Claims for Patent: 10,646,550

Summary for Patent: 10,646,550

Title:	Use of C-type natriuretic peptide variants to treat skeletal dysplasia
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.
Inventor(s):	Bullens; Sherry (Novato, CA), Bunting; Stuart (Novato, CA), Chou; Tianwei (Novato, CA), Okhamafe; Augustus O. (Concord, CA), Price; Christopher P. (Munich, DE), Wendt; Daniel J. (Novato, CA), Yap; Clarence (Novato, CA)
Assignee:	BioMarin Pharmaceutical Inc. (Novato, CA)
Application Number:	15/880,002
Patent Claims:	1. A method of treating skeletal dysplasia in a subject comprising the step of administering to said subject a composition comprising a CNP variant peptide in an amount of at least 7.5 .mu.g/kg of said CNP variant peptide, wherein the CNP variant peptide is selected from the group consisting of: TABLE-US-00007 [CNP-37(M32N); SEQ ID NO: 1] QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; (Met-CNP-37; SEQ ID NO: 2) MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; (Pro-CNP-37; SEQ ID NO: 3) PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; [Gly-CNP 37(M32N); SEQ ID NO: 4] GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC; (Pro-Gly-CNP-37; SEQ ID NO: 5) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; (Met-Gly-CNP-37; SEQ ID NO: 6) MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC; and (Gly-CNP-37: SEQ ID NO: 7) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC, wherein said composition comprises a formulation comprising citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, D-mannitol, L-methionine and polysorbate 80, and wherein the step of administering treats said skeletal dysplasia. 2. The method of claim 1, wherein the treatment results in an improvement in one or more symptoms of skeletal dysplasia selected from the group consisting of increased absolute growth, increased growth velocity, increased QCT bone mineral density (BMD), improvement in growth plate morphology, increased long-bone growth, improvement in morphology of the spine, improved elbow joint range of motion and decreased sleep apnea. 3. The method of claim 1 wherein the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, short stature, dwarfism, osteochondrodysplasias, thanatophoric dysplasia, osteogenesis imperfecta, achondrogenesis, chondrodysplasia punctata, homozygous achondroplasia, chondrodysplasia punctata, 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, metatrophic dysplasia and spondyloepimetaphyseal dysplasia. 4. The method of claim 1, wherein said composition is administered once daily. 5. The method of claim 4, wherein said composition is administered once daily over a period of at least 6 months. 6. The method of claim 1, wherein said composition is administered subcutaneously. 7. The method of claim 1 comprising administering said composition comprising said CNP variant peptide to said subject in an amount of at least about 15 .mu.g/kg per day of said CNP variant peptide. 8. The method of claim 1, wherein the formulation is lyophilized, is in liquid form, or is reconstituted from a lyophilized formulation. 9. The method of claim 1, wherein the formulation comprises at least about 2.0 mg/ml of the CNP peptide variant. 10. The method of claim 1, wherein, in the formulation, citric acid monohydrate is present at a concentration of from about 0.15 mg/ml to about 0.40 mg/ml, sodium citrate dihydrate is present at a concentration of from about 0.5 mg/ml to about 1.5 mg/ml, trehalose dihydrate is present at a concentration of from about 30 mg/ml to about 70 mg/ml, D-mannitol is present at a concentration of from about 10 mg/ml to about 20 mg/ml, L-methionine is present at a concentration of from about 0.5 mg/ml to about 1.5 mg/ml and polysorbate 80 is present at a concentration of from about 0.01 mg/ml to about 0.1 mg/ml. 11. The method of claim 1, wherein, in the formulation, citric acid monohydrate is present at a concentration of about 0.28 mg/ml, sodium citrate dihydrate is present at a concentration of about 1.08 mg/ml, trehalose dihydrate is present at a concentration of about 58.01 mg/ml, D-mannitol is present at a concentration of about 15 mg/ml, L-methionine is present at a concentration of about 0.73 mg/ml and polysorbate 80 is present at a concentration of about 0.05 mg/ml. 12. The method of claim 1, wherein the formulation is preservative-free. 13. The method of claim 1, wherein the formulation has a pH of between about 5.0 and about 6.0.