Combination therapy with controlled-release CNP agonists
The present invention relates to a combination of a CNP agonist and at least one further biologically active moiety or drug for use in a method for the treatment or prevention of disorders that benefit from stimulating growth, pharmaceutical compositions comprising at least one CNP agonist, preferably controlled-release CNP agonist, wherein the pharmaceutical composition comprises at least one further biologically active moiety or drug, to using these pharmaceutical compositions as a medicament, to their use in the treatment of disorders that benefit from stimulating growth and to methods of preventing or treating a patient having a disorder that benefits from stimulating growth.
1 . A method of stimulating bone growth in a patient, the method comprising administering to the patient an effective amount of a controlled-release C-type natriuretic peptide (CNP) agonist, wherein the patient is also administered human growth hormone resulting in a synergistic increase in bone growth from the controlled-release CNP agonist and the human growth hormone acting in combination;
wherein the controlled-release CNP agonist releases a CNP moiety, the amino acid sequence of which consists of SEQ ID NO:24, under physiological conditions with a release half-life of at least 6 hours, wherein the controlled-release CNP agonist is a compound of formula (IIf):
or a pharmaceutically acceptable salt thereof;
wherein
the unmarked dashed line indicates the attachment to a nitrogen provided by the side-chain of the lysine at position 26 of the CNP moiety by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to —Z having the structure
wherein
each —Z a is
wherein
each c1 is an integer independently ranging from 200 to 250.
2 . The method of claim 1 , wherein the human growth hormone is in its free form.
3 . The method of claim 1 , wherein the human growth hormone is in the form of a stable conjugate.
4 . The method of claim 1 , wherein the human growth hormone is a controlled-release compound.
5 . The method of claim 1 , wherein the controlled-release CNP agonist and the human growth hormone are administered separately.
6 . The method of claim 1 , wherein the controlled-release CNP agonist and the human growth hormone are formulated in one pharmaceutical composition for simultaneous administration.
7 . The method of claim 1 , wherein the disorder that benefits from stimulating bone growth 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, metatrophic dysplasia, and spondyloepimetaphyseal dysplasia.
8 . The method of claim 1 , wherein the disorder that benefits from stimulating bone growth is achondroplasia.
9 . The method of claim 1 , further comprising administering the human growth hormone to the patient.
10 . The method of claim 9 , wherein the CNP agonist and the human growth hormone are administered separately to the patient.
11 . The method of claim 9 , wherein the human growth hormone is of formula (A1):
wherein n=200-250, or a pharmaceutically acceptable salt thereof.
12 . The method of claim 1 , wherein the controlled-release CNP agonist is a compound of formula (IIf′):
or a pharmaceutically acceptable salt thereof.
13 . The method of claim 12 , wherein
the dashed line marked with the asterisk in formula (IIf′), indicates attachment to —Z having the structure:
14 . The method of claim 1 , wherein each c1 is about 225.
15 . The method of claim 1 , wherein the amino acid sequence of the human growth hormone consists of SEQ ID NO:99.
16 . The method of claim 1 , wherein the controlled-release CNP agonist and human growth hormone are administered subcutaneously.
17 . The method of claim 1 , wherein the controlled-release CNP agonist and human growth hormone are administered via subcutaneous injection.