variants to treat skeletal dysplasia
Inventors
Bullens, Sherry • Bunting, Stuart • Chou, Tianwei • Okhamafe, Augustus O. • Price, Christopher P. • Wendt, Daniel J. • Yap, Clarence
Assignees
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Publication Number
US-12076372-B2
Publication Date
2024-09-03
Expiration Date
Abstract
The present disclosure provides for use of variants of C-type natriuretic peptide (CNP), and novel pharmaceutical compositions and formulations comprising CNP variant peptides for the treatment of skeletal dysplasias, one or more symptoms of skeletal dysplasias, such as long bone growth or growth velocity, and other disorders having a skeletal dysplasia and/or CNP-associated symptom or component.
Core Innovation
The invention relates to methods of treating skeletal dysplasias by administering a composition comprising a C-type natriuretic peptide (CNP) variant peptide. The CNP variant peptide is selected from defined sequences (SEQ ID NO: 1 to SEQ ID NO: 7) and is administered in an amount of at least 7.5 μg/kg. In the disclosed context, the methods are directed to treating hypochondroplasia and to increasing long bone growth and/or growth velocity.
The CNP variant peptide is provided in a formulation comprising citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine and polysorbate 80. The disclosed framing addresses CNP short half-life via increased serum half-life and/or NEP resistance, supporting administration of a CNP variant peptide formulation. The formulation is described in connection with treating outcomes such as growth, growth velocity, and skeletal morphology.
The treatment is associated with improvements in measurable skeletal and functional outcomes. The disclosed outcomes include increased quantitative computed tomography (QCT) bone mineral density (BMD), improvement in growth plate morphology, improvement in spine morphology, improved elbow joint range of motion, and decreased sleep apnea. The disclosed use includes administration of the composition to a subject in need thereof to treat hypochondroplasia and to increase long bone growth and/or growth velocity.
Claims Coverage
The provided claim set includes three independent claims that cover treating hypochondroplasia, increasing long bone growth, and increasing growth velocity. Each independent claim centers on administering a CNP variant peptide selected from a defined set of SEQ ID sequences at an amount of at least 7.5 μg/kg in a formulation with specified excipients.
Treating hypochondroplasia with a CNP variant formulation
Administering to a subject in need of treatment a composition comprising a C-type natriuretic peptide (CNP) variant in an amount of at least 7.5 μg/kg, where the CNP variant is selected from SEQ ID NOs: 1 to 7, and where the variant is in a formulation comprising citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine and polysorbate 80, thereby treating hypochondroplasia.
Increasing long bone growth with a CNP variant formulation
Administering to a subject in need of treatment a composition comprising a C-type natriuretic peptide (CNP) variant peptide in an amount of at least 7.5 μg/kg, where the CNP variant peptide is selected from SEQ ID NOs: 1 to 7, and where the CNP variant is in a formulation comprising citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine and polysorbate 80, thereby increasing long bone growth.
Increasing growth velocity with a CNP variant formulation
Administering to a subject in need of treatment a composition comprising a C-type natriuretic peptide (CNP) variant peptide in an amount of at least 7.5 μg/kg, where the CNP variant peptide is selected from SEQ ID NOs: 1 to 7, and where the CNP variant is in a formulation comprising citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine and polysorbate 80, thereby increasing growth velocity.
Across the independent claims, coverage is directed to administering a defined set of CNP variant peptides (SEQ ID NOs: 1 to 7) at an amount of at least 7.5 μg/kg using a formulation comprising citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine and polysorbate 80, with the intended outcomes specified as treatment of hypochondroplasia, increased long bone growth, and/or increased growth velocity.
Stated Advantages
Increases long bone growth.
Increases growth velocity.
Improves hypochondroplasia outcomes, including increased QCT bone mineral density (BMD).
Improves growth plate morphology.
Improves spine morphology.
Improves elbow joint range of motion.
Decreases sleep apnea.
Addresses CNP short half-life via increased serum half-life and/or NEP resistance.
Documented Applications
Treating hypochondroplasia in a subject in need thereof using a CNP variant peptide composition.
Increasing long bone growth in a subject in need thereof using a CNP variant peptide composition.
Increasing growth velocity in a subject in need thereof using a CNP variant peptide composition.
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