Controlled-release CNP agonists with low NPR-C binding

A method of administering a controlled-release C-type natriuretic peptide (CNP) agonist to a subject in need of treatment of a disease, the method comprising

• administering the controlled-release CNP agonist via subcutaneous injection;
• wherein the controlled-release CNP agonist releases a CNP agonist in its free form with a release half-life of at least 6 hours under physiological conditions and which controlled-release CNP agonist has an IC50 to the NPR-C receptor that is at least 5-fold higher than the IC50 of the corresponding free CNP agonist, wherein the controlled-release CNP agonist is of formula (Ia) or (Ib):
• wherein
• -D is the CNP agonist moiety having an amino acid sequence which consists of any sequence selected from the group consisting of SEQ ID NO:
• 1, SEQ ID NO:
• 2, SEQ ID NO:
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• 95;
• -L1- is a reversible prodrug linker moiety which is covalently and reversibly conjugated to the side chain of an amino acid residue of the ring moiety of -D or to the backbone of the ring moiety of -D;
• -L2- is a chemical bond or a spacer moiety;
• —Z is a water-soluble branched polymer moiety having a first branching point less than 50 atoms from the CNP moiety;
• x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16;
• and
• y is an integer selected from the group consisting of 1, 2, 3, 4 and 5;
• wherein the disease is selected from the group consisting of achondroplasia, hypochondroplasia, short stature, dwarfism, osteochondrodysplasias, thanatophoric dysplasia, osteogenesis imperfecta, achondrogenesis, chondrodysplasia punctata, homozygous achondroplasia, camptomelic dysplasia, congenital lethal hypophosphatasia, perinatal lethal type of osteogenesis imperfecta, short-rib polydactyly syndromes, rhizomelic type of chondrodysplasia punctata, Jansen-type metaphyseal dysplasia, spondyloepiphyseal dysplasia congenita, atelosteogenesis, diastrophic dysplasia, congenital short femur, Langer-type mesomelic dysplasia, Nievergelt-type mesomelic dysplasia, Robinow syndrome, Reinhardt syndrome, acrodysostosis, peripheral dysostosis, Kniest dysplasia, fibrochondrogenesis, Roberts syndrome, acromesomelic dysplasia, micromelia, Morquio syndrome, Kniest syndrome, metatropic dysplasia, spondyloepimetaphyseal dysplasia, neurofibromatosis, Legius syndrome, LEOPARD syndrome, Noonan syndrome, hereditary gingival fibromatosis, neurofibromatosis type 1, cardiofaciocutaneous syndrome, Costello syndrome, SHOX deficiency, idiopathic short stature, growth hormone deficiency, osteoarthritis, cleidocranial dysostosis, craniosynostosis, dactyly, brachydactyly, camptodactyly, polydactyly, syndactyly, dyssegmental dysplasia, enchondromatosis, fibrous dysplasia, hereditary multiple exostoses, hypophosphatemic rickets, Jaffe-Lichtenstein syndrome, Marfan syndrome, McCune-Albright syndrome, osteopetrosis and osteopoikilosis.